American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 175C:70–115 (2017) RESEARCH REVIEW

The Ehlers–Danlos Syndromes, Rare Types ANGELA F. BRADY, SERWET DEMIRDAS, SYLVIE FOURNEL-GIGLEUX, NEETI GHALI, CECILIA GIUNTA, INES KAPFERER-SEEBACHER, TOMOKI KOSHO, ROBERTO MENDOZA-LONDONO, MICHAEL F. POPE, MARIANNE ROHRBACH, TIM VAN DAMME, ANTHONY VANDERSTEEN, CAROLINE VAN MOURIK, NICOL VOERMANS, JOHANNES ZSCHOCKE, AND FRANSISKA MALFAIT *

Dr. Angela F. Brady, F.R.C.P., Ph.D., is a Consultant Clinical Geneticist at the North West Thames Regional Genetics Service, London and she has a specialist interest in Ehlers–Danlos Syndrome. She was involved in setting up the UK National EDS Diagnostic Service which was established in 2009 and she has been working in the London part of the service since 2015. Dr. Serwet Demirdas, M.D., Ph.D., is a clinical geneticist in training at the Erasmus Medical Center (Erasmus University in Rotterdam, the Netherlands), where she is involved in the clinical service and research into the TNX deficient type of EDS. Prof. Sylvie Fournel-Gigleux, Pharm.D., Ph.D., is a basic researcher in biochemistry/pharmacology, Research Director at INSERM (Institut National de la Sante et de la Recherche Medicale) and co-head of the MolCelTEG Research Team at UMR 7561 CNRS-Universite de Lorraine. Her group is dedicated to the pathobiology of connective tissue disorders, in particular the Ehlers–Danlos syndromes, and specializes on the molecular and structural basis of glycosaminoglycan synthesis enzyme defects. Dr. Neeti Ghali, M.R.C.P.C.H., M.D., is a Consultant Clinical Geneticist at the North West Thames Regional Genetics Service, London and she has a specialist interest in Ehlers–Danlos Syndrome. She has been working in the London part of the UK National EDS Diagnostic Service since 2011. Dr. Cecilia Giunta, Ph.D., is a molecular geneticist and established scientist working in the field of Ehlers–Danlos Syndrome and other heritable connective tissue disorders (CTD) since 1995. Together with Dr. Marianne Rohrbach she runs the diagnostic and research activities of the Connective Tissue Unit as part of the Division of Metabolism at the University Children's Hospital, Zurich since September 2008. Her research focuses on the understanding of the Molecular Basis and Pathology of Connective Tissue Disorders, in particular the rare forms of EDS and osteogenesis imperfecta. She is currently a member of the medical and scientific board of the Ehlers–Danlos Society. Dr. Ines Kapferer-Seebacher, D.M.D., is a periodontist with a clinical and research focus on dental and periodontal manifestations of rare diseases. She is an Associate Professor at the Department of Restorative and Operative Dentistry, Medical University Innsbruck, Austria. Dr. Tomoki Kosho, M.D., Ph.D., is a pediatrician and clinical geneticist. He is an Associate Professor at the Center for Medical Genetics at Shinshu University Hospital, where he directs clinical service for heritable connective tissue disorders and research especially on D4ST1-deficient EDS. Dr. Roberto Mendoza-Londono, M.D., is the Director of the EDS clinic at the Hospital for Sick Children (HSC) and University Health Network (UHN) in Toronto and the interim head of the Division of Clinical of Metabolic Genetics at HSC/University of Toronto. He is a clinical geneticist with expertise in skeletal dysplasia's and connective tissue disorders who has an interest in gene discovery and studies of natural history of disease. He has participated in several collaborative projects that led to the identification and characterization of genes that regulate the formation and maintenance of bone and connective tissue. Prof. Michael F. Pope, M.B.B.Ch., F.R.C.P., M.D., is Consultant in Charge of the new NHS National Commissioning Group Complex EDS Service at the Kennedy Galton Center, Northwick Park Hospital. He is especially interested in the classification, genetics, and diagnosis of Ehlers–Danlos syndrome, osteogenesis imperfecta, pseudoxanthoma elasticum, cutis laxa, Stickler syndrome, the Marfan syndrome, many of which overlap with the benign hypermobility syndrome (BHS). His expertise lies in the differentiation, separation, and testing of these disorders from BHS. Dr. Marianne Rohrbach, M.D., Ph.D. in molecular genetics, is a trained pediatrician and clinical geneticist. Together with Dr. Giunta, she leads the diagnostic and research activities of the Connective Tissue Unit at University Children's Hospital in Zurich, Switzerland. Dr. Rohrbach established a multidisciplinary Connective tissue clinic including clinical, biochemical, and molecular diagnosis, as well as patient management and counseling. Her research focus includes long-term follow up and natural history of all connective tissues diseases and the understanding of the Molecular Basis and Pathology of Connective Tissue Disorders, in particular the rare forms of EDS and osteogenesis imperfecta. Dr. Tim Van Damme is an M.D., Ph.D. student at the Center for Medical Genetics Ghent, Belgium, whose research involves the study of clinical, genetic and pathogenetic aspects of the Ehlers–Danlos syndromes and related disorders. Dr. Anthony Vandersteen, M.A., Ph.D., M.D., is a medical geneticist, assistant professor at IWK Health Center and Dalhousie University, Nova Scotia, Canada. He has a special interest in EDS and previously worked in the UK National EDS Diagnostic Service. Caroline van Mourik, B.Ed., M.Sc., Ph.D. (Biology and Geology), has been active in the Swedish patient-organization, previously as Chair but later mainly as the scientific editor. She even presented a paper at the first international symposium on EDS in Ghent, 2012 and frequently lectures about EDS, both for the medical field as well as laymen. Nicol Voermans, M.D., Ph.D., is a neurologist specialized in neuromuscular disorders at the Radboud University Medical Center (Nijmegen, the Netherlands). She directs the clinical service for neurological and neuromuscular features of various types of EDS, and has a large experience with the TNX-deficient type EDS. Prof. Johannes Zschocke, M.D., Ph.D., is Professor and Chair of Human Genetics at the Medical University Innsbruck, Austria, where he is also Acting Director of the Department of Medical Genetics, Molecular and Clinical Pharmacology. As Head of the Center for Medical Genetics Innsbruck, he is responsible for the provision of genetic services for the Western Austria and beyond. His clinical and research focus is on inherited metabolic diseases, and he has been involved in the genetic characterization of several Ehlers–Danlos Syndrome subtypes. Prof. Fransiska Malfait, M.D., Ph.D., is a rheumatologist and clinical geneticist. She is an Associate Professor at the Center for Medical Genetics at the Ghent University Hospital, where she directs the research, clinical service, and laboratory facility for diagnosis and genetic testing for the Ehlers–Danlos syndrome and other heritable disorders of connective tissue. She is the current Chair of the medical and scientific board of the Ehlers–Danlos Society. *Correspondence to: Fransiska Malfait, M.D., Ph.D., Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, Gent 9000, Belgium. E-mail: [email protected] DOI 10.1002/ajmg.c.31550 Article first published online in Wiley Online Library (wileyonlinelibrary.com).

ß 2017 Wiley Periodicals, Inc. RESEARCH REVIEW AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 71

The Ehlers–Danlos syndromes comprise a clinically and genetically heterogeneous group of heritable connective tissue disorders, which are characterized by joint hypermobility, skin hyperextensibility, and tissue friability. In the Villefranche Nosology, six subtypes were recognized: The classical, hypermobile, vascular, kyphoscoliotic, arthrochalasis, and dermatosparaxis subtypes of EDS. Except for the hypermobile subtype, defects had been identified in fibrillar collagens or in collagen-modifying enzymes. Since 1997, a whole spectrum of novel, clinically overlapping, rare EDS-variants have been delineated and genetic defects have been identified in an array of other extracellular matrix genes. Advances in molecular testing have made it possible to now identify the causative mutation for many patients presenting these phenotypes. The aim of this literature review is to summarize the current knowledge on the rare EDS subtypes and highlight areas for future research. © 2017 Wiley Periodicals, Inc.

KEY WORDS: Ehlers–Danlos syndromes; heritable connective tissue disorders; collagen How to cite this article: Brady AF, Demirdas S, Fournel-Gigleux S, Ghali N, Giunta C, Kapferer-Seebacher I, Kosho T, Mendoza-Londono R, Pope MF, Rohrbach M, Van Damme T, Vandersteen A, van Mourik C, Voermans N, Zschocke J, Malfait F. 2017. The Ehlers–Danlos syndromes, rare types. Am J Med Genet Part C Semin Med Genet 175C:70–115.

INTRODUCTORY Brittle cornea syndrome (BCS): Ma- substitutions in the proa1(I) chain of type STATEMENT rianne Rohrbach, Tim Van Damme I collagen, c.1720C>T, p.(Arg574Cys) Spondylodysplastic EDS (spEDS- and c.3277C>T, p.(Arg1093Cys°), were For each genetic EDS subtype, a sub- B4GALT7 and spEDS-B3GALT6): identified in two other adults with committee of authors performed a com- Sylvie Fournel-Gigleux, Tim Van vascular rupture, but without EDS-signs prehensive literature search. All articles Damme, Fransiska Malfait [Malfait et al., 2007]. The p.(Arg312Cys) were reviewed for relevance and addi- Spondylodysplastic EDS (spEDS- mutation has subsequently been identi- tional articles were identified from the SLC39A13): Cecilia Giunta fied in two other individuals with EDS literature. The articles were summarized Musculocontractural (mcEDS): To- and complications of vascular fragility and divided into themes: (1) the historyof moki Kosho, Fransiska Malfait [Ritelli et al., 2013; Gaines et al., 2015]. the EDS subtype, (2) mechanisms of Myopathic EDS (mEDS): Roberto In view of the major clinical overlap of disease, (3) allelic heterogeneity, (4) Mendoza-Londono, Fransiska Malfait the p.(Arg312Cys)-associated phenotype clinical description, (5) genotype–phe- Periodontal EDS (pEDS): Ines Kapferer- with classical EDS due to COL5A1 or notype correlations and penetrance, (6) Seebacher, Michael Pope, Anthony Van- COL5A2 mutations, both conditions management, and (7) differential diagno- dersteen, Johannes Zschocke are grouped within the same clinical sis. The summary of these themes was entity (“Classical EDS”) in the new critically reviewed by all authors. EDS classification. Patients with the Subcommittees: CLASSICAL EDS DUE TO p.(Arg312Cys) mutation are particularly COL1A1 p.(Arg312Cys) at risk for vascular events, highlighting the (COL1A1-cEDS) Classical EDS due to COL1A1 benefit of molecular confirmation in p.(Arg312Cys) (cEDS-COL1A1): Synonyms: Classic-like Ehlers–Danlos classical EDS patients for management Fransiska Malfait syndrome with propensity to arterial purposes. Classical-like EDS due to Tenascin-X rupture, Vascular-like EDS deficiency (clEDS): Serwet Demirdas, Nicol Voermans The History of Classical EDS Cardiac-valvular EDS (cvEDS): Fran- In view of the major clinical due to COL1A1 p.(Arg312Cys) siska Malfait overlap of the p.(Arg312Cys)- (COL1A1-cEDS) Arthrochalasia EDS (aEDS): Tomoki associated phenotype with Kosho, Cecilia Giunta, Marianne Nuytinck et al. [2000] reported two Rohrbach, Fransiska Malfait children with a classical EDS phenotype, classical EDS due to COL5A1 Dermatosparaxis EDS (dEDS): Tim including skin hyperextensibility, easy or COL5A2 mutations, both Van Damme, Fransiska Malfait bruising, atrophic scarring, and joint Kyphoscoliotic EDS (kEDS-PLOD1): hypermobility, with a c.934C>T, conditions are grouped within Angela Brady, Neeti Ghali, Cecila p.(Arg312Cys) mutation. Malfait et al. the same clinical entity Giunta, Marianne Rohrbach, Tim [2007] identified the same mutation in “ ” Van Damme, Anthony Vandersteen an adult who suffered from a rupture ( Classical EDS ) in the new Kyphoscoliotic EDS (kEDS-FKBP14): of medium-sized arteries, reminiscent EDS classification. Cecila Giunta, Marianne Rohrbach, of vascular EDS. In addition, two Tim Van Damme, Fransiska Malfait other arginine-to-cysteine (Arg-to-Cys) 72 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) RESEARCH REVIEW

The prevalence of this condition is with other EDS signs. It is a rare, but spontaneous dissection of the right iliac unknown. important differential diagnosis of vas- artery at 43 years. Her affected 16-year- cular EDS. old son did not have complications of Mechanism of Disease vascular fragility, except for unusual Reported clinical features for the bruising. The patient, reported by The pathogenetic basis for the phenotype p.(Arg312Cys) substitution Gaines et al. [2015] suffered from a resulting from these specific Arg-to-Cys spontaneous rupture of the common substitutions is currently not well under- Reproductive, including pregnancy iliac artery at 39 years. The patient, stood. Ultrastructural studies of dermal Premature preterm rupture of the fetal reported by Ritelli et al. [2013] had collagen fibrils have shown fibrils membranes (PPROM) was reported in mild mitral and aortic valve regurgita- with variable diameters, and slightly one patient. One patient was reported tion, left ventricular wall thickening, irregular contour, and, in case of the to have neonatal hypotonia. No preg- aortic root dilatation, vertebral artery p.(Arg312Cys), flower-like abnormali- nancy-related complications were re- tortuosity, and a hepatic hemangioma at ties [Malfait et al., 2007]. ported (one known pregnancy in an 53 years. The two children reported by Several mechanisms have been sug- affected female). Nuytinck et al. [2000] did not show gested to be involved in the pathogenesis Craniofacial features signs of vascular fragility at the time of [Malfait et al., 2007], including local None of the patients had characteristic report. Clinical follow-up is not avail- destabilization of the triple helix due to features of vascular EDS. One patient able for these patients. loss of the stabilizing arginine residue; was reported to have redundant skin introduction of a cysteine residue, which folds on the eyelids and soft earlobes, can lead to disulfide-bonding with reminiscent of classical EDS. One Other Arg-to-Cys substitutions that lead to other collagenous or non-collagenous patient had blue sclerae, high palate, vascular fragility proteins, either intracellularly or in the and hypoplastic uvula. EDS-like signs have only been observed extracellular matrix (ECM), thereby Musculoskeletal system in association with the p.(Arg312Cys) disturbing normal physiological interac- Generalized joint hypermobility was mutation. One patient harboring a tions; interference with pericellular reported in four patients. One patient p.(Arg574Cys) (male, 42 years) suffered processing of the amino-propeptide of had congenital bilateral hip dislocation from a dissection of the left femoral procollagen type I, and/or local unwind- and a traumatic shoulder dislocation. artery and an aortic aneurysm. One ing of the region surrounding the Another patient was also reported to patient harboring a p.(Arg1093Cys) mutations, thereby disturbing specific have sporadic joint dislocations. Pectus (male, 40 years) had a left kidney interactions with type I collagen ligands excavatum was reported twice. Two infarction at age 34 years, and a [Malfait et al., 2007]. patients complained from chronic joint dissection of the infrarenal aorta and pain. None of the patients had a history left iliac artery, with aneurysm of the left Allelic Heterogeneity of fractures; DEXA Z-score was normal renal artery at age 39 years. He also had Three different heterozygous COL1A1 in two patients. mitral valve bulging [Malfait et al., mutations, leading to a Arg-to-Cys Skin and integument 2007]. substitution have been reported in Skin involvement included skin hyper- ¼ association with vascular fragility: extensibility (n 4); soft, doughy skin – ¼ ¼ Genotype Phenotype Correlation c.934C>T, p.(Arg312Cys); c.1720C>T, (n 2); thin or translucent skin (n 3); ¼ and Penetrance p.(Arg574Cys); and c.3277C>T, p. friable skin/skin splitting (n 2); atro- ¼ a (Arg1093Cys). phic scars (n 4); delayed wound heal- The Arg-to-Cys substitutions in the 1 ing (n ¼ 1); unusual tenderness upon (I) collagen chain seem to be associated touch (hyperalgesia) (n ¼ 1); piezogenic with specific phenotypes: Classical EDS Clinical Description papules (n ¼ 1); molluscoid pseudotu- with vascular fragility for p.(Arg312Cys) To date, six patients from five families mors (n ¼ 1); varicose veins (n ¼ 1). Easy and isolated vascular fragility for have been reported with the p. bruising was reported in all patients p.(Arg574Cys) and p.(Arg1093Cys). (Arg312Cys) (Table S1). These include (n ¼ 6). Finallyone patient had hiatal and In addition, three other Arg-to-Cys two females (respectively 5 and 43 years abdominal and inguinal hernias. substitutions have been reported for old) and five males (respectively 7, 16, Ocular involvement this gene: c.3040C>T,p.(Arg1014Cys) 39, and 53 years old). [Nuytinck et al., Blue sclerae were observed on one is associated with autosomal dominant 2000; Malfait et al., 2007; Ritelli et al., patient. One patient was operated for Caffey disease [Gensure et al., 2005], 2013; Gaines et al., 2015]. strabismus. whereas c.3106C>T,p.(Arg1036Cys) The hallmark of this condition is Cardiovascular system and c.3196C>T,p.(Arg1066Cys) are the “vascular fragility,” leading to spon- All three adults had severe cardiovascu- reported in patients with an OI/EDS taneous dissection or rupture of lar complications. The patient repo- overlap phenotype without signs of medium-sized arteries, in combination rted by Malfait et al. [2007] had a vascular fragility [Cabral et al., 2007; RESEARCH REVIEW AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 73

Lund et al., 2008]. The pathogenic basis (CAH) due to 21-hydroxylase defi- Allelic Heterogeneity for theses specific clinical consequences ciency as well as hyperextensible skin, A total of 24 patients with a complete is unknown. hypermobile joints, easy bruising, TNX-deficiency without involvement Penetrance is unknown. and poor wound healing. Skin biopsy of the CYP21B gene have been of this patient showed small collagen reported. In 19 of these patients (15 fibers of normal shape and a complete Management families), the molecular diagnosis is absence of tenascin XB (TNX). known. Homozygous and compound Key management guidelines focus on Cultured dermal fibroblasts also heterozygous mutations have been iden- the cardiovascular system. lacked TNX. PCR of the patients tified. Mutations have been identified Specific management guidelines DNA revealed a 30 kb deletion in throughout the TNXB gene, and in- include: chromosome 6 overlapping both the clude missense, frameshift, and nonsense CYP21B gene and the TNXB mutations. – Measurement of aortic root size and gene. Subsequently, Schalkwijk et al. There is a registry of reported assessment of heart valves by echocar- [2001] measured TNX in the serum of TNXB gene variants [Dalgleish, 1998]. diogram at the time of diagnosis or by 151 EDS patients (classical and vascular In five out of the 24 reported age 5 years type), 168 diseased controls (psoriasis patients, no genetic confirmation of – Echocardiogram at 5-year intervals, and rheumatoid arthritis), and 21 the clinical diagnosis after TNX serum even if the initial echocardiogram is healthy controls. They detected a measurement was performed. normal complete TNX deficiency in five – Vigilant observation and control of EDS patients and three affected blood pressure can reduce the risk of siblings (one of which with the contig- Clinical Description arterial rupture uous gene syndrome). Mutation analy- The clinical phenotype of the 24 – Further vascular surveillance ought to ses revealed mostly homozygous patients with a complete TNX- be considered mutations in the TNXB gene for deficiency without involvement of the – Consider bone densitometry evaluation these patients. The authors concluded CYP21B gene was reviewed (Table S1) that the TNX-deficient type is very [Schalkwijk et al., 2001; Peeters et al., Guidelines for management of similar to the classical type of EDS with 2004; Lindor and Bristow, 2005; Voer- musculoskeletal problems, skin in- two major differences: (1) No atrophic mans et al., 2007, 2009b; O’Connell volvement, ophthalmologic and dental scarring was apparent, and (2) the et al., 2010; Hendriks et al., 2012, follow-up, and pregnancy should fol- inheritance pattern was autosomal Penisson-Besnier et al., 2013; Sakiyama low those formulated for other forms recessive. et al., 2015; Demirdas et al., 2016]. of EDS (for reference: See “manage- The prevalence of this condition is The absence of TNX throughout ment guidelines for the classical unknown. the body leads to a phenotype resem- Ehlers–Danlos syndrome,” by Bowen bling the classical type of EDS. The et al., this issue). Mechanism of Disease hallmarks of the disorders are GJH, hyperextensible, soft and/or velvety TNX is one of the three known large Differential Diagnosis skin, without the typical atrophic scar- matricellular proteins of the tenascin ring seen in classical EDS, easy bruising, family [Mao and Bristow, 2001; and an autosomal recessive inheritance Vascular EDS Valcourt et al., 2015]. Although the pattern. Classical EDS due to COL5A1 or precise function of TNX is unknown, COL5A2 mutations it is known to play a role in the ECM OI as it is highly expressed in connective Reproductive, including pregnancy tissue of muscle, around tendons, Egging et al. [2008] retrospectively ligaments,andinskin[Maoand investigated genitourinary and obstetric Bristow, 2001]. The glycoprotein is complications in seven women with CLASSICAL-LIKE EDS encoded by the TNXB gene in classical-like EDS, aged 38–57 years (six DUE TO TENASCIN-X humans. Classical-like EDS is caused from the cohort of Schalkwijk et al. DEFICIENCY (clEDS) byacompletelackofTNXdueto [2001] and Patient 1 from the series of homozygous or compound heterozy- Lindor and Bristow [2005]). These The History of the Classical-Like gous TNXB mutations, that lead to women have had a total of 13 pregnan- EDS nonsense-mediated mRNA decay cies and 12 deliveries. Two women (one This type of EDS was first described by (NMD), or biallelic deletion of with CAH due to 21-hydroxylase Burch et al. [1997]. The authors TNXB. As a result, the TNX protein deficiency as a contiguous gene syn- described a 26-year-old male patient is completely absent [Mao and Bris- drome; one with additional spina bifida with congenital adrenal hyperplasia tow, 2001]. who decided to have no biological 74 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) RESEARCH REVIEW

children) did not have any pregnancies. of age by O’Connell et al. [2010]. patients from the cohort of Demirdas One out of 13 pregnancies ended in Furthermore, in some adult cases, a et al. [2016] were described to have intrauterine death of the fetus, and one childhood onset of hypermobility and frequent subconjunctival hemorrhage. out of 12 deliveries was complicated dermatological symptoms was reported. Dental involvement with post-partum hemorrhage. No Demirdas et al. [2016] reported that all Recurrent periodontitis was reported in premature births or neonatal complica- patients (n ¼ 17) had a clinical onset in one, and another patient was described tions were reported. No urinary incon- childhood, ranging from the neonatal to have dental crowding due to a narrow tinence was seen. Vaginal (n ¼ 1), age to puberty. The most encountered palate. uterine (n ¼ 2), and rectal (n ¼ 1) initial symptoms in this group were Cardiovascular system prolapse were present. One undefined (sub)luxations, hypermobility, and vel- Peeters et al. [2004] investigated the prolapse was mentioned. Three out of vety/hyperextensible skin. Based on the cardiac features in seven TNX-deficient five women had partus-related compli- data we found, we conclude that patients (all from the cohort of Schalk- cations (vaginal uterine extirpation after patients already experience symptoms wijk et al. [2001]). They found a systolic uterine prolapse, post-partum hemor- such as skin hyperextensibility, a velvety murmur at the apex in one patient. rhage, intra-uterine death at 24 weeks skin, easy bruising/spontaneous ecchy- Three of the seven patients were found with post-partum hemorrhage, and mosis, subluxations, and joint hyper- to have mitral valve abnormalities precipitous second stage during at mobility in childhood. Piezogenic (billowing of the mitral valve in two term deliveries). The authors con- papules of the feet and pes planus are patients of the same family and a severe cluded that pregnancy is without major also apparent at the pediatric age. mitral valve prolapse (MVP) in another complications in TNX-deficient pa- Craniofacial features patient). Although the number of tients, apart from one incident of Craniofacial features reported in the patients was small and such abnormali- postpartum hemorrhage. However, patients included a slight asymmetry of ties are not infrequent in the general uterine and vaginal prolapse regularly the face (n ¼ 1), lax skin of the cheeks population, the authors recommended occurs in TNX-deficient women, even (n ¼ 1), and a narrow and/or high echocardiography at baseline and if a at a young age, suggesting laxity of the arched palate (n ¼ 4). cardiac murmur appears [Peeters et al., genitourinary tissues. Furthermore, no Musculoskeletal system 2004]. Subsequently, Lindor and Bristow premature births have been observed in Frequently described musculoskeletal [2005] also described a patient who had the offspring; however, some patients features included joint and/or muscular mitralvalvesurgeryduetoaMVP. had been born prematurely themselves. pains. Furthermore, one paper reported Demirdas et al. [2016] also described Demirdas et al. [2016] described the frequently observed deformities of the cardiologic features of their patients. Four gynecologic and obstetric history of hands and feet. Twelve out of 17 out of 17 of the patients had hypertension seven women in their cohort. Three of included patients had pes planus and and two patients (4/17 patients were these women had previously been four patients had short/broad feet with previously included by Peeters et al. included in the study by Egging et al. brachydactyly of the toes. Four of the [2004]) had mitral valve abnormalities. [2008]. The other four women reported patients had deformities of the fingers One patient developed a post-partum a total of 10 pregnancies, two of which and acrogeric hands [Demirdas et al., cardiomyopathy [Demirdas et al., 2016]. ended in intrauterine demise of the 2016]. Gastrointestinal system fetus. Furthermore, four out of 10 Skin and integument Two patients reported by Lindor and deliveries were complicated with post- It is noted that all reported patients had Bristow [2005] suffered from bleeding of partum hemorrhage, two women had hyperextensible skin, frequently de- gastrointestinal structures, namely the perineal rupture, and one pregnancy scribed to be soft and velvety of sigmoid and duodenum, secondary to was complicated by PPROM. In this structure. The atrophic scars typical diverticulitis and as complications of cohort, another woman was reported to for classical EDS were not observed. spontaneous ileus. Hendriks et al. have pelvic instability without ever Bilateral inguinal hernia was described [2012] reported a gastric hemorrhage having been pregnant [Egging et al., in a male patient and unilaterally in a duetoulcersinamalepatientinitially 2008]. female patient. An umbilical hernia was reported by Schalkwijk et al. [2001]. He Obviously, some caution must be described in a 6-year-old male. died at the age of 57 years due to a septic taken in making conclusions and ex- Ocular involvement shock following elective mitral valve trapolating data from such a small group Ocular involvement was infrequently replacement surgery, which was compli- of TNX-deficient patients (n ¼ 11) reported in patients with TNX-defi- cated by a sinuspiriformis perforation by [Egging et al., 2008]. cient classical-like EDS. One patient a transesophageal ultrasound probe Age of onset was described to have esotropia/ambly- [Hendriks et al., 2012; Knuijt et al., Symptoms of patients with the TNX- opia [Lindor and Bristow, 2005], an- 2014]. Sakiyama et al. [2015] also pre- deficiency have been described as other to have astigmatism, and a third sented a patient who had recurrent starting as early as 5 years of age in a patient was described to have bilateral gastrointestinal perforation due to tissue girl by Hendriks et al. [2012] and 7 years conjunctivochalasis. Five out of 17 fragility (diverticulitis, spontaneous ileus RESEARCH REVIEW AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 75

and a subsequent perforation of the (one of the cohort of Schalkwijk et al. reported hypermobile joints [Demirdas duodenum). Demirdas et al. [2016] did [2001] and three of the other patients et al., 2016]. not observe severe gastrointestinal in the study of Voermans et al. problems in their patients. However, [2009b] showing that in response to one patient had a gastric ulcer at age 16 the increased compliance of the Genotype–Phenotype Correlations and a bowel perforation due to extracellular matrix in muscle of and Penetrance diverticulitis at age 48 years [Demirdas TNX-deficient EDS patients, a et al., 2016]. marked intracellular stiffening of the No genotype–phenotype correlations Neuromuscular features and motor sarcomere protein titin occurs. The are reported within the group. We development stiffening of titin most likely com- assume that penetrance is high, but the A total of six articles describe pensates for the muscle weakness research to support this assumption is research concerning muscular func- [Ottenheijm et al., 2012]. The lacking. Family members with a hap- tion in patients with TNX-deficiency report by Penisson-Besnier et al. loinsufficient mutation in the TNXB or their muscle tissue [Voermans [2013] presented a 42-year-old gene have been described to have et al., 2007, 2009b; Ottenheijm male patient with proximal limb symptoms of joint hypermobility in et al., 2012; Gerrits et al., 2013; muscle weakness, subclinical heart 60% of the cases, but more research is Penisson-Besnier et al., 2013; involvement, minimal skin hyperex- needed to confirm this [Zweers et al., Sakiyama et al., 2015]. All papers tensibility, no joint abnormalities, 2003]. concludethatthereissomedegreeof and a history of easy bruising. He muscle weakness in patients with had been asymptomatic until age 30 Management TNX-deficiency. Voermans et al. but mentioned low performances [2007] studied a cohort of 40 EDS at upper bodybuilding exercises. No specific guidelines for management patients, among which 10 with Since then, he experienced gradually of patients with classical-like EDS are TNX-deficiency (six of the cohort worsening lower limb weakness, lead- available. Guidelines for management of Schalkwijk et al. [2001], and four ing to inability to run from age 40, of musculoskeletal problems, skin in- additional patients). Muscle weakness, frequent falls, and the recent need of a volvement, cardiovascular involve- myalgia, and easy fatigability were banister for stairs. He was initially ment, and pregnancy should follow reported by the majority of patients, diagnosed as having a primary myop- those formulated for other forms of whereas all patients were able to walk athy and only later diagnosed EDS (for reference: See “management independently without aids. Mild-to- with EDS [Penisson-Besnier et al., guidelines for the classical Ehlers– moderate muscle weakness (80%) and 2013]. Danlos syndrome,” by Bowen et al., reduction of vibration sense (60%) Motor development was not stud- this issue). were common. Other findings were ied in the included papers. We detected Specific management guidelines axonal polyneuropathy (40%) on no comments on delayed motor devel- may include: nerve conduction studies and mild opment other than mild to moderate myopathic features on muscle biopsy muscle weakness. Musculoskeletal (20%). Patients with hypermobile Neurological features and neuromotor In case of operations, special attention EDS (hEDS) caused by TNXB hap- development for the effect of general anesthesia and of loinsufficiency were less affected Cognitive development was not studied adequate positioning and support is [Voermans et al., 2009b]. This was in the included papers. Intellectual important to prevent pressure or stretch confirmed in a quantitative study on disability was not reported. neuropathies [Voermans et al., 2006]. isometric function of the thigh Other Furthermore, intubation and endo- muscles in seven patients (four of Severe edema of the ankles and/or feet scopic studies should be performed the cohort of Schalkwijk et al. was described in four patients. carefully in order to prevent rupture of [2001] and three of the other patients Family history trachea or esophagus [Besselink-Loba- in the study of Voermans et al. Demirdas et al. [2016] asked their nova et al., 2010; Hendriks et al., 2012] [2009b] and Gerrits et al. [2013]). patients about family history and found Pregnancy The results showed that muscle that 4/11 mothers and 5/11 fathers Gynecological follow-up throughout weakness in this type of EDS is complained of (sub)luxations (n ¼ 4), pregnancy is not warranted based on most likely due to increased compli- pes planus (n ¼ 2), easy bruising (n ¼ 1), the retrospective study in five patients ance of the series-elastic component artralgia (n ¼ 4), hyperextensible skin [Egging et al., 2008]. However, the of muscle tissue and failure of maxi- (n ¼ 3), hypermobility (n ¼ 1), and severe complications that have been mal voluntary muscle activation. Fur- inguinal hernia (n ¼ 1). Of the 17 reported during insertion of a trachea ther proof of this concept was patient’s siblings, 11 out of 26 were tube and a transesophageal ultrasound obtained in single fiber study of tested and proven heterozygous car- probe call for a very careful handling muscle tissue of four of these patients riers. Three of these 11 carrier siblings of patients, especially in emergency 76 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) RESEARCH REVIEW

situations. Therefore, we advise a clini- during intubation. During elective carried a contiguous deletion that cal delivery for all patients surgery at the age of 41 years (because extended into TNXB. One patient of a luxation of the left knee joint) a carried a TNXB premature stop codon. tracheal rupture developed, despite Twelve of 13 patients with CAH-X had the initially uneventful intubation. EDS clinical features. Patients with Differential Diagnosis The authors acknowledge that the CAH-X were more likely than age- patient had other anatomic risk factors matched controls to have joint hyper- Classical EDS for a tracheal rupture (obesity and mobility (P < 0.001), chronic joint pain Congenital myopathies, including col- short stature for example). However, (P ¼ 0.003), multiple joint dislocations lagen VI- and collagen XII-related the authors also state that TNX alters (P ¼ 0.004), a structural cardiac valve disorders the characteristics of the ECM and abnormality by echocardiography therefore advise caution when intu- (P ¼0.02), and reduced TNX expres- bating patients with TNX-deficiency, sion by Western blot and immuno- THE CONTIGUOUS or even to refrain from intubating staining. Piezogenic papules on the feet GENE SYNDROME WITH entirely [Besselink-Lobanova et al., were also observed. A subset of parents CONGENITAL ADRENAL 2010]. was investigated (five mothers, two HYPERPLASIA AND fathers), of which three had GJH with TNX-DEFICIENCY a Beighton score of 5 or more [Merke TNXB Haploinsufficiency Burch et al. [1997] first described the et al., 2013]. TNX-deficient pheno- and genotype in Zweers et al. [2003] studied the 20 Morissette et al. [2015] investigated a male patient (26 years old) with heterozygous family members of the the genetic background of this cohort hyperextensible skin, hypermobile index cases in Schalkwijk et al. in the same natural history study joints, easy bruising and 21-hydroxylase [2001] regardless of clinical symptoms. (n ¼ 246). Seven families (10 patients) deficiency. A heterozygous 30 kb dele- In all of these individuals, significantly harbored a novel TNXB missense tion was found on chromosome 6 reduced serum TNX levels were variant c.12174C>G,p.(Cys4058Trp) involving both the CYP21B gene and detected, and in 17 of them, they and had a clinical phenotype consistent the TNX gene as a causative explanation confirmed heterozygosity for a trun- with hEDS. Fourteen CAH probands for all symptoms. They also reported cating TNXB mutation. Clinical ex- carried previously described TNXA/ that TNX in serum, skin and muscle was amination in these family members TNXB chimeras, resulting in a CAH- measured and absent. The authors showed generalized joint hypermobil- X prevalence of 8.5%. This highly concluded that a small deletion or ity (GJH) in nine family members conserved pseudogene-derived variant missense mutation had probably re- (45%; all female). Skin hyperextensi- in the TNX fibrinogen-like domain is mained undetected on the maternal bility and easy bruising, frequently seen predicted to be deleterious and disul- allele [Burch et al., 1997]. in the individuals with complete TNX fide-bonded, resulting in reduced der- The second patient with this deficiency, were absent. Subsequently, mal elastin and fibrillin-1 staining and Continuous gene syndrome was in- they measured serum TNX levels (by altered TGF-1 binding, and represents cluded in the initial series of Schalk- ELISA) in an unselected cohort of 80 anovelTNXA/TNXB chimera. TNX wijk et al. [2001] (Patient 3) and patients with hEDS. Six of these protein expression was normal in subsequent cohorts [Egging et al., patients (7.5%; all female) had serum dermal fibroblasts, suggesting a domi- 2008; Voermans et al., 2009b; Gerrits TNX levels more than 2.5 SD below nant-negative effect. They concluded et al., 2013]. She was homozygous for the mean for unaffected individuals. that the CAH-X syndrome is com- the 30-kb deletion detected in the Clinically, patients with reduced TNX monly found in CAH due to 21- index case reported by Bristow. Both levels showed hypermobile joints, of- hydroxylase deficiency and may result her parents and two siblings were ten associated with joint subluxations from various etiological mechanisms heterozygous for the deletion and and chronic musculoskeletal pain. The [Morissette et al., 2015]. Patients in this were clinically normal, providing evi- authors concluded that TNXB hap- cohort were considered to be hetero- dence of recessive inheritance in this loinsufficiency is associated with hEDS zygous for the TNXB deletion, and family. This 32-year female patient [Zweers et al., 2003]. had reduced but not absent TNX levels was described to have recurrent (sub) Merke et al. [2013] investigated the in serum. Therefore, this phenotype is luxations, hypermobile joints, hyper- prevalence of a Continuous gene syn- likely be more in line with what is extensible, and velvety skin that drome in a cohort of 192 consecutive reported by Zweers et al. [2003] in easily bruises, musculoskeletal pain, unrelated CAH patients. TNXB hap- patients with reduced serum levels of and CAH. Besselink-Lobanova et al. loinsufficiency, here termed CAH-X TNX, and with the reported features [2010] presented the follow-up of this syndrome, was present in 13 patients in some of the sibs who are obligate case in order to draw attention to (and two sibs). Twelve of 91 patients carriers of the mutation in their the severe complications encountered carrying a CYP21A2 deletion (13%) affected family member. RESEARCH REVIEW AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 77

CARDIAC-VALVULAR EDS escapes nonsense-mediated mRNA de- small joints. One patient had shoulder (cvEDS) cay (NMD) and the mRNA is stable, but dislocations, pectus excavatum, and the proa2(I) chains fail to fold normally muscle and tendon tears. One patient History of Cardiac-Valvular EDS and are degraded, which eventually also had recurrent patellar dislocations. Foot results in the production of pro-a1(I) deformities were reported in three In 1987 and 1988, Sasaki et al. [1987], homotrimers [Pihlajaniemi et al., 1984]. patients: A 6-year-old boy displayed Kojima et al. [1988], and Hata et al. Given that proa(I) homotrimer forma- pes planus with valgus heels, hallux [1988] reported two Japanese patients tion alone does not lead to OI, the OI valgus, and subluxations of the toes; a with complete absence of the proa2(I) phenotype in the latter patient suggests 9-year-old girl had pedes palonvalgi collagen chains, both presenting EDS- that the intracellular accumulation of with secondary shortening of Achilles like features, including joint hypermobil- mutant proa2(I) chains and the cellular tendon; and in an adult man pes planus ity, skin hyperextensibility, abnormal alterations, resulting from a high rate of and calcaneovalgus were reported. One wound healing, but also cardiac-valvular degradation of these chains, contributes patient had increased bone fragility. problems. Nicholls et al. [2001]reported a to the skeletal phenotype. In contrast, Skin and integument total absence of a2(I) collagen chains in a the EDS phenotype that results from Reported skin abnormalities included: 9-year-old girl with phenotypic manifes- unstable mRNA and no proa2(I) chains Skin hyperextensibility (n ¼ 4) (ranging tationsofbothOIandEDS,butwithout reflects what appears to be a more from mild to severe), soft skin (n ¼ 2), cardiovascular anomalies. A homozygous limited response in the ECM. atrophic scar formation (classical EDS- splice site mutation led to the introduc- like) (n ¼ 2), easy bruising (n ¼ 2) tion of a premature termination codon delayed wound healing (n ¼ 1), thin (PTC). Schwarze et al. [2004] reported Allelic Heterogeneity skin (n ¼ 1), striae (n ¼ 1). Inguinal four patients from three independent Seven different mutations have been hernia was reported in two males, families (including the patient reported reported in five independent cardiac- including congenital bilateral inguinal by Kojima et al. [1988]) with a rare, valvular EDS patients. These include hernia in one. recessively inherited form of EDS, char- one homozygous nonsense mutation Ocular involvement acterized by joint hypermobility, skin (c.213dupC,p.(Arg99)), and six splice Myopia and astigmatism was reported in hyperextensibility, and severe cardiac- site mutations (two homozygous one patient; one patient was reported to valvular defects, resulting from biallelic (c.3105þ2T>C and c.3601G>T)) and have blue sclerae. COL1A2 mutations, leading to complete two compound heterozygous Cardiovascular system absence of proa2(I)-chains. Because of (c.70þ717A>G; c.1404þ1G>A and All four reported adults had severe the severe cardiac valve problems in most c.540þ5G>A; c.1404G>C). The pa- cardiac-valvular problems, resulting in of the adult patients, this phenotype was tient reported by Sasaki et al. [1987] was valve replacement surgery.A 45-year-old called “cardiac-valvular EDS” [Schwarze only analyzed at the biochemical level male had severe mitral valve regurgitation et al., 2004]. One additional child with and no molecular data were reported. due to MVP,resulting in left atrium and this condition was subsequently reported ventricle dilatation and mild ventricular by Malfait et al. [2006]. hypertrophy. He also had aortic valve The exact prevalence of this rare Clinical Description insufficiency, eventually necessitating condition is unknown. To date, six patients from five indepen- mitral and aortic valve replacement. dent families have been reported Post-surgery, there was dehiscence of Mechanism of Disease (Table S1). Their age at diagnosis ranged the mitral annulus from the ventricle, and The biallelic COL1A2 mutations result from 6 to 65 years [Hata et al., 1988; of the aortic valve from the atrioventric- in the complete absence of proa2(I)- Kojima et al., 1988; Nicholls et al., ular groove. Finally, there was massive chains. Cells from affected individuals 2001; Schwarze et al., 2004; Malfait leakage through the left ventricular produce type I collagen molecules that et al., 2006]. myocardium with disintegration of the contain only proa1(I) chains. The The hallmark of the condition is the entire left ventricle, from which the mRNA from the mutant alleles is severe cardiac-valvular disease, necessi- patient died. A 65-year-old woman had unstable and degraded so that no protein tating valve replacement surgery at adult mitral valve insufficiency with uncom- is produced. Nicholls et al. [1984] age, in conjunction with variable skin plicated replacement surgery. A 30-year- reported a 5-year-old boy with severe, hyperextensibility, atrophic scarring and old male had a secundum-type atrial progressively deforming OI (OI type joint hypermobility, and autosomal septum defect (ASD), MVP with regur- III). No cardiac abnormalities were recessive inheritance. gitation, and aortic valve regurgitation. reported in this patient [Nicholls et al., He underwent mitral and aortic valve 1984]. A homozygous 4-nucleotide Muscoloskeletal system replacement with no complications. His frame shift deletion within the carboxy Three patients were reported to have 25-year-old brother had aortic valve (C)-terminal propeptide of pro-a2(I) GJH, whereas in the other three the replacement because of aortic insuffi- collagen was identified. This mutation hypermobility was restricted to the ciency [Schwarze et al., 2004]. 78 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) RESEARCH REVIEW

The two reported children had no The History of EDS Arthrochalasia that lead to entire or partial loss of severe cardiovascular features, although Type exon 6 of either COL1A1 or mitral valve bulging was noted in one COL1A2 determines lack of the N- Hass and Hass [1958] proposed pres- [Nicholls et al., 2001; Malfait et al., telopeptide linking the N-propeptide ence of a distinct entity of congenital 2006]. to the major triple helical domain of flaccidity of the joints, which they the a1(I) or the a2(I) chain. Deletion called “arthrochalasis multiplex con- of the respective 24 and 18 amino acid genita” and which may or may not residues in the pro-a1(I) and the pro- Genotype–Phenotype Correlations involve skin changes. In 1973, three a2(I) chain results in loss of the small and Penetrance patients with the condition “EDS VII” globular region of the N-propeptide were reported with accumulation of All mutations result in complete absence (present only in the pro-a1(I) chain), procollagen in their skin and tendon of the proa2(I) chains. There are no the procollagen N-proteinase cleavage [Lichtenstein et al., 1973a]. The disor- reported genotype–phenotype correla- site (Pro-Gln and Ala-Gln at positions der was therefore supposed to be tions. Obligate carriers displayed no 4–5, respectively), the cross-linking caused by a defect in the conversion overt symptoms. Penetrance is presum- lysine residue at position 13 and 9, of procollagen to collagen, resembling ably complete. respectively, of the N-telopeptide dermatosparaxis in cattle, and the and the first triplet of the main helical activity of the converting proteinase Gly-X-Y domain [Giunta et al., Management in the cultured fibroblasts from these 1999]. patients was found to be reduced to Key management guidelines focus on between 10 and 40% of normal the cardiovascular system. [Lichtenstein et al., 1973b]. However, Allelic Heterogeneity Specific management guidelines Steinmann et al. [1980] demonstrated, include: Most of the mutations are splice site through reinvestigation of the fibro- mutations leading to skipping of exon 6 blasts from one of the patients, the – Measurement of aortic root size and in COL1A1 (intron 52A>G/T; in- presence of mutant pNa2(I) collagen assessment of heart valves by echocar- tron 51G>A/C/T; exon 61G>A/ chains (precursor procollagen chains diogram at the time of diagnosis or by C) or COL1A2 (intron 52A>G; in which the (C)- but not the age 5 years intron 51G>A/C; exon 61G>A; N-propeptide is cleaved off) in colla- – Yearly echocardiogram, even if the intron 6þ1G>A/T/C; intron gen extracted from skin or produced initial echocardiogram is normal 6þ2T>C/G) [Steinmann et al., 2002]. by fibroblasts and the normal activity – Cardiac valve replacement surgery Genomic deletions of exon 6 [Byers of procollagen N-proteinase in cell – Consider bone densitometry evaluation et al., 1997] and exon 5þ6 [Nicholls extracts. They concluded the condition et al., 2000] were also reported. to be caused by a structural abnormal- Management guidelines for mus- There is a registry of reported ity in the portion of the pro-a2(I) culoskeletal problems, skin, ophthal- COLI gene variants [Dalgleish, 1998]. chain that is normally cleaved by mologic and dental follow-up, and N-proteinase (and other proteinases) pregnancy should follow those formu- [Steinmann et al., 1980]. Subsequently, Clinical Description lated for other forms of EDS (for Cole et al. [1987] found mutant reference: See “management guide- At present, 49 patients from 36 pNa1(I) in a patient with similar lines for the classical Ehlers–Danlos families have been published (Table features. EDS VII was, therefore, syndrome,” by Bowen et al., this S1). The ages at the publication subdivided into types VIIA and issue). ranged from 2.5 months to 46 years type VIIB, depending on whether (n ¼ 35; Median age, 7.5 years of age) the a1(I) or the a2(I) chain is [Steinmann et al., 1980; Eyre et al., Differential Diagnosis affected, respectively [Beighton et al., 1985; Cole et al., 1986; Viljoen et al., 1998]. 1987; D’Alessio et al., 1991; Nicholls Prevalence of this condition is Classical EDS et al., 1991; Vasan et al., 1991; Chiodo unknown. Hypermobile EDS et al., 1992; Pope et al., 1992; Carr et al., 1994; Ho et al., 1994; Lehmann Mechanism of Disease et al., 1994; Byers et al., 1997; Giunta et al., 1999; Hudgins et al., 1999; ARTHROCHALASIA EDS Arthrochalasia EDS is caused by Nicholls et al., 2000; Whitaker et al., (aEDS) heterozygous mutations in either 2009; Giovannucci Uzielli et al., Synonyms: Ehlers–Danlos syndrome, COL1A1 (previously EDS type 2011; Klaassens et al., 2012; Giunta type VII (VIIA, VIIB); Arthrochalasis VIIA) or COL1A2 (previously EDS and Steinmann, 2014; Hatamochi multiplex congenita type VIIB). Heterozygous mutations et al., 2014]. RESEARCH REVIEW AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 79

The hallmarks of the disorder are picture of the phenotype are given in a total of 11 children, including seven severe generalized joint hypermobility, Fig. 1). affected ones. Pregnancy or delivery- congenital bilateral hip dislocation, and related complications included breech recurrent subluxations and dislocations Reproductive, including pregnancy presentation (n ¼ 4), PPROM (n ¼ 2), of both small and large joint At least four affected women were polyhydramnios (n ¼ 2), and decreased [Steinmann et al., 2002] (Representative reported to be pregnant, and to deliver fetal movement (n ¼ 2).

Figure 1. Clinical photographs and radiological images of patients with aEDS. A girl (A–G) with a c.279þ1G> mutation in COL1A2 and a mother and her two sons (H–J) with a c.279þ2T>CinCOL1A2.(A) X-rays of the hip at age 7 days showing congenital bilateral hip dislocation and femoral and acetabular deformities. (B and C) Status of the hip dislocation at age 5 months and 3 years, respectively. (D) An anterioposterior total body radiograph at age 11 years showing unsuccessful treatment of the hip dislocation with harness and bracing. (E) A left lateral total body radiograph at age 11 years showing lumbar lordosis. (F and G) The patient at age 9 years with umbilical hernia, lordotic posture of the spine, and foot deformities. Foot deformities of an affected mother at age 38 years (H), her first son at age 14 years (I), and her second son at age 5 years (J) (Images A–G kindly provided by Prof. Maria Luisa Giovannucci-Uzielli, with permission). 80 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) RESEARCH REVIEW

Craniofacial characteristics Neurological features and neuro- the disorder. Stable reductions of Characteristic craniofacial features in- development congenital hips dislocations were not clude large fontanelle (n ¼ 6), frontal Mild learning disability was recorded in achieved frequently through closed bossing (n ¼ 9), hypertelorism (n ¼ 4), a patient with leptomeningocele and reductions with orthoses or hip spica. blue sclerae (n ¼ 3), epicanthal folds intracranial hemorrhage, presenting Anterolateral open reductions with (n ¼ 3), depressed nasal bridge (n ¼ 6), with seizures, the 3rd cranial nerve capsular plication were also ineffective. midfacial hypoplasia (n ¼ 3), and mi- palsy, left hemiparesis, and left homon- In contrast, open reductions with an crognathia (n ¼ 6). ymous hemianopsia. iliac osteotomy, with or without femo- Musculoskeletal features ral osteotomy, were favorable in some Congenital bilateral hip dislocation patients. Appropriate surgical interven- was described in all reported patients tion is therefore difficult to plan but is Genotype–Phenotype Correlations (n ¼ 41). One unreported patient is crucial for reducing the risk of recur- and Penetrance known to have had a unilateral congen- rence of hip dislocations, avascular ital hip dislocation (Byers et al, personal Interfamilial and intrafamilial variability necrosis, and premature osteoarthritis communication). Joint hypermobility seems to be slight [Steinmann et al., [Giunta et al., 1999; Steinmann et al., (n ¼ 29) and recurrent dislocations or 2002]. TypeI collagen consists of two a1 2002; Giunta and Steinmann, 2014] subluxations affecting both large and (I) and one a2(I) chains, thus three – Recurrent and/or persistent disloca- small joints (n ¼ 26) were frequent. quarters of the collagen I molecules in tions and hypermobility of upper Foot deformities (n ¼ 15), including aEDS due to COL1A1 mutations limb joints are also disabling, but pes equinovarus (n ¼ 8), pes planus contain one or two mutant pNa1(I) operative intervention is rarely con- (n ¼ 7), pes valgus (n ¼ 2) and hallux chains, whereas only half of the collagen sidered because limited effectiveness valgus (n ¼ 6) (Fig. 1), and spinal I molecules in aEDS due to COL1A2 of operative procedures is predicted deformities (n ¼ 13), including scoliosis mutations are affected [Steinmann et al., [Giunta et al., 1999; Steinmann et al., (n ¼ 9), kyphoscoliosis (n ¼ 2), and 2002; Giunta et al., 2008a]. This 2002; Giunta and Steinmann, 2014] lordosis (n ¼ 3), were also frequent. difference in the stoichiometry suggests – Orthotic management and early Swan neck deformity of hands was that COL1A1-associated aEDS might intervention, including physical and described in several adults (n ¼ 3). be more severe than COL1A2-assiated occupational therapy are recom- Pectus excavatum was observed in aEDS. Because the number of patients mended to assist standing, walking, some (n ¼ 3). Fractures (n ¼ 9) and with a COL1A1 mutation is small, it is and activities of daily living [Giunta Wormian bones on cranial radiographs uncertain whether this correlation holds et al., 1999; Steinmann et al., 2002; (n ¼ 5) suggested bone fragility, similar true [Giunta et al., 2008a]. Severe Giunta and Steinmann, 2014] to patients to mild OI. phenotypes in patients with a – Contact sports should be avoided to Skin and integument COL1A1 mutation have been de- prevent dislocations The skin was often described to be scribed: A patient with a COL1A1 – Consider bone mineral density studies hyperextensible; hyperelastic or redun- “intron 51G>A” leading to complete dant (n ¼ 26); soft, doughy, or velvety loss of exon 6 presented with dermato- The advice to management of the skin, (n ¼ 17); and/or fragile (n ¼ 9). Easy sparaxis EDS-like features [Nicholls cardiovascular, and ophthalmological bruising (n ¼ 12), atrophic scarring et al., 2000] and a patient with a features is similar to that for patients (n ¼ 10), abnormal wound healing COL1A1 mutation “intron 52A>T” with classical EDS (see “management (n ¼ 3), and crisscross patterning of had multiple congenital dislocations and guidelines for the classical Ehlers– palms/soles (n ¼ 4) were also noted. dermatosparaxis EDS-like skin features Danlos syndrome,” by Bowen et al., Umbilical hernia was sometimes de- (doughty, redundant) [Giunta et al., this issue) scribed (n ¼ 8). 2008a]. Pregnancy management Ocular involvement Penetrance is complete. – Follow-up throughout pregnancy is Blue sclerae (n ¼ 3) and ectopia lentis warranted (n ¼ 1) were recorded. – Delivery should be performed in a Management Dental involvement medical center where intensive treat- Dentinogenesis imperfecta was re- Key management guidelines focus on ment could be given to an affected corded in a few patients (n ¼ 3). the musculoskeletal system and the skin. pregnant woman and an affected Neuromuscular features and motor neonate development The advice to management of the – Breech presentation is frequent if the Motor developmental delay was re- musculoskeletal system is: fetus is affected. Though not de- corded in 16 patients, six of whom were – At diagnosis a whole body skeletal scribed previously, affected pregnant not ambulatory at the time of publica- survey is recommended women might be predisposed to tion because of hypotonia and/or foot – Management of orthopedic problems tearing of the perineal skin and deformity. is the center of care for patients with to have postpartum extension of RESEARCH REVIEW AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 81

episiotomy incisions as well as pro- procollagen chains was eventually dem- pN-collagen type I, resulting in poly- lapse of the uterus and/or bladder, as onstrated [Smith et al., 1992]. Although merization of abnormal collagen fibers described in cEDS animal dermatosparaxis was the first that appear thin, irregular, branched and recognized collagen disorder, it took “hieroglyphic” in cross-section. more than 20 years to confirm the Differential Diagnosis existence of a human counterpart for Allelic Heterogeneity the disorder. In 1992, three independent infants were reported with clinical signs Up till now eight biallelic mutations have Larsen syndrome resembling dermatosparaxis [Nusgens been reported in 15 patients (14 indepen- Classical EDS et al., 1992; Smith et al., 1992]. dent families), including a recurrent Dermatosparaxis EDS Ultrastructural studies of the dermis homozygous nonsense mutation p. Kyphoscoliotic EDS demonstrated the same “hieroglyphic” (Gln225) in six patients, a unique Musculocontractural EDS pattern of the collagen fibrils as those homozygous nonsense mutation p. Loeys–Dietz syndrome observed in dermatosparactic animals, (Trp795), a homozygous in-frame skip PYCR1-related autosomal recessive and biochemical studies on cultured of exons three to five a homozygous in- cutis laxa human fibroblasts confirmed deficient frame skip of exon 17 and compound cleavage of the proa1(I) and proa2(I) heterozygosity for an out-of-frame exon- N-propeptides. Seven additional pa- skip of exon 3 and an in-frame skip of DERMATOSPARAXIS EDS tients were identified subsequently, all exons 14–16, three homozygous loss-of- (dEDS) of them displaying a severe phenotype function mutations (c.2927_2928delCT, Synonyms: Dermatosparaxis; Ehlers– with an extremely fragile and lax skin, p.(Pro976Argfs42); c.669-670dupG, p. Danlos dermatosparaxis type; EDS- severe bruising, and a characteristic (Pro224Argfs41); c.2751-2A>T) and VIIC; EDS7C dysmorphic face, leading to a diagnosis one compound heterozygous mutation usually within the first few months of (c.2T>C, p.? and c.888-891delTGAA, p. life. It lasted until 1999 to identify the (Met295Thrfs25)). All mutations result The History of Dermatosparaxis first biallelic mutations in ADAMTS2, in deficient activity of ADAMTS-2. EDS the gene encoding the procollagen I N- There is a registry of reported Dermatosparaxis was first reported in proteinase ADAMTS-2 (a disintegrin ADAMTS2 gene variants [Dalgleish, 1998] cattle [Lenaers et al., 1971; Hanset and and metalloproteinase with thrombo- Lapiere, 1974] and subsequently in spondin motifs 2), in several patients Clinical Description sheep [Fjolstad and Helle, 1974], cats with the dermatosparaxis type of EDS as [Counts et al., 1980; Holbrook and well as in a strain of dermatosparactic Todate 15 patients from 14 independent Byers, 1982] and dogs [Holbrook and cattle [Colige et al., 1999]. families have been reported. Three Byers, 1982]. Affected animals display a The exact prevalence of this rare patients were born to known consan- loose and extremely fragile skin (der- condition is unknown. guineous parents (Table S1). Age at matosparaxis means “tearing of the diagnosis ranged from birth to 13 years. skin”), resulting in large skin lacerations [Nusgens et al., 1992, Smith et al., 1992; Mechanism of Disease during delivery or early in life, with Wertelecki et al., 1992; Reardon et al., subsequent infections and premature Dermatosparaxis EDS (dEDS) is caused 1995; Fujimoto et al., 1997; De Coster death. Early ultrastructural studies by homozygous or compound hetero- et al., 2003; Malfait et al., 2004; Bar- showed alterations in the dermis of zygous mutations in ADAMTS2, the Yosefet al., 2008; Solomons et al., 2013; these animals, with loosely packed, thin, gene that encodes ADAMTS-2. Van Damme et al., 2016]. Clinical and twisted ribbon-like collagen fibrils ADAMTS-2 is a metalloproteinase con- follow-up into puberty and early adult- that displayed a typical “hieroglyphic taining properdin repeats and a cysteine- hood is reported for only two patients. aspect” on cross sections, pointing rich domain with similarities to the The hallmark of the disorder is the toward impaired collagen biosynthesis disintegrin domain of reprolysin. This extreme skin fragility with redundant, and fibrillogenesis. Subsequent bio- enzyme is the main procollagen I N- almost lax skin, and the severe suscepti- chemical studies performed on derma- proteinase, but it can also cleave the N- bility of bruising. tosparactic cattle revealed that these propeptides of type II and type III abnormal collagen molecules were procollagens [Colige et al., 2005]. The Reproductive, including pregnancy composed of incompletely processed mutations result in decreased activity of Preterm birth was reported in nine type I procollagen precursor molecules, ADAMTS-2, which leads to defects in patients, and was preceded by PPROM in which the N-propeptide was insuffi- processing of type I procollagen to in six. Mean gestational age was 34 ciently cleaved [Lenaers et al., 1971]. mature type I collagen [Colige et al., weeks and 4 days (n ¼ 14, range: 28–41 Deficient activity of the endopeptidase 1999; Colige et al., 2004; Van Damme weeks). The umbilical cord was noted that excises the N-propeptide of et al., 2016]. There is an accumulation of to be friable in two infants; one of them 82 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) RESEARCH REVIEW

also had a short umbilical cord that retardation was reported in all patients, seven patients, ranging from severe ruptured after clamping. Perinatal com- except for those that died shortly after epistaxis and gum bleeds to internal plications were reported in several birth (n ¼ 13). Eleven patients pre- and (congenital) cerebral hemorrhages. patients. One patient died shortly after sented with non-rhizomelic shortening Arterial rupture or aortic dilatation has birth (39 weeks gestation) due to severe of the limbs and short, plump hands and not been reported so far. hemorrhage and shock. A boy with a feet with stubby fingers and toes. Joint Neuromuscular features and motor gestational age of 33 weeks was born hypermobility was a consistent finding development with multiple skull fractures and an (n ¼ 11), but often mild at birth. A mild delay in gross motor develop- extensive subgaleal hemorrhage. A dural Follow-up data in older patients dem- ment was reported in about half of the tear at the site of the skull fracture led to onstrated that the joint hypermobility patients (n ¼ 8). the development of a large cerebrospinal becomes more pronounced later on. Visceral complications fluid collection, and he died due to Four patients had a history of fractures, A 9-year-old girl ruptured her dia- secondary infection at 145 days of age. including (congenital) skull fractures in phragm due to postoperative vomiting. Three other prematurely born infants three. Several other skeletal abnormali- She subsequently developed a para- were admitted to a neonatal intensive ties were reported, including delayed esopagheal hernia with incarceration of care unit for several weeks for a range of ossification of the cranial vault (n ¼ 3), the stomach that was further compli- complications, including cerebral hem- Wormian bones (n ¼ 2), delayed bone cated by the occurrence of a large orrhage (n ¼ 2); pneumothorax and age (n ¼ 2), and persistence of woven abdominal hematoma after reduction. respiratory distress (n ¼ 1); hydroneph- bone in the ribs of one patient 15. Two patients had bladder diverticula, rosis (n ¼ 1); and hypoglycemia, hypo- Osteopenia was reported in only two complicated by spontaneous bladder calcemia, and hypothyroidism (n ¼ 1). patients. rupture, and two other patients devel- No pregnancies have been reported in Skin and integument oped rectal prolapse with profuse anal affected individuals. Frequently occurring skin features, bleeding in puberty. Craniofacial involvement apart from the severe skin fragility Most patients were born with a severe (n ¼ 14) and loose, lax, or hyperexten- and recognizable facial gestalt, including sible skin (n ¼ 15), included a soft and Genotype–Phenotype Correlations prominent and protuberant eyes with doughy skin texture (n ¼ 12), increased and Penetrance puffy, edematous eyelids and excessive palmar wrinkling (n ¼ 6), and atrophic periorbital skin, large fontanels and/or scarring (n ¼ 5). One of the most The patients harboring the wide cranial sutures, a hypoplastic chin consistent clinical findings was an c.2927_2928delCT and the c.2751- and bluish or greyish discoloration of the umbilical hernia at birth (n ¼ 14). 2A>T mutations have a relatively milder sclerae (n ¼ 12). Less frequent findings Ocular involvement phenotype compared to the others. included gingival hyperplasia (n ¼ 6), One patient had severe, congenital These mutations lead to introduction dental lamina cysts (n ¼ 2), and general- myopia, whereas several others pre- of a PTC. The milder phenotype could ized hypertrichosis (n ¼ 6). These pa- sented with early onset and progressive be due to the fact that NMD might be tients also presented extreme skin fragility myopia (n ¼ 5). Three others had only partially efficient for these alleles with tearing of the skin, either at birth astigmatism, and one patient developed and some transcripts can escape NMD. (n ¼ 2) or within the first few years of life severe glaucoma at very young age. As such, these alleles could produce (n ¼ 10). In addition, they had a lax and Dental involvement truncated ADAMTS-2 enzymes lacking sagging skin with redundant skin folds, In addition to gingival hyperplasia and either the last thrombospondin 1 (TSP1) especially in the neck, and around wrists dental lamina cysts, several other dental domain and the PLAC (protease and and ankles (n ¼ 10). Together, these abnormalities have been reported. lacunin) domain (c.2927_2928delCT), findings led to an early diagnosis in these These include microdontia (n ¼ 6) or or the two most C-terminal TSP1 patients. A number of patients displayed a even agenesis of several permanent domains and the PLAC domain strikingly milder phenotype, with ab- teeth (n ¼ 3), and tooth discoloration (c.2751-2A>T) [Van Damme et al., sence of obvious congenital facial dys- (n ¼ 3). Abnormal morphology of the 2016]. Interestingly, investigation of morphic features, skin fragility or molars (n ¼ 2) and severe enamel attri- the N-endopeptidase activity of various redundancy. Mild dysmorphic features, tion of the deciduous teeth (n ¼ 2) have forms of recombinant ADAMTS-2 has skin fragility, and features of generalized been reported in a limited number of previously shown that removal of one or connective tissue fragility however grad- patients [De Coster et al., 2003; Malfait two of the most C-terminal TSP1 and ually became more apparent during et al., 2004]. the PLAC domain results in an enzyme childhood and adolescence. Cardiovascular system which is still significantly active [Colige Musculoskeletal system Easy bruising was frequent (n ¼ 11) and et al., 2005]. In addition, two other Whereas height, weight, and orofacial often very severe with the formation of members of the ADAMTS family, circumference were usually within large subcutaneous hematomas. Bleed- ADAMTS-3 and ADAMTS-14, have normal limits at birth, postnatal growth ing problems were encountered in been shown to possess procollagen RESEARCH REVIEW AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 83

N-endopeptidase activity, and could defect, it was suggested that they be glucosyl-galactose), and (2) in the forma- compensate for the reduced activity of classified as a new subtype, EDS VI, the tion of intra- and intermolecular collagen ADAMTS-2 [Fernandes et al., 2001; ocular type or the ocular-scoliotic type cross-links. LH1 deficiency results in Colige et al., 2002; Le Goff et al., 2006]. [McKusick, 1972]. Later, it was recog- underhydroxylation of lysyl residues and Penetrance is presumably complete. nized that the ocular signs, though underglycosylation of hydroxylysyl resi- dramatic, were far less frequent than dues in collagens and, hence, impaired initially reported, prompting the Ville- cross-link formation with consequent Management franche Nosology to reclassify the mechanical instability of the affected No specific guidelines for management disorder as the kyphoscoliotic type of tissues [Rohrbach et al., 2011]. of patients with dEDS are available. EDS [Beighton et al., 1998]. At that Management guidelines should follow time it was recognized that in the Allelic Heterogeneity those formulated for other forms of EDS majority of cases, the condition was (for reference: See “management guide- caused by the lysyl hydroxylase 1 A total of 139 mutations in PLOD1 have lines for the classical Ehlers–Danlos enzyme deficiency and specified as the been identified in the 84 confirmed syndrome,” by Bowen et al., this issue). kyphoscoliotic form of EDS (EDS cases, of these there are 39 different VIA), whereas a rarer, clinically similar mutations. The 8.9 kb duplication of condition with normal lysyl hydroxylase 7 exons (exons 10–16; c.1067_1846 Differential Diagnosis activity was designated EDS VIB [Stein- dup) is the most common and has been mann et al., 2002; Walker et al., 2004b]. reported in 42/139 (30%) mutations (20 Classical EDS Thereafter, it was recognized that the individuals homozygotes; 2 patients Cutis laxa syndromes Nevo Syndrome, first reported in 1974, compound heterozygotes). Nine pa- OI was an allelic condition to kEDS tients from six families are homozygous Arthrochalasia EDS [Giunta et al., 2005a]. for the nonsense mutation p.Arg319, all RIN2 syndrome Recently, a number of rare autoso- of Arab descent. The nonsense mutation Achondroplasia mal recessive entities with distinct mo- p.Tyr511 has been identified in five lecular and biochemical abnormalities patients, two of whom are homozygous. that clinically overlap with kEDS have There is a registry of reported been described, and are discussed below: PLOD1 gene variants [Dalgleish, 1998]. KYPHOSCOLIOTIC EDS kEDS due to FKBP14 mutations, (kEDS) DUE TO LYSYL the Brittle cornea syndrome (BCS) HYDROXYLASE 1 Clinical Description (ZNF469 and PRDM5), the spondylo- DEFICIENCY (kEDS-PLOD1) dysplastic form of EDS caused by At present, 84 patients from 73 families Synonyms: Kyphoscoliotic EDS; EDS SLC39A13 mutations (previously called with confirmed kEDS-PLOD1 (either Type 6; EDS Type VIA; Ocular- spondylocheirodysplastic EDS), and by demonstration of biallelic PLOD1 scoliotic EDS; Nevo syndrome; Cutis musculocontractural EDS (CHST14 mutations or by urinary analysis) have hyperelastica; Lysyl hydroxylase- and DSE). been identified [Beighton, 1970b; Krieg deficient EDS The exact prevalence of kEDS due et al., 1979; Ihme et al., 1983; Dembure to lysylhydoxylase 1 deficiency is et al., 1984; Chamson et al., 1987; unknown. Wenstrup et al., 1989; Hyland et al., The History of Kyphoscoliotic 1992; Hautala et al., 1993; Ha et al., EDS 1994; Al-Gazali et al., 1997; Yeowell and Mechanism of Disease Kyphoscoliotic EDS was the first inborn Walker, 1997; Brinckmann et al., 1998; error of human collagen metabolism to kEDS-PLOD1 is caused by deficiency of Heikkinen et al., 1999; Walker et al., be defined at the biochemical level, as the collagen-modifying enzyme procolla- 1999, 2004a, 2005; Yeowell et al., 2000a, early as 1972. Based on a family study in gen-lysine, 2-oxoglutarate 5-dioxygenase b, 2005; Brunk et al., 2004; Giunta et al., which two sisters had marked muscular 1 (PLOD1 or LH1 [lysylhydroxylase1]) 2005b; Yis et al., 2008; Esaka et al., 2009; hypotonia, severe progressive scoliosis due to homozygosity or compound Voermans et al., 2009a; Kariminejad from birth, marked joint hypermobility, heterozygosity for mutated PLOD1 al- et al., 2010; Rohrbach et al., 2011; and recurrent joint dislocations [Krane leles. Lysylhydroxylase 1 (LH1) plays an Gok et al., 2012; Busch et al., 2014; et al., 1972; Pinnell et al., 1972], the important role as a post-translational Tosun et al., 2014; Abdalla et al., 2015]. authors found lysyl-hydroxylase defi- modifying enzyme in collagen biosynthe- The ages at publication ranged from 5 ciency in fibroblasts from the two sis through (1) hydroxylation of helical months to 54 years. Clinical features were siblings that produced hydroxylysine- lysyl residues in Xaa-Lys-Gly collagen adequately reported in 74 patients with deficient collagen. Because the sisters sequences to hydroxylysyl residues kEDS-PLOD1 (either by demonstration also presented microcornea, fragility of which serve as sites of attachment for of biallelic PLOD1 mutations or by ocular tissues, and a distinct biochemical carbohydrate units (either galactose or urinary analysis) (Table S1). 84 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) RESEARCH REVIEW

The hallmarks of the disorder Craniofacial features equinovarus. Pes planus was reported include (congenital) kyphoscoliosis, A number of dysmorphic features have in 11 patients. muscle hypotonia, and joint hypermo- been reported. However, individual A marfanoid habitus has been bility (Representative pictures of the case series often report the same reported in 19/74 patients. Arach- phenotype are given in Fig. 2). feature in a number of patients. As a nodactyly was reported in eight result, the occurrence of certain separate patients. High palate was Reproductive, including pregnancy features may be over-represented. recorded in 11 patients, and in Pregnancy of an affected fetus is usually The most frequently observed features association with arachnodactyly in uneventful although reduced fetal are high palate, epicanthal folds, five, or with marfanoid habitus in movements have been reported down-slanting palpebral fissures, syn- three patients. A pectus deformity (n ¼ 7). PPROM was reported in three ophrys and low-set ears. was observed, with pectus excavatum cases, four patients were known breech Musculoskeletal system being more common (n ¼ 12) than presentation and there were three Kyphoscoliosis is present and usually pectus carinatum (n ¼ 2). Osteopenia reports of oligohydramnios. severe and progressive. In most pa- (n ¼ 17) or osteoporosis (n ¼ 2) was Affected pregnant women may be at tients, this is congenital (n ¼ 55) but sometimes seen on X-ray; however, increased risk for spontaneous abor- postnatal kyphoscoliosis (n ¼ 12) or fractures were not reported in any tions, premature rupture of mem- scoliosis alone (n ¼ 1) have been patients. branes, and rupture of arteries. The reported. Almost all patients have joint Skin and integument patient reported by Esaka et al. hypermobility (n ¼ 69). Joint disloca- Skin abnormalities are almost univer- [2009] experienced minor trauma at tions/subluxations are common. Con- sally described. Skin hyperextensibility 29 weeks gestation resulting in a genital hip dislocations has been (n ¼ 48) and soft, doughy, or velvety stillbirth and maternal death. Post reported in 15 patients and post-natal skin (n ¼ 43) were most frequently mortem autopsy showed a spontane- hip dislocation in an additional three observed. Fragility was reported ous rupture of the right iliac artery patients. Besides hip, shoulder (n ¼ 26) with easy bruising (n ¼ 26); [Esaka et al., 2009]. Two affected (n ¼ 12), knee (n ¼ 5), and wrist thin, translucent skin (n ¼ 8); and women had a total of seven pregnan- (n ¼ 2) were the most commonly abnormal wound healing (n ¼ 17). cies resulting in three miscarriages and noted dislocations/subluxations. Gen- Atrophic scarring was reported in 35 four healthy children, three of whom erally, recurrent dislocations were patients. Criss-cross patterning of the were born vaginally at term and one of noted in 18 patients. Hand deformities palms was only reported in one patient. whom was born at 24 weeks; there were noted in 13 patients. Foot Hernia was reported in 12 patients were no maternal complications deformities were also noted in 17, including six umbilical and five [Steinmann, unpublished]. which included four cases of talipes inguinal.

Figure 2. Clinical findings in patients with kEDS: (A and B) Kyphoscoliosis in two unrelated patients homozygous for causative mutations in PLOD1.(C) Severe kyphoscoliosis in a patient homozygous for a causative mutation in FKBP14 (Images kindly provided by Prof. Ebtesam Abdalla and Dr. Matthias Baumann, with permission). RESEARCH REVIEW AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 85

Ocular involvement The patient reported by Yeowell reported by Hyland et al. [1992]. The Ophthalmic features are variable and et al. [2000a] had an intracranial younger sibling appears be much less include bluish sclerae (n ¼ 18), mi- haemorrhage and brachial plexus inju- severely affected. Intrafamilial variation crocornea (n ¼ 16), and myopia ries at birth; he had dextrocardia and has been observed. (n ¼ 16).Ruptureoftheeyeglobe, mild aortic root dilatation with mild Penetrance is complete. following minimal trauma has been aortic insufficiency due to a biscuspid reported in five individuals including aortic valve and he died from arterial Management one patient with both eyes affected rupture age 14 years. Voermans et al. [Beighton, 1970a; Pinnell et al., [2009a] followed-up patient 7 from Key management guidelines focus on 1972; Ihme et al., 1983; Kariminejad Giunta et al. [2005b] who had a the musculoskeletal system, skin, and et al., 2010]. ruptured aneurysm of the left popliteal the cardiovascular system. Cardiovascular system artery at the age of 15 years. Rohrbach Medium-sized vessel rupture has been et al. [2011] reported a 27-year-old man The advice to management of the reported in several individual case with chest symptoms who during musculoskeletal system is: reports. These events appear to be coronary angiography had a spontane- – According to that for patients with more prevalent from teenage years and ous dissection of the ramus interven- classical EDS (for reference: See into adulthood; however, there have tricularis anterior (RIVA) and main “management guidelines for the been six cases of antenatal/neonatal coronary artery causing acute cardiac classical Ehlers–Danlos syndrome,” brain haemorrhage [Wenstrup et al., failure. A Turkish boy presented with a by Bowen et al., this issue) 1989; Yeowell and Walker, 1997; left brachial artery pseudo-aneurysm at – Photographic and radiologic docu- Yeowell et al., 2000a; Giunta et al., the age of 12 [Gok et al., 2012]. There mentation of the spine is recom- 2005b; Rohrbach et al., 2011; Tosun has been one report of aortic stenosis mended in view of the progressive et al., 2014]. Arterial rupture has been [Ihme et al., 1983]. Another three kyphoscoliosis. Regular follow-up reported in various locations and during patients were reported to have MVP by an orthopedic surgeon for man- pregnancy as mentioned above [Esaka [Pinnell et al., 1972; Rohrbach et al., agement of kyphoscoliosis is et al., 2009]. 2011]. appropriate In one of the first reported siblings Neuromuscular features and motor – Any surgery should be carried out [Beighton, 1970b], the sister died development with caution due to the risk of from a dissecting aortic aneurysm at One of the key features of the condition vascular complications the age of 50 and the brother had a is congenital muscular hypotonia – Consider bone densitometry eval- cerebral bleed in the distribution of the (n ¼ 56), with associated feeding prob- uation right middle cerebral artery at the lems (n ¼ 17). Gross motor delay is – Consider sleep study to assess for age of 19. Dembure et al. [1984] common (n ¼ 54) with varying severity, nocturnal hypoxemia, and night- reported a patient, who was then but with only one non-ambulatory case. time ventilation in case of severe followed up by Ha et al. [1994] who Neurological features and neuro- muscle hypotonia had a spontaneous arterial rupture into development The advice to management of the skin his upper thigh at the age of 15. In Intelligence is usually normal but is: Wenstrup et al. [1989], one patient learning disabilities have been reported – According to that for patients with had a rupture of a vertebral artery in eight patients (two of these classical EDS (see “management and another patient had multiple patients were reported to have antena- guidelines for the classical Ehlers– ruptures of the femoral artery and tal or perinatal intracranial bleeds) Danlos syndrome,” by Bowen et al., two episodes of spontaneous intra- [Wenstrup et al., 1989; Rohrbach this issue) thoracic arterial rupture. Brinckmann et al., 2011]. – Routine examination for hernia and et al. [1998] reported two patients surgical referral as necessary with vascular complications; one The advice for management of the suffered a stroke at the age of 15 years cardiovascular system is: Genotype–Phenotype Correlation and subsequently at age 30 years, – Measurement of aortic root size and and Penetrance he had spontaneous bleeding of assessment of heart valves by echo- minor pancreatic arteries; and at A range of clinical severity is observed in cardiogram at the time of diagnosis or age 32 years, he had spontaneous individuals with kEDS-PLOD1 for each by age 5 years bleeding from branches of the of the systems discussed as detailed in the – Echocardiogram at 5-year intervals, right profundal femoral artery above section [Steinmann et al., 2002; even if the initial echocardiogram is [Brinckmann et al., 1998; Busch Rohrbach et al., 2011]. No specific work normal et al., 2014]; another patient had an has been carried out looking at geno- – Vigilant observation and control of aneurysm of the mesenteric artery age type–phenotype correlations. There are blood pressure can reduce the risk of 12 years. two siblings with the same mutations arterial rupture 86 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) RESEARCH REVIEW

– Further vascular surveillance ought variant of EDS, characterized by severe Allelic Heterogeneity to be considered congenital muscle hypotonia, joint hy- Four different FKBP14 mutations have The advice for management of the permobility, skin hyperextensibility, been identified to date [Baumann et al., ophthalmologic system is: progressive kyphoscoliosis, and sensori- 2012; Aldeeri et al., 2014; Murray et al., – Formal ophthalmologic evaluation at neural hearing loss. The condition was 2014; Dordoni et al., 2016]. The diagnosis for myopia, astigmatism, shown to be caused by biallelic muta- c.362dup, p.(Glu122Argfs7) has been and potential for retinal detachment tions in FKBP14 [Baumann et al., identified in homozygous state in five – Routine ophthalmologic examina- 2012]. In view of the major clinical independent families. Furthermore, this tion for management of myopia overlap of this phenotype with kEDS- mutation was twice identified in com- and early detection of ophthalmic PLOD1, both conditions are grouped pound heterozygosity with another complications within the same clinical entity (“Ky- mutation: One with a nonsense muta- – Myopia and/or astigmatism may be phoscoliotic EDS” in the new EDS tion (c.42_60del, p.(Thr15)) and once corrected by glasses or contact lenses classification). with a 3-bp deletion (c.573_576del, p. – Laser treatment of the retina is (Gly191del)). A homozygous deletion indicated in case of imminent of four amino acids was recently detachment reported: c.197þ5_197þ8delGTAA Pregnancy management Baumann et al. [2012] [Alazami et al., 2016]. – Follow-up throughout pregnancy reported five families with an and delivery should be performed in a specialized fetal medicine center autosomal recessive variant of Clinical Description – Measurement and monitoring of EDS, characterized by severe To date, 10 patients with kEDS- aortic root size by echocardiogram congenital muscle hypotonia, FKBP14 from nine independent fami- during pregnancy joint hypermobility, skin lies have been described: Five pediatric (<12 years), three adolescents (16 years), hyperextensibility, progressive and two adults (42- and 48-year-old) Differential Diagnosis kyphoscoliosis, and (Table S1) [Baumann et al., 2012, Aldeeri et al., 2014, Murray et al., sensorineural hearing loss. 2014, Alazami et al., 2016, Dordoni Kyphoscoliotic EDS-FKBP14 et al., 2016]. Sufficient clinical data are Brittle cornea syndrome The condition was shown to available for nine patients. Spondylodysplastic EDS be caused by biallelic The hallmarks of the disorder in- Musculocontractural EDS mutations in FKBP14. clude kyphoscoliosis (either progressive Classical EDS or non-progressive), severe congenital Congenital myopathies, including col- muscle hypotonia with muscle atrophy, lagen VI and collagen XII-associated The prevalence of kEDS-FKB14 is joint hypermobility, and congenital hear- myopathies (myopathic EDS) unknown. ing loss (sensorineural, conductive, or Metabolic disorders mixed) (Representative pictures of the Vascular EDS The Mechanisms of Disease phenotypearegiveninFig.2). Marfan syndrome Loeys–Dietz syndrome FKBP14 encodes FKBP22, a member of the F506-binding family of peptidyl- Craniofacial features prolyl cis–trans isomerases found in the Facial dysmorphisms are not always lumen of the endoplasmic reticulum described and a facial “gestalt” is not KYPHOSCOLIOTIC EDS (ER), where it is thought to catalyze recognizable. Some patients had epi- (kEDS) DUE TO cis–trans-isomerization of peptidyl-prolyl canthal folds (n ¼ 3), micrognathia FKBP22-DEFICIENCY peptide bonds and to accelerate protein (n ¼ 3), hypotelorism (n ¼ 1), square (kEDS-FKBP14) folding, particularly of procollagens nasal root (n ¼ 1), or long-narrow face Synonyms: FKBP14-related EDS, [Galat, 2003]. FKBP22 interacts with (n ¼ 1). FKBP22-deficient EDS types III, VI, and X collagen, but does not Musculoskeletal show direct binding to other types of Kyphoscoliosis was noted at a mean age collagen, such as type I or V collagen of 12 months (range 2–18 months) and The History of Kyphoscoliotic [Ishikawa and Bachinger, 2014]. Defi- was either non-progressive (n ¼ 3) or EDS (kEDS) due to FKBP22- ciency of FKBP22 was shown to result in progressive (n ¼ 7). Orthotic treat- Deficiency (kEDS-FKBP14) enlarged ER cisternsindermal fibroblasts, ment seemed successful in case of Baumann et al. [2012] reported five and an altered assembly of the ECM non-progressive kyphoscoliosis, pro- families with an autosomal recessive [Baumann et al., 2012]. gressive kyphoscoliosis required a RESEARCH REVIEW AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 87

surgical approach. Atlantoaxial insta- the final ability to walk ranged from Marfan syndrome bility was reported in one patient, the myopathic gait, impossibility of Loeys–Dietz syndrome other patients presented uncompli- walking without aids, to a motor cated joint hypermobility without self-sufficiency from 200 m to 1 km. recurrent dislocations/sprains or Muscle biopsy showed pathological BRITTLE CORNEA chronic pain (mean value of Beighton results in six patients, with myopathic SYNDROME (BCS) score 7/9). Height was generally changes and/or fiber atrophy; creatine within the normal range, but at lower kinase was generally within the normal Synonyms: EDSVIB level (10th–25th centile in 4 of 8), two range or slightly elevated and electro- patients had short stature (lower than myographic patterns were usually nor- History of Brittle Cornea third centile). mal at very young age, but sometimes Syndrome Skin and integument myopathic later on [Baumann et al., The most distinctive cutaneous fea- 2012]. Brittle cornea syndrome is a rare autosomal tures in kEDS-FKBP14 are soft skin Visceral complications recessive generalized HCTD, hallmarked (n ¼ 8), hyperextensible skin (n ¼ 7) Large bladder diverticula (n ¼ 3) by a thin and fragile cornea that tends to and hyperkeratosis follicularis or rectal prolapse (n ¼ 1) were perforate spontaneously or after minor (n ¼ 5). Other skin features include reported. trauma. It was originally described as a atrophic scarring, umbilical skin re- constellation of brittle cornea, blue sclerae, dundancy, and multiple merging and red hair [Ticho et al., 1980; Cameron, comedones in a few patients. Four 1993]. On the basis of overlapping clinical Genotype–Phenotype Correlation patients had a hernia, including features, BCS and EDS kyphoscoliosis and Penetrance umbilical hernia in three and inguinal type were previously considered to repre- hernia in one. No genotype–phenotype correlations sent the same disorder [Cameron, 1993]. Ocular features have been described. Penetrance is Because of subtle clinical differences, this Opthalmologic features include myo- presumably complete. claim was later questioned and proven pia, hypermetropia, and blue sclerae. wrong on the basis of biochemical studies. Hearing In kEDS-PLOD1 thereisdeficientactiv- Management Hearing impairment was noted in ity of LH1 whereas in BCS the LH1- most patients. It varied from sensori- Key management guidelines focus on activity is normal [Royce et al., 1990; Al- neural (n ¼ 6), to conductive (n ¼ 2), the musculoskeletal, cardiovascular, Hussain et al., 2004]. or mixed. In one patient, because and auditory systems. No specific Abu et al. [2008] first mapped the of the mixed origin of this sign, guidelines for management of patients BCS gene to a 4.7 Mb region on hearing improved after transtympanic with kEDS-FKBP14 are available. chromosome 16q24 and later identified drains. Guidelines for management of recessive mutations in ZNF469 (MIM Cardiovascular system musculoskeletal problems, skin in- 612078). The single exon gene ZNF469 Vascular complications were de- volvement, cardiovascular involve- encodes a C2H2 zinc finger protein of scribed in an adult patient, who ment, ophthalmologic and dental which the function is yet to fully be presented a celiac artery pseudoa- follow-up, and pregnancy should understood. Because not all BCS patients neurysm rupture at the age of 41 follow those formulated for kEDS- harbored ZNF469 mutations, a second years, and in the older likely affected PLOD1. locus for BCS was suspected. This was sister of a patient, likely affected but Specific management guidelines confirmed by the discovery of mutations without molecular confirmation, should also include hearing evaluation in PRDM5 (MIM 614161) [Burkitt who died due to unspecified aortic at initial diagnosis and annual hearing Wright et al., 2011]. PRDM5 encodes rupture at age 12 years. Celiac artery evaluation. a C2H2 zinc finger protein of the PR/ pseudoaneurysm rupture was ob- SET family of proteins. PRDM5 was first served in a child at age 6 years. characterized as a potential tumor sup- Differential Diagnosis Neuromuscular features and motor pressor gene in the development of development several types of cancer [Watanabe et al., Myopathic signs include muscle hy- Kyphoscoliotic EDS-PLOD1 2007, 2009; Cheng et al., 2010], but has potonia and atrophy, poor head Musculocontractural EDS now been shown to regulate transcrip- control in infancy, and delayed motor Spondylodysplastic EDS tion of collagen and several other ECM development. Muscular weakness Congenital myopathies, including col- genes in a mouse osteoblast cell line seemed to regress with age and all lagen VI and collagen XII-associated (MC3T3) [Galli et al., 2012]. In addition, of the subjects-but one-became able myopathies (myopathic EDS) expression profiling studies suggest that to walk at the mean age of 33 months. Vascular EDS both PRDM5 and ZNF469 might be The outcome was very variable and Classical EDS part of a common pathway regulating the 88 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) RESEARCH REVIEW expression of ECM genes such as several types of cancer and its tumor (Table S1) [Al-Hussain et al., 2004; Abu fibrillary collagens, and several studies suppressor activity by modulating the et al., 2008; Christensen et al., 2010; Khan have suggested a role for ZNF469 Wnt signaling pathway and expression of et al., 2010; Burkitt Wright et al., 2011; normal corneal development [Lu et al., oncogenes [Watanabe et al., 2007, 2009; Al-Owain et al., 2012; Aldahmesh et al., 2010; Vitart et al., 2010; Vithana et al., Meani et al., 2009; Cheng et al., 2010]. Its 2012; Rohrbach et al., 2013; Ramappa 2011; Rohrbach et al., 2013]. involvement invertebrate development has et al., 2014; Avgitidou et al., 2015b; Porter The report of a single BCS family been addressed in zebrafish studies; prdm5 et al., 2015]. Only those patients with with mutations in neither PRDM5 or was shown to be essential for convergent individual clinical and molecular data were ZNF469 suggests the existence of a extension movements through regulation included in the review. Their age ranged third genetics locus, but the large of Wnt signaling [Meani et al., 2009]. between 6 months and 48 years. majority of cases is probably attributable The hallmarks of the condition in to mutations in ZNF469 or PRDM5 the thin, fragile cornea, with an in- Allelic Heterogeneity [Rohrbach et al., 2013]. creased risk for spontaneous corneal The exact prevalence of BCS is The following ZNF469 mutations have rupture (Representative pictures of the unknown. been reported: 13 frameshift mutations: phenotype are given in Fig. 3). c.9611del, p. (Gln3206Argfs23); c.9483 delG, p.(His3162Thrfs20); c.8901_89 Craniofacial involvement Mechanism of Disease 14dup, p.(Glu2972Glyfs50); c.6647 In the experience of the authors, patients ZNF469 encodes ZNF469, a zinc finger delA, p.(Gln2216Argfs19); c.6444 with BCS present with a somewhat protein of unknown function, but lim- delG, p.(Gln2149Serfs51); c.6638del, recognizable facial gestalt, including ited homology (30%) with a number of p.(Leu2210Trpfs27); c.6027delA, p. frontal bossing, high palate, depressed collagens suggests that ZNF469 could be (Gly2011Alafs16); c.5787ins, p.(Gln1 nasal bridge, and/or prominent chin. involved in collagen transcription and 902Profs13); c.5787delG, p.(Gln190 These features may however be mild. fibrillogenesis. Genome-wide associa- 2Argfs6); c.3476del, p.(Gly1159Ala Musculoskeletal system tion studies have consistently associated fs15); c.2234del, p.(Phe717Serfs15); Joint hypermobility was a frequent finding single nucleotide polymorphisms (SNPs) c.2150delT, p.(Phe717Serfs15); and (n ¼ 40), and was sometimes complicated in the vicinity of the ZNF469 locus with c.350dupC, p.(Gln118Thrfs32), five by joint dislocations (n ¼ 6), but appeared central corneal thickness (CTT) [Lu missense mutations: c.10106G>C, p. mostly limited to small joints. Other et al., 2010; Vitart et al., 2010; Vithana (Arg3369Pro); c.10100G>A, p.(Cys frequent features include developmental et al., 2011; Hoehn et al., 2012; Ulmer 3339Tyr); c.7508C>A, p.(Arg2478 dysplasia of the hip (DDH, n ¼ 16), et al., 2012], and pathogenic ZNF469 Glu); c.7424C>A, p.(Arg2478Glu); kyphoscoliosis (n ¼ 22), foot deformities alleles have been identified as the single and c.5686C>G, p.(Pro1896Ala), and (n ¼ 22) including pedes planovalgi and most significant genetic risk factor in the four nonsense mutations: c.5353C>T, p. hallux valgus, and arachnodactyly (n ¼ 6). development of keratoconus (relative risk (Gln1785); c.4258G>T, p.(Glu1420); Fractures (n ¼ 5) and osteopenia/osteo- of 12) [Lechner et al., 2014]. c.3304G>T, p.(Glu1109); and porosis (n ¼ 2) have been reported in a PRDM5 encodes a protein of the c.2029G>T, p.(Gly677). limited number of patients. PR/SET protein family that lacks the The following PRDM5 mutations Skin and integument intrinsic histon methyltransferase activity have been reported: Three frameshift Patients with BCS have a mild skin of other PR-domain containing proteins, mutations: c.1517_1527del11, p. phenotype with soft, velvety (n ¼ 16), but suppresses or activates the transcrip- (Val506Glufs5); c.974delG, p.(Cy- and transparent (n ¼ 11) skin. A hyper- tion of its target genes by recruiting the s325Leufs2); and c.711_714delTGTT, extensible skin was noted in a minority histone methyltransferase G9a and class I p.(Val238Alafs35), one nonsense of patients (n ¼ 3), and is often mild. histone deacetylases [Duan et al., 2007]. mutation (c.1768C>T, p.(Arg590)), Wound healing and easy bruising was InlinewithitsroleinBCS,PRDM5was two missense mutations (c.320A>G, sometimes delayed (n ¼ 4), but atrophic shown to regulate transcription of ECM p.(Tyr107Cys) and c.17T>G, p. scarring was absent. genes, including several collagen genes (Val6Gly)), one splice site mutation Soft connective tissue herniations were and small leucine-rich proteoglycans (c.93þ1G>A), and one multiple-exon reported in five patients. (SLRP) in pre-osteoblastic mouse cells. deletion (exons 9–14) [Burkitt Wright Ocular More specifically, it regulates collagen et al., 2011; Avgitidou et al., 2015a]. BCS is associated with a severe ocular transcription and fibrillogenesis by bind- phenotype. Its most striking feature is a ing collagen genes and maintaining RNA high risk of corneal perforation Clinical Description polymerase II occupancy [Galli et al., (n ¼ 36), either spontaneously or after 2012].The role of PRDM5 does not To provide a comprehensive overview of minor trauma, due to extreme corneal appear to be limited to ECM develop- the clinical phenotype of BCS, we thinning (central corneal thickness ment. Early studies focused on hyper- reviewed the data on 51 patients or CCT: 220–450 mm, normal range methylation of the PRDM5 promotor in (ZNF469:n¼ 32; PRDM5: n ¼ 19) 520–560 mm), and often leading to RESEARCH REVIEW AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 89

present, and in particular may not be striking in adult carriers. Heterozygous carriers may have very mild corneal thinning (e.g., CCT around 500 mm). Keratoconus has also been diagnosed in a young adult, heterozygous for a PRDM5 mutation [Burkitt Wright et al., 2011].

Management Early diagnosis (prior to ocular rupture) is possible and desirable to make anticipatory management as effective as possible. The distinctive syndromic features of BCS, such as DDH, kypho- scoliosis, blue sclerae, soft and/or Figure 3. Clinical findings of a 13 year old female BCS patient homozygous for a translucent skin, and hypercompliant causative mutation in PRDM5:(A) Marfanoid habitus with heigth on P75 and weigth on P3; velvety skin, hematomas lower leg and hallux valgus bilaterally, pectus excavatum. tympanic membranes, serve as impor- Shoulder symmetrical, spine straight. Facial: depressed nasal bridge and/ prominent tant diagnostic clues in the early recog- chin. (B) Blue sclerae. (C) Current protective spectacles after bilateral successful cornea- nition of patients with this condition, crosslinking (Images kindly provided by Dr. Marianne Rohrbach, with permission). particularly where they are the only affected individual in their family. Key management guidelines focus irreversible blindness. Ocular rupture been comprehensively studied. Ap- on the ocular system, with primary frequently occurred at young age, but proximately, one third was affected prevention of corneal rupture by provi- several adults without ocular rupture with hearing loss (n ¼ 19). The most sion of protective polycarbonate eye- have been described. Prior to rupture, frequent type was mixed conductive/ glasses and careful screening of vision, visual acuity in BCS patients was often sensorineural hearing loss (n ¼ 11) with but also hearing. An overview of clinical affected by keratoconus and/or kerato- a predominance of conductive hearing management strategies for BCS patient globus (n ¼ 27) and high myopia loss in childhood. Both inter- and is given in Burkitt Wright et al. [2013]. (n ¼ 17). The most consistent ophthal- intrafamilial variability with respect to Guidelines for management of mic feature was blue sclerae (n ¼ 49). age of onset and progression of deafness musculoskeletal problems, skin involve- Secondary glaucoma was reported in were observed. The combined hearing ment, cardiovascular problems, and several patients (n ¼ 5), particularly those loss and decreased visual acuity often led pregnancy should follow those formu- with extensive corneal damage following to severe sensorineural disability. lated for other forms of EDS (for rupture. Retinal detachment and neo- Cardiovascular reference: See “management guidelines vascularization were both reported once. Cardiovascular defects were uncom- for the classical Ehlers–Danlos syn- Of note and in contrast to kEDS- mon, but mitral valve insufficiency has drome,” by Bowen et al., this issue). PLOD1, microcornea was never ob- been described (n ¼ 3). Notably and in served. Megalocornea, on the other contrast to kEDS, vascular and visceral Differential Diagnosis hand, was reported in three cases. BCS fragility has not been described in the usually presents as a generalized connec- context of BCS. tive tissue disorder with multi-tissue Kyphoscoliotic EDS involvement, but one adult case with Spondylodysplastic EDS Genotype–Phenotype Correlation isolated ocular findings has been de- Musculocontractural EDS and Prevalence scribed [Khan et al., 2012]. This suggests OI that recessive mutations in ZNF469 and There is currently no evidence of a clear PRDM5 could be a rare cause of isolated genotype–phenotype correlation: All keratoconus or corneal rupture. It should types of mutations scattered across SPONDYLODYSPLASTIC be noted however that the majority of both genes appear to cause indistin- EDS DUE TO BCS cases has been reported in ophthal- guishable clinical phenotypes. B4GALT7-DEFICIENCY mological journals, and that extraocular Penetrance is presumably complete. (spEDS-B4GALT7) findings might be underestimated. Individuals heterozygous for BCS- Hearing associated mutations have been reported Synonyms: EDS progeroid type, EDS Hearing loss has been recognized as a to have blue sclerae and small joint progeroid type 1, EDS with short stature predominant feature, but has not yet hypermobility. These are not always and limb anomalies 90 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) RESEARCH REVIEW

The History of Spondylodysplastic TheprevalenceofspEDS-B4GALT7 in fibroblasts harboring this mutation. EDS due to b4GalT7-Deficiency is unknown. They showed a reduced sulfation degree (spEDS-B4GALT7) of HS, delayed in vitro wound repair, and increased fibronectin adhesion, impaired Hernandez et al. [1979, 1981, 1986] Mechanism of Disease actin stress fiber formation, delayed reported five patients with EDS-features B4GALT7 encodes galactosyltransfer- collagen gel extraction with reduced and features of early aging, including ase I (b1,4-galactosyltransferase 7 or formation of pseudopodia and filopodia, wrinkled facies, significant growth failure, b4GALT7), a Golgi-resident enzyme, and finally diminished formation of fine/curly hair, periodontitis, bilateral that is involved in synthesizing the GAG collagen suprastructures. cryptorchidism, apparent intellectual def- linker region of proteoglycans. GAGs Bui et al. [2010] studied the icit. Kresse et al. [1987] reported a patient are long, unbranched polysaccharides ability of mutant b4GalT7 harboring with a similar phenotype, and showed its composed of repeating disaccharide either the homozygous p.(Arg186Asp), skin fibroblasts converted only half of units, which consist of alternating p.(Leu206Pro), and p.(Arg270Cys) the core protein of the small dermatan uronic acids and amino sugars. Most substitution to prime GAG biosynthesis sulfate proteoglycan decorin to a mature GAGs are covalently attached to specific in recombinant cells. Whereas the glycosaminoglycan (GAG) bearing pro- serine residues of core proteins via a p.(Arg185Asp) did not affect GAG teoglycan. This defective proteoglycan defined linker region of xylose, two biosynthesis severely, the p.(Leu206Pro) biosynthesis was shown to result from galactoses and one glucuronic acid, thus mutation led to complete inhibition and biallelic mutations in B4GALT7,encod- assembling to proteoglycans (PG). Al- the p.(Arg270Cys) to significant reduc- ing galactosyltransferase I [Quentin et al., ternative addition of N-acetylglucos- tion of GAG biosynthesis. Molecular 1990; Okajima et al., 1999]. Cartault et al. amine or N-galactosylglucosamine to modeling predicted that the p.(Leu206- [2015] detected a homozygous missense the terminal glucuronic acid of the Pro) mutation located in a conserved mutation (c.808C>T, p.(Arg270Cys)) in linker region leads to the formation of secondary structure affected the B4GALT7 in a series of 22 patients with heparan sulfate (HS) or chondroitin/ overall structure of the protein, whereas Larsen of Reunion Island syndrome dermatan sulfate (CS/DS), respectively p.(Arg186Asp) is located in a less (LRS), a skeletal dysplasia with clinically (Fig. 4). Cosynthetic modifications such structural critical domain and the p. overlaps with spEDS-B4GALT7. as epimerization and sulfation result in (Arg270Cys) in the vicinity of the In view of the major clinical overlap the formation of diverse motifs in the substrate active site. of EDS caused by B4GALT7 mutations GAG chains, that allow binding of a with the phenotypes caused by variety of ligands, thus regulating B3GALT6 and by SLC39A13 muta- Allelic Heterogeneity growth factor signaling, cell adhesion, tions, these three conditions are now proliferation, differentiation, and motil- In total, seven missense and two frame- grouped within the same clinical entity ity. The b1,4-galactosyltransferase 7 is a shift mutations have been reported (“Spondylodysplastic EDS”) in the new glycosyltransferase catalyzing the trans- for B4GALT7. The c.808C>T, EDS classification. fer of the first galactose onto the xylose p.(Arg270Cys) is most frequent. It has residue of the PG core protein-GAG once been reported in homozygous state, linker region. once in compound heterozygosity with In view of the major clinical Seidler et al. [2006] studied fibro- c.122T>C, p.(Leu41Pro), and once in blasts of a patient harboring the homozy- compound heterozygous state with overlap of EDS caused gous p.(Arg270Cys) substitution and c.421C>T, p.(Arg141Trp). Further- by B4GALT7 mutations showed reduced b1,4-galactosyltransfer- more, the c.557C>A, p.(Ala186Asp) ase 7 activity, reduced glycanation of mutation was identified in compound with the phenotypes caused decorin and biglycan, and reduced heterozygosity with the c.617T>G, p. by B3GALT6 and by epimerization of the decorin GAG chain. (Leu206Pro) mutation, the c.641G>A, SLC39A13 mutations, In addition, morphological alterations p.(Cys214Tyr) with c.277dup, p. and intracellular accumulation of degra- (His93Profs73) and finally a homozygous these three conditions dative vacuoles were seen in the patient’s c.970T>A, p.(Cys324Ser) was reported. are now grouped within the fibroblasts. Analysis of the collagen fibrils All mutations are localized in the showed that the b4GalT7-deficient cells luminal catalytic domain, except for the same clinical entity had an altered suprastructure, no banded p.(Leu41Pro), which is localized in (“Spondylodysplastic EDS”) collagen fibrils and an altered ratio of a1– the transmembrane domain. a b in the new EDS 2 collagen chains. Finally the 4GalT7- deficient cells showed reduced prolifera- Clinical Description classification. tion rates compared to controls. Gotte et al. [2008] analyzed structural alterations At present seven patients from six in HS and their functional consequences families with molecularly confirmed RESEARCH REVIEW AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 91

Figure 4. Biosynthesis of the HS and CS/DS GAG chains is initiated by the attachment of a common tetrasaccharide linker region to a specific serine residue of the core protein. This linker region is synthesized by the stepwise action of specific enzymes: Xylosyltransferase I/ II (encoded by XYLT1 and XYLT2, respectively), galactosyltransferase I (b4GalT7, encoded by B4GALT7) and II (b3GalT6, encoded by B3GALT6), and glucuronyltransferase I (encoded by B3GAT3). Following completion of the linker region, the addition of the next residue determines whether HS or CS/DS is synthesized. CS is formed by the alternating addition of N-acetylgalactosamine (GalNAc) and glucuronic acid (GlcA) residues, which are subsequently modified by several sulfotransferases. The formation of DS requires the epimerisation of GlcA residues to iduronic acid (IdoA), an event catalyzed by dermatan sulfate epimerases I and II (DS-epi1 encoded by DSE and DS-epi2 encoded by DSEL, respectively), and subsequent 4-O-sulfation of the adjacent GalNAc residue by dermatan 4-O- sulfotransferase-1 (D4ST1, encoded by CHST14). Defects in the initiation and modification of the GAG chains are associated with different EDS subtypes (indicated in black boxes). Defects in linker enzymes B4GALT7 and B3GALT6 lead to spEDS and affect the formation of both HS and CS/DS whereas alterations in DSE and CHST14 result in mcEDS and compromise the formation of DS.

spEDS-B4GALT7 have been identified radio-ulnar synostosis, and intellectual Craniofacial features (Table S1). The ages at publication disability. The most consistent craniofacial fea- ranged from 2 years to 33 years [Kresse tures include triangular face (n ¼ 7), et al., 1987, Faiyaz-Ul-Haque et al., Reproductive, including pregnancy wide-spaced eyes (n ¼ 6), proptosis 2004, Guo et al., 2013, Arunrut et al., Antenatal ultrasonography showed (n ¼ 6), narrow mouth (n ¼ 5), low- 2016, Salter et al., 2016]. The clinical asymmetrical ventriculomegaly in one set ears (n ¼ 5), sparse scalp hair (n ¼ 4), features reported in the patients with patient and severe intrauterine growth abnormal dentition (n ¼ 4), flat face LRS are not included in this review. retardation in another patient. No (n ¼ 4), wide forehead (n ¼ 4), blue The hallmarks of the disorder pregnancies have been reported in sclerae (n ¼ 3), cleft palate/bidif uvula include short stature, muscle hypotonia, affected individuals. (n ¼ 2), high palate (n ¼ 1), small jaw 92 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) RESEARCH REVIEW

(n ¼ 1). Of note, none of the patients hypermetropia, pendular nystagmus, Management was described to have progeroid coloboma of iris and optic nerves, and No specific guidelines for management features. posterior subcapsular cataracts. of patients with spEDS-B4GALT7 are Musculoskeletal features Dental features available. Management guidelines The most consistent musculoskeletal Yellowish teeth with defective enamel should be tailored to the individual’s features include severe growth retarda- was reported in one patient. specific problems and should follow tion (n ¼ 7), present at birth but Hearing those formulated for other forms of progressing later on, generalized joint Mild conductive hearing loss was EDS. hypermobility (n ¼ 7), which was reported in one patient, likely related Specific management guidelines noted to be quite severe in several to cleft palate. may include: patients, bowing of limbs (n ¼ 5), and Neuromuscular features and motor foot deformities (pes planus (n ¼ 4), pes development equinovarus (n ¼ 1)). Other reported Muscle hypotonia was reported in all Musculoskeletal: symptoms include dislocations/sublux- patients but ranged from mild to very – At diagnosis a whole body skeletal ations (n ¼ 3), bilateral elbow contrac- severe. Three patients were reported to survey and bone densitometry studies tures or limited elbow movement be “floppy” at birth, one had mild are recommended (n ¼ 3), syndactyly (n ¼ 2), pectus car- congenital hypotonia, and the other – In patients with recurrent fractures, inatum (n ¼ 2), scoliosis (n ¼ 1), long three were reported to be mildly bisphosphonate therapy should be fingers (n ¼ 4), thin fingers with bul- hypotonic later in childhood. Delayed considered, with treatment protocols bous tips and broad thumbs (n ¼ 1). motor development was reported in 6/7 following those formulated for pa- One patient with low-impact rib and patients, but none of them remained tients with OI vertebral fractures in infancy received non-ambulatory. In none of the re- bisphosphonate treatment, with im- ported patients, a muscle biopsy was provement of bone pain and muscle taken. Differential Diagnosis function [Salter et al., 2016]. Neurological features and neuro- Skeletal X-ray imaging development Reported abnormalities include: Five patients were reported to have mild Spondylodysplastic EDS-B3GALT6 Radio-ulnar synostosis (n ¼ 6), meta- intellectual deficit. This included Spondylodysplastic EDS-SLC39A13 physeal flaring (n ¼ 4), osteopenia speech delay in three patients, mild Musculocontractural EDS (n ¼ 4), radial head subluxation or learning difficulties in one, and a kEDS (PLOD1 and FKBP14) dislocation (n ¼ 3), short clavicles with somewhat more severe delay in one Chondrodysplasia broad medial ends (n ¼ 3), anterior patient. splaying of ribs (n ¼ 2), swedish key feature of the femur (n ¼ 1), bulbous SPONDYLODYSPLASTIC appearance of distal phalangeal tufts Genotype–Phenotype Correlation EDS DUE TO (n ¼ 1), coxa valga (n ¼ 1), reduced and Penetrance B3GALT6-DEFICIENCY height of vertebral bodies (n ¼ 1). (spEDS-B3GALT6) Skin and integument Although marked differences in ability Hyperextensible (n ¼ 6), single trans- to prime GAG biosynthesis have Synonyms: EDS progeroid type 2 verse palmar crease (n ¼ 5), loose skin been described for different missense (n ¼ 3), atrophic scarring (n ¼ 3), soft substitutions (see “Mechanism of The History of b3GalT6-Deficient and doughy skin (n ¼ 2), reduced Disease” section), no genotype– EDS subcutaneous fat (n ¼ 1), prominent phenotype correlations have emerged scalp veins (n ¼ 1), prominent venous to date. It remains also unclear why In 2013, two independent research pattern on chest (n ¼ 1). the p.(Arg270Cys) is associated with studies identified biallelic mutations in Ocular features either an EDS phenotype or with B3GALT6, encoding b3GalT6 (galacto- Hypermetropia at very young age was LRS. Cartault et al. [2015] hypothe- syltransferase II or b1,3-galactosyltrans- reported in 5/7 patients. In most of sized this could be due to the high ferase 6), in two different conditions. them, it was severe. One patient was levels of homozygosity among the Nakajima et al. [2013] identified operated at age 3 months for unilateral LRS population and modification B3GALT6 mutations in seven Japanese ptosis. He also had astigmatism and by interaction with other variants families with spondyloepimetaphyseal intermittent exotropia. Small optic in close linkage disequilibrium to dysplasia with joint laxity type 1 nerves (n ¼ 1), and strabismus (n ¼ 1) B4GALT7. (SEMD-JL1 or SEMD-JL Beighton were reported. Arunrut et al. Penetrance is presumably complete. type) by whole exome sequencing. In [2016] reported a patient with congen- Obligate carriers display no overt clini- three other families with a phenotype ital cloudy cornea, bilateral high cal symptoms. resembling b4GalT7-deficient EDS, RESEARCH REVIEW AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 93 targeted B3GALT6 sequencing subse- collagen fibril formation, as well as in (n ¼ 2 families), p.(Glu265Asp) (n ¼ 2 quently identified causal mutations in all various physiological functions of con- families), p.(Ser309Thr) (n ¼ 2 families), of them. Coincidently, Malfait et al. nective tissue, such as cicatrisation. and p.(Glu174Alafs266) (n ¼ 2 fami- [2013] identified B3GALT6 mutations Nakajima et al. [2013] showed that a lies). The p.(Met1?) was reported in five in three unrelated families with a pleio- recombinant mutant, lacking the initia- families. tropic EDS-like connective tissue disor- tion codon (p.Met1) produced a trun- Other reported missense mutations der, characterized by severe cated protein that was mislocalized to include: p.(Val61Leu), p.(Ser65Gly), p. kyphoscoliosis, joint hypermobility and the cytoplasm and nucleus, presumably (Asp144Asn), p.(Asp156Asn), p.(Ser158- contractures, multiple early-onset frac- inactive. Also using recombinant pro- Tyr), p.Tyr182Cys, p.(Pro211Ser), p. tures, SEMD, skin fragility, and intellec- teins, they reported that both enzyme (Gly217Ser), p.(Arg256Trp), p.(Ar- tual disability. Following the mutants (p.(Ser65Gly), p.(Pro67Leu)) g261His), p.(Cys300Ser), p.(Tyr310Cys), identification of B3GALT6 as the causal were inactive, emphasizing the role of and p.(Pro318Leu). gene for SEMD-JL1, Vorster et al. the conserved N-terminal end of the Other reported frameshift muta- [2015] identified the same mutations catalytic domain in the functional tions are: p.(Ile76Thrfs202), p.(Ala108 and a novel p.(Thr79Ala) mutations, all activity of the enzyme. Other mutants Glyfs163), p.(Asp118Alafs160), p. located in or in the vicinity of the stem studied, harboring mutations in the (Met 139Ala141del), p.(Phe180Se region, in eight prototype South African central or C-terminal part of the rfs118), and p.(Arg197Alafs81). Fi- families. A few additional patients with an catalytic domain, that is, p.(Asp156Asn) nally, p.(Arg179_Arg180dup), and p. EDS/SEMDJL1 overlap phenotype have and p.(Cys300Ser), also exhibited se- (Ala66_Arg84del) were each reported also been reported [Sellars et al., 2014; verely impaired enzyme activity except once. Ritelli et al., 2015; Alazami et al., 2016]. for p.(Glu174Asp) (50% loss in activity). Out of 36 families, 25 were com- In view of the major clinical overlap Importantly, in the lymphoid cells of pound heterozygous and 11 were homo- of EDS caused B3GALT6 mutations, three SEMD-JL1 patients, the amount zygous. Except for the homozygous p. with the phenotypes caused by of HS was reduced whereas CS/DS was (Arg179_Arg180dup), compound het- B4GALT7 and by SLC39A13 muta- increased (2–5-fold). The molecular erozygosity always included a missense tions, these three conditions are grouped basis of these observations remains to mutation on one of the two alleles. within the same clinical entity (“Spon- be established. In two patients harboring Four highly deleterious mutations dylodysplastic EDS”) in the new EDS a compound deletion and catalytic are found outside the catalytic domain, classification. domain mutation [Ritelli et al., one mutant lacking the initiation Met The exact prevalence of spEDS- 2015] showed by micro-array transcrip- codon (p.(Met1?), one mutant in the B3GALT6 is unknown. tome and immunofluorescence analyses cytoplasmic tail (p.(Arg6Trp)), and two a reduced expression of cartilage oligo- in the stem region (p.(Ser65Gly) and p. meric matrix protein (COMP) and (Pro67Leu)). Other mutations are lo- Mechanisms of Disease osteopontin (SPP1). Interestingly, these cated in the luminal catalytic domain. B3GALT6 encodes galactosyltransfer- authors reported reduced expression and ase II (b1,3-galactosyltransferase 6 or disassembly of HS GAG chains and of Clinical Description b3GalT6), a membrane Golgi-resident the HS-matrix PG perlecan. enzyme, that catalyzes the addition of At present, 47 patients from 36 families the third galactose onto the second with molecularly confirmed spEDS- Allelic Heterogeneity galactose of the GAG linker region (for B3GALT6 have been identified (Table introduction, see also “Mechanism of In total, 22 missense mutations, eight S1). The ages at publication ranged from Disease for spEDS-B4GALT7” sec- frameshift mutations, two in-frame dele- birth to 33 years [Malfait et al., 2013; tion). Malfait et al. [2013] showed, using tions, two start codon mutations, one Nakajima et al., 2013; Sellars et al., cultured dermal fibroblasts, that GAG splice site, and one in-frame duplication 2014; Ritelli et al., 2015; Alazami et al., synthesis and activity was strongly have been reported for B3GALT6. 2016; Honey, 2016, Van Damme et al., reduced by the homozygous or com- The most frequent mutation is the p. unpublished]. Detailed clinical data are pound p.(Asp207His) mutation found in (Pro67Leu) substitution, which is fre- available for 36 patients. This overview two patients, as well as by the homozy- quent among South Africaner patients, includes the SEMD-JL1 patients re- gous p.(Gly217Ser) mutation present in but which was also reported in a ported by Nakajima et al. [2013], but one of the patients. Expression of both Vietnamese patient, followed by the p. not those reported by Vorster et al. HS and CS GAG chains was affected in (Thr79Ala) mutation, identified seven [2015], since detailed clinical data of the these patients. This study also showed times among South Africaner patients. latter patients were not available. that the GAG defects were associated Other recurrent substitutions include p. The hallmarks of the disorder with abnormal collagen structure and (Arg232Cys) (n ¼ 4 families), p.(As- include: (1) Characteristic craniofacial delayed migration in a wound healing p207His) (n ¼ 3 families), p.(Phe186- features, (2) kyphoscoliosis, (3) joint assay, emphasizing the role of GAG in Leu) (n ¼ 3 families), p.(Arg6Trp) hypermobility, mostly of distal joint, 94 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) RESEARCH REVIEW

(4) joint contractures, (5) short stature, develop during the first 24 months of atlanto-axial subluxation. In two pa- (6) muscle hypotonia, (7) osteoporosis age, and is usually progressive. Severe tients, the cervical instability was asso- with multiple fractures, (8) radiographic short stature was frequently reported ciated with hydrocephalus [VanDamme skeletal abnormalities compatible with (n ¼ 26). While stature may be short at et al., unpublished]. SEMD, and (9) intellectual disability birth, growth restriction usually evolved Skin and integument (Representative pictures of the pheno- postnatally. Patients present joint hy- The skin was usually described as type are given in Fig. 5). permobility (n ¼ 27), either generalized hyperextensible or loose (n ¼ 19), soft or restricted to distal joints, and and doughy (n ¼ 18), and/or thin or Reproductive, including pregnancy sometimes complicated by dislocations translucent (n ¼ 8). In 10 patients, Antenatal ultrasound abnormalities of large and small joints (n ¼ 14). Joint increased palmar wrinkling of the hands were reported in eight pregnancies. contractures were frequent (n ¼ 21); was reported. Atrophic scarring (n ¼ 5) Reported abnormalities included pre- they were either congenital, such as and easy bruising (n ¼ 3) were rarely natal kyphoscoliosis (n ¼ 2), shortening talipes equinovarus (n ¼ 21), and/or reported. Other reported skin features of tubular bones (n ¼ 2), contractures of evolved postnatally, and mostly affected include wrinkling of the skin on the wrists and clubfeet (n ¼ 1), oligohy- fingers (e.g., adducted thumbs, camp- dorsum of the hands (n ¼ 1), and loose, dramnios (n ¼ 1); polyhydramnios todactyly), wrists, elbows, feet, and redundant skin folds on wrists and (n ¼ 1), decreased fetal movements knees. Pectus deformities, either car- ankles (n ¼ 1). Bilateral inguinal hernia (n ¼ 1), and small cerebellum (n ¼ 1). inatum or excavatum, were reported in was described in one patient. For two siblings, the pregnancy was 8 patients. A total of 13 patients had a Ocular involvement terminated around 22 weeks of gesta- history of multiple spontaneous bone Refractive errors were reported in five tion because of “severe skeletal fractures and 12 had documented patients. Other ocular problems include dysplasia.” generalized osteoporosis or osteopenia. microcornea (n ¼ 1); intermittent glau- Reported perinatal complications in- Finger shapes were characteristically coma (n ¼ 1); congenital corneal cloud- clude breech presentation (n ¼ 3), con- described as “slender,”“arachnodac- ing with sclerocornea (n ¼ 1), and genital kyphoscoliosis (n ¼ 3), tyly,” or “tapering,” with “spatulate or repetitive retinal detachment (n ¼ 1). congenital bilateral hip dislocation broad distal phalanges” (n ¼ 13). One patient had optic nerve atrophy. (n ¼ 1), bilateral clubfeet (n ¼ 3), con- Skeletal X-ray imaging Dental involvement genital fractures (n ¼ 1), cloudy cornea Reported abnormalities include: Short Dental involvement was reported in a (n ¼ 1), unilateral unilateral agnesis of ilia (n ¼ 17), platyspondyly (n ¼ 16) number of patients and includes tooth the kidney (n ¼ 1), open foramen ovale (described as becoming less conspicu- discoloration (n ¼ 5), hypoplastic teeth (n ¼ 1), cleft palate (n ¼ 3), Pierre– ous over time by Nakajima et al. (n ¼ 4), and early decay of teeth (n ¼ 1). Robin sequence (n ¼ 1), severe con- [2013]), ovoid vertebra (n ¼ 1), meta- Hearing genital muscle hypotonia or floppy physeal flaring (n ¼ 13), osteopenia Hearing impairment with a conductive infant (n ¼ 2), and a cerebral hemor- (n ¼ 12), anterior beak of vertebral component was described in one patient. rhage following vaginal delivery (n ¼ 1) body (n ¼ 12), prominent lesser tro- Cardiovascular system Craniofacial features chanter (n ¼ 11), elbow malalignment Two patients had a dilation of the Characteristic craniofacial features in- (n ¼ 10), epihyseal dysplasia femoral ascending aorta in infancy, two patients clude blue sclerae (n ¼ 24), frontal head (n ¼ 10), metacarpal shortening had a mitral valve prolapse, two patients bossing (n ¼ 21), midfacial hypoplasia (n ¼ 7), overtubulation (n ¼ 6), radial had an atrial septum defect, one patient (n ¼ 20), downslanting palpebral fis- head dislocation (n ¼ 5), advanced car- had a patent ductus arteriosus, and one sures (n ¼ 4), low-set, sometimes pos- pal ossification (n ¼ 5), bowing of long patient had a patent foramen ovale. Two teriorly rotated, ears (n ¼ 19), bones (n ¼ 3), narrowing of long bones patients suffered from a cerebral hem- prominent eyes/proptosis (n ¼ 15), (n ¼ 3), acetabular dysplasia (n ¼ 2), orrhage. One patient was reported with long philtrum (n ¼ 15), micrognathia vertebral listhesis (n ¼ 2), radioulnar severe bruising, spontaneous scalp he- (n ¼ 11), depressed nasal bridge (n ¼ 9), synostosis (n ¼ 1), craniosynostosis matomas, and multiple hemorrhagic small nose (n ¼ 6), tooth discoloration (n ¼ 1), coxa valga (n ¼ 1), coxa valga blisters. (n ¼ 5), hypoplastic teeth (n ¼ 4), sparse (n ¼ 1), wedged vertebral bodies Gastro-intestinal system hair (n ¼ 4), high arched palate (n ¼ 3), (n ¼ 1), bony fusion of proximal ends Constipation was described in one prominent chin (n ¼ 2), cleft palate of ulna and radius (n ¼ 1), carpal fusion patient, and gastro-oesophageal reflux (n ¼ 3), Pierre–Robin sequence (n ¼ 1). One patient had a severe in another. (n ¼ 1), asymmetrical skull (n ¼ 2), torticollis at 12 months due to a Urogenital system large anterior fontanel (n ¼ 1), short posterior displacement of the vertebral Hydronephrosis was detected in one neck with low hairline (n ¼ 1) column, with atlanto-occipital and patient, unilateral renal agenesis in one, Musculoskeletal system atlanto-axial dislocation. Two patients dilatation of renal pelvis ureterocoele in Kyphoscoliosis is very frequent had an invagination of the atlas into one and bladder atonia in one. One (n ¼ 32), and may be congenital or the foramen magnum and anterior patient developed a Wilms tumor. RESEARCH REVIEW AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 95

Figure 5. Clinical characteristics of patients with spEDS-B3GALT6. Facial characteristics at 2 years of age (A), 6 years of age (B) and 2 months of age (younger sister in panel C) include long face with mild micrognatia in infancy,proptotic eyes with shallow orbits and blue tint to the sclerae. The palpebral fissures are downslanting. The nasal bridge is broad and there is a low nasal ridge. Chest shows moderate pectus excavatum. The limbs show significant hyperextensibility, reduced movement of distal joints that leads to absent creases of the distal interphalangeal joints (D), increased creases of the skin of the palms (D) and club feet (E). There is muscle hypotonia, which is compounded by the hyperextensibility of the joints and makes anti-gravitational movements difficult (F) (Images kindly provided by Dr. Roberto Mendoza-Londono, with permission).

Pulmonary involvement non-ambulatory during childhood. In are available. Management guidelines ’ Several pulmonary problems were three patients, feeding problems, due to should be tailored to the individual s reported: Three patients were re- muscle hypotonia, were reported. specific problems and should follow ported with restrictive lung disease; Neurological features and neuro- those formulated for other forms of in one of them this was due to lung development EDS. hypoplasia and a diaphragmatic her- Two patients were reported with brain Specific management guidelines nia. Respiratory distress due to lung atrophy, and two patients had hydro- may include: hypoplasia was reported in another cephalus. patient. Other reports included mild Mild to moderate cognitive delay was Musculoskeletal: respiratory deficiency (n ¼ 1), sleep suggested in 11 patients. – At diagnosis a whole body skeletal apneu (n ¼ 1), chronic aspiration and survey and bone densitometry studies pneumonia (n ¼ 1), and asthma are recommended (n ¼ 1). – In patients with recurrent fractures, Genotype–Phenotype Correlation Neuromuscular features and motor bisphosphonate therapy should be and Penetrance development considered, with treatment protocols Muscle hypotonia was reported in 16 No genotype–phenotype correlations following those formulated for pa- patients, and four of them had docu- have been described. tients with OI mented muscle hypoplasia. Gross motor Penetrance is complete. Obligate – Physical therapy for the contractures developmental delay, with a delay in carriers display no overt clinical and muscle hypotonia, and monitor- sitting and walking, was described in symptoms. ing for any signs of feeding or seven patients mainly because of muscle respiratory difficulties, in particular hypotonia. The age at which unassisted nocturnal hypoventilation. If the Management walking occurred in patients who latter is present then assisted non- accomplished ranged between 2 and No specific guidelines for management interventional ventilation at night 7 years. Three patients remained of patients with spEDS-B3GALT6 may be indicated 96 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) RESEARCH REVIEW

Cardiovascular system: patients presented with EDS-like fea- eight transmembrane domain proteins – Measurement of aortic root size and tures, short stature, finger contrac- known to transport zinc and/or other assessment of heart valves by echo- tures, distinct radiological features, metal ions from the extracellular space cardiogram at the time of diagnosis or elevated ratios of lysyl pyridinoline or from the organellar lumen into the by age 5 years. to hydroxylysyl pyridinoline (LP/HP) cytoplasm [Eide, 2006]. Mutant ZIP13 – Echocardiogram at 5-year intervals, (but to a lesser degree then in EDS proteins are easily degraded, and þþ even if the initial echocardiogram is type VIA), and underhydroxylated disturb the intracellular Zn homeo- normal collagens in culture despite normal stasis [Bin et al., 2014a,b]. It has been – Further vascular surveillance ought in vitro activities of lysyl hydroxylase shown that ZIP13 loss-of-function to be considered and prolyl 4-hydroxylase, respectively. leads to a generalized disturbed hy- The underhydroxylation was a gener- droxylation of lysyl and prolyl residues alized process which occurs along the in collagen a chains [Giunta et al., þþ entire molecule, and is not confined to 2008b]. Since Zn was found to be Differential Diagnosis specific residues as shown by tandem an effective competitive inhibitor with þþ mass spectrometry of the a1(I)- and respect to iron (Fe ) for prolyl Spondylodysplastic EDS-B4GALT7 a2(I)-chain derived peptides of colla- 4-hydroxylase and for lysyl hydroxy- Spondylodysplastic EDS-SLC39A13 gen type I and involves at least lase, it was initially suggested that the Kyphoscoliotic EDS (PLOD1 and collagen types I and II [Giunta et al., generalized underhydroxylation of col- þþ FKBP14) 2008a]. Subsequently, Fukada et al. lagen was likely due to Zn overload þþ þþ Musculocontractural EDS [2008] reported a third family with in the ER. Zn competes with Fe OI two affected siblings presenting with for binding to lysyl hydroxylase, Cutis laxa syndromes similar clinical findings who were prolyl 4-hydroxylase, and prolyl 3- Chondrodysplasia homozygous for a missense mutation hydroxylase, thus impairing hydroxyl- Congenital myopathies in SCL39A13 [Fukada et al., 2008]. ation of lysyl and prolyl residues The authors furthermore generated a [Giunta et al., 2008b]. Further studies Slc39a13/ knockout mouse that however have disputed this hypothesis. recapitulated defects observed in the One study proposed that trapping of SPONDYLODYSPLASTIC þþ patients, thereby demonstrating that Zn in vesicular stores reduces the EDS DUE TO mutations in SLC39A13 cause Spon- availability of Zn in the ER and other SLC39A13 MUTATIONS dylocheiro-dysplastic EDS [Fukada cellular components and induces ER (spEDS-SLC39A13) et al., 2008]. stress [Jeong et al., 2012]. Another Synonyms: spondylocheirodysplastic In view of the clinical overlap of study showed that ZIP13 is required for EDS (SCD-EDS) EDS caused by SLC39A13 mutations, full activation of BMP/TGF-b signal- with the phenotypes caused by ing via regulation of the intracellular B3GALT6 and by B4GALT7 muta- localization of Smad proteins in con- History of Spondylodysplastic EDS tions, these three conditions are grouped nective tissue forming cells; this study due to SLC39A13 Mutations within the same clinical entity (“Spon- put forward the hypothesis that incom- (spEDS-SLC39A13) dylodysplastic EDS”) in the new EDS plete activation of BMP/TGF-b sig- Giunta et al. [2008b] reported a “new” classification. naling is responsible for the observed clinical entity caused by a mutation in The exact prevalence of spEDS- phenotype [Fukada et al., 2013]. the zinc transporter gene SLC39A13. SLC39A13 is unknown. The clinical features of six patients Allelic Heterogeneity from two unrelated consanguineous Mechanisms of Disease families were similar to those of Three mutations have been identified so kEDS-PLOD1, but lack (kypho)scolio- SpEDS-SLC39A13 is caused by ho- far in a total of eight patients from three sis and in addition presented distinct mozygous loss-of-function mutations independent families. phenotypic components, including in the zinc transporter gene A homozygous 9-bp in-frame de- platyspondyly, osteopenia, short stature SLC39A13. This gene encodes the letion in exon 4, c.483_491del9 was and widened metaphyses, tapered fin- homodimeric transmembrane Zrt/irt- found in two unrelated consanguineous gers, and a tendency to develop con- like protein 13 (ZIP13) protein, a families originating from North-West- tractures of small joints. Because of member of the SLC39A/ZIP family ern Iraq and the Southeastern part of þþ features affecting mainly the spine that regulates the influx of zinc (Zn ) Turkey, respectively. At the protein (spondylo) and the hands (cheiro) this into the cytosol [Bin et al., 2011]. This level, the c.483_491del9 mutation leads variant was termed the Spondylocheiro- protein is a member of the LIV-1 to the deletion of the highly conserved dysplastic form of EDS (SCD-EDS) subfamily of ZIP zinc Transporters amino acid residues Phe-Leu-Ala from [Giunta et al., 2008b]. The six (LZT), a highly conserved group of the third transmembrane domain of RESEARCH REVIEW AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 97

ZIP13 [Giunta et al., 2008b]. The widening of the ends with relative involvement, cardiovascular problems, second mutation, a homozygous mis- narrowing of the diaphyses and flat and pregnancy should follow those sense variant c.221G>A, p.(Gly64Asp) epiphyses of metacarpals and phalanges, formulated for other forms of EDS (for [Bin et al., 2011] has been identified in small ileum, mildly flat proximal epiph- reference: See “management guidelines two siblings from Portugal [Fukada yses, and short and wide femoral necks. for the classical Ehlers–Danlos syn- et al., 2008]. It is localized in the second Skin and integument drome,” by Bowen et al., this issue). transmembrane domain of SLC39A13 The most distinctive cutaneous features and is conserved through all vertebrate were thin, velvety and fragile, easy species down to fish. bruisable skin with atrophic, cigarette MUSCULOCONTRACTURAL paper-like scars. The skin of the palm of EDS (mcEDS) the hands was wrinkled in all affected Clinical Description Synonyms: Adducted thumb, clubfoot, individuals. In some individuals the skin and progressive joint and skin laxity To date, eight patients with spEDS- was translucent particularly on legs and syndrome; Adducted thumb-club foot SLC39A13 from three independent feet with easily visible veins. syndrome (ATCS); Dundar€ syndrome; families have been described: Three Ocular features EDS Kosho type (EDS-KT); EDS pediatric (<12 years), two adolescents Opthalmologic features included myo- musculocontractural type 1 (EDS- (12.5 and 14.5 years), and three adults pia, hyperopia, astigmatism, and blue MC); EDS type VIB, EDS6B; Distal (>20 years) (Table S1) [Fukada et al., sclerae. arthrogtyposis with peculiar facies and 2008, Giunta et al., 2008b]. Dental features hydronephrosis The hallmarks of the disorder Hypodontia of one or few teeth in include: (1) Moderate short stature; (2) permanent dentition or abnormally hyperelastic, velvety, thin skin with an shaped teeth were described in all The History of easily visible venous pattern, and bruis- affected individuals, but one. Musculocontractural EDS ability which leads to atrophic scars; (3) Cardiovascular system EDS caused by D4ST1 deficiency has slender, tapering fingers, wrinkled palms, Vascular complications were described initially been reported as three indepen- and considerable thenar (and hypothe- in the male patient from Portugal who dent conditions: A rare type of arthrog- nar) atrophy; (4) distal joint hypermobil- suffered from a cerebral hemorrhage ryposis syndrome, “adducted thumb- ity which later results in contractures; (5) posteriorly to the left putamen at age 21 clubfoot syndrome (ATCS)”; a specific characteristic radiographic abnormali- years, from which he recovered type of EDS, “EDS, Kosho Type ties; and (6) a ratio of urinary pyridino- completely. The adult patients had (EDSKT)”; and a subset of kEDS lines, LP/HP, of 1.0 [Giunta et al., venous varicosities on their feet and without lysyl hydroxylase deficiency, 2008b] (Representative pictures of the legs in adulthood. “musculocontractural EDS (MCEDS),” phenotype are given in Fig. 6). Neuromuscular features and motor all of which are now concluded to be a development single clinical entity [Kosho et al., 2005, Reproductive, including pregnancy The most distinctive muscular feature Malfait et al., 2010, Janecke et al., 2011, All affected individuals were born at was atrophy of the thenar and the Kosho et al., 2011, Shimizu et al., 2011]. term from uncomplicated pregnancies. hypothenar and muscle weakness of No pregnancies have been reported in the fingers. This feature was not the affected individuals. reported in the two adult siblings Craniofacial features described by Fukada et al. [2008]. EDS caused by D4ST1 Protuberant eyes and down-slanting Motor development was normal. palpebral fissures were described in deficiency has initially been the majority of affected from the three reported as three independent families. Genotype–Phenotype Correlation Musculoskeletal system conditions: A rare type of and Penetrance Short stature with height at the third arthrogryposis syndrome, – centile or below was reported for all No genotype phenotype correlations “adducted thumb-clubfoot patients but one, whose height was at have been described. Penetrance is the 10th centile at age 8.5 years. The presumably complete. Obligate carriers syndrome (ATCS)”; a specific adult patients presented with mildly have no overt phenotype. type of EDS, “EDS, Kosho shortened truck. Slender tapering fin- ” gers were also reported in the majority Type (EDSKT) ; and a Management of the affected. subset of kEDS without lysyl Skeletal X-ray imaging No specific management guidelines have hydroxylase deficiency, Reported features include: platyspon- been reported. Guidelines for manage- dyly, osteopenia of the axial skeleton, ment of musculoskeletal problems, skin “musculocontractural EDS 98 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) RESEARCH REVIEW

Figure 6. Clinical and radiological findings in patients with spEDS-SLC39A13.(A) Appearance of the hand in a 10.1 years old patient. Excessively wrinkled palm, thenar and hypothenar atrophy, tapering fingers, and contracted thumb. (B and C) Abnormal scar formation in two patients. (D) Abnormal dentition and hypodontia. (E) Radiograph of the low thoracic and lumbar spine in a patient aged 11.5 year with flattening, irregular endplates, and osteopenia of the vertebral bodies. (F) Radiograph of the hand of a 3.5 years old patient showing alterations of shape and flat epiphyses of the short tubular bones. (G) Radiograph of the pelvis of a 10 years old patient showing small ilia, mild flattening of the proximal epiphyses, short and wide femoral necks (Images kindly provided by Prof. Beate Albrecht and Prof. Nursel Elcioglu,S with permission).

(mcEDS),” all of which are siblings who died of an unknown the syndrome, through homozygosity now concluded to be a single etiology in early infancy [Dundar€ mapping using samples from previously et al., 2001]. The authors suggested described consanguineous families. clinical entity. that two brothers from a Japanese They also described follow-up clinical consanguineous family, manifesting findings of previously reported patients, multiple distal arthrogryposis, charac- including GJH, delayed wound healing, The prevalence is unknown. teristic facial features, cleft palate, short ecchymoses, hematomas, and osteope- stature, hydronephrosis, cryptorchi- nia/osteoporosis, from which the au- Adducted thumb-clubfoot syndrome dism, and normal intelligence, also thors categorized the syndrome into a Dundar€ et al. [1997] originally reported had the syndrome [Sonoda and Kouno, generalized connective tissue disorder. on two cousins from consanguineous 2000]. Janecke et al. [2001] described EDS, Kosho Type Turkish family, both having develop- two affected brothers from another In 2000, Kosho and colleagues encoun- mental delay, ocular abnormalities, consanguineous Austrian family, and tered the first patient with a specific type characteristic facial features, generalized concluded that the syndrome would of EDS, and the second unrelated joint laxity, arachnodactyly, camptodac- represent a new type of arthrogryposis patient with parental consanguinity in tyly, and distal arthrogryposis with with central nervous system involve- 2003. Both patients were Japanese girls adducted thumbs and clubfeet. The ment, congenital heart defects, urogen- with characteristic craniofacial features, authors named this condition adducted ital defects, myopathy, connective tissue skeletal features (multiple congenital thumb-clubfoot syndrome (ATCS) involvement (GJH), and normal or contractures, marfanoid habitus, pectus [Dundar€ et al., 1997]. They subse- subnormal intellectual development excavatum, GJH recurrent dislocations, quently reported a similar patient from [Janecke et al., 2001]. Dundar€ et al. progressive talipes, and spinal defor- another consanguineous Turkish family [2009] reported that loss-of-function mity), cutaneous features (hyperexten- with three other similarly affected mutations in CHST14 was causal for sibility, bruisability, and fragility with RESEARCH REVIEW AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 99

atrophic scars), recurrent large subcuta- mutation, through positional candidate p.(Pro281Leu)/p.(TyrY293Cys) and to neous hematomas, and hypotonia with gene approach, in a boy from a 14.5% in a patient with the homozygous mild motor developmental delay consanguineous Indian family, who mutation p.(Pro281Leu), compared [Kosho et al., 2005] which were had characteristic facial features, con- with each age- and sex-matched control strikingly similar manifestations ob- genital contractures of the thumbs and [Miyake et al., 2010]. Disaccharide served in Pakistani siblings classified as the feet, joint hypermobility, muscle composition analysis of CS/DS chains having a rare variant of kEDS with weakness, and atrophic scars and was isolated from the affected skin fibroblasts normal lysyl hydroxylase activity (“EDS diagnosed with MCEDS [Muller€ et al., in these two patients showed a negligible type VIB”) [Steinmann et al., 1975]. 2013]. Malfait and colleagues found a amount of DS and excess amount of CS, Kosho et al. [2005] proposed that these missense DSE mutation in two affected which was suggested to result from patients represented a clinically recog- sisters from a Spanish family, who shared impaired 4-O-sulfation lock due to nizable subgroup of EDS, tentatively hyperextensible and fragile skin, recur- D4ST1 deficiency, followed by back- classified as EDS type VIB. Kosho et al. rent large hematomas, long slender epimerization from IdoA to GlcA [2010] described four additional unre- fingers, and clubfeet, but no adducted [Dundar€ et al., 2009; Miyake et al., lated Japanese patients with similar thumbs [Syx et al., 2015]. In OMIM, the 2010; Syx et al., 2015]. Decorin, a major features, including a patient with pa- syndrome is termed as EDS, musculo- DS-PG in the skin, consists of a core rental consanguinity and a patient contractural type 2 (EDSMC2) to be protein and a single GAG chain that plays reported by Yasui et al. [2003]. They distinguished from EDS caused by an important role in assembly of collagen concluded that these patients repre- D4ST1-deficiency termed as EDS, mus- fibrils, possibly through an electrostatic sented a new clinically recognized form culocontractural type 1 (EDSMC1). interaction between decorin DS chains of EDS with distinct craniofacial fea- and adjacent collagen fibrils. GAG tures, multiple congenital contractures, chains of decorin from the affected and multisystem fragility-related man- skin fibroblasts contained exclusively Mechanisms of Disease ifestations [Kosho et al., 2010]. The CS and no DS disaccharides, while those syndrome was registered as “EDS, from the controls contained mainly DS Kosho type” in the London Dysmor- D4ST1 deficient EDS disaccharides (approximately 95%) phology Database (http://www. EDS caused by D4ST1-deficiency re- [Miyake et al., 2010; Syx et al., 2015]. lmdatabases.com/index.html) and also sults from recessive mutations in the Light microscopy of the affected skin in POSSUM (http://www.possum.net. carbohydrate sulfotransferase 14 gene specimens using hematoxylin and eosin au/). Miyake et al. [2010] identified (CHST14), localized at 15q14. staining showed that fine collagen fibers CHST14 as the causal gene for this CHST14 is a single-exon gene encod- were predominantly present in the condition through homozygosity map- ing carbohydrate sulfotransferase 14 or reticular to papillary dermis with marked ping using the two consanguineous dermatan 4-O-sulfotransferase 1 [Evers reduction of normally thick collagen families. et al., 2001]. D4ST1 is a Golgi-resident bundles [Miyake et al., 2010]. Transmis- Musculocontractural EDS enzyme which is involved in the sion electron microscopy showed that Malfait et al. [2010] found mutations in biosynthesis of the GAG dermatan collagen fibrils in the affected skin CHST14 through homozygosity map- sulfate, where it catalyzes 4-O-sulfation specimens were dispersed in the reticular ping in two Turkishsisters and an Indian of N-acetylgalactosamine (GalNAc) in dermis in contrast to the regularly and girl, both with parental consanguinity. the sequence “L-iduronic acid (IdoA)- tightly assembled collagen fibrils ob- The patients shared characteristic cra- GalNAc,” immediately after epimeriza- served in the controls and that each niofacial features, joint contractures, tion of D-glucuronic acid (GlcA) to collagen fibril in affected skin specimens and wrinkled palms in addition to IdoA by dermatan sulfate epimerase was smooth and round, not varying in common features of kEDS, including (DSE) [Evers et al., 2001]. size and shape, similar to that in the kyphoscoliosis; joint hypermobility; The sulfotransferase activity of controls [Miyake et al., 2010]. muscular hypotonia; hyperextensible, cos-7 cells transfected with CHST14 In view of these findings, skin thin, and bruisable skin with atrophic containing p.(LysK69), p.(Pro281Leu), fragility in patients with EDS caused scarring; and ocular complications. The p.(Cys289Ser), or p.(Tyr293Cys) muta- by D4ST1 deficiency is postulated to authors concluded that these patients tions was decreased at almost the same result from impaired assembly of colla- and those diagnosed with ATCS or level, suggesting that loss-of-function gen fibrils caused by the replacement of EDS, Kosho type had a single clinical mutations in CHST14 (i.e., D4ST1 a DS with a CS chain of decorin condition, which they termed “Mus- deficiency) are the basis of this disorder through alterations in the electrostatic culocontractural EDS (MCEDS)” [Miyake et al., 2010]. binding of decorin to collagen fibrils [Malfait et al., 2010]. Sulfotransferase activity toward DS followed by difference in the spatial EDS caused by DSE deficiency in mutant skin fibroblasts was signifi- relationship between collagen fibrils Janecke and colleagues identified a cantly decreased to 6.7% in a patient with and decorin [Kosho, 2013; Kosho homozygous loss-of-function DSE the compound heterozygous mutation et al., 2014; Kosho, 2016]. 100 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) RESEARCH REVIEW

DSE-deficient EDS 11 missense mutations, six frameshift involvement (Representative pictures of EDS caused by DSE deficiency results mutations, and two nonsense mutations. the phenotype are given in Fig. 7). from recessive mutations in the derma- The p.(Pro281Leu) was most frequent tan sulfate epimerase gene (DSE). DSE (n ¼ 9), other recurrent mutations include Reproductive, including pregnancy is a Golgi-resident enzyme that cata- p.(Val49)(n¼ 3), p.(Arg213Pro) (n ¼ 2), Pregnancy-related findings include lyzes the epimerization of D-glucuronic and p.(Tryr293Cys) (n ¼ 4). All other hand/foot anomalies (n ¼ 3), oligohy- acid (GlcA) toward iduronic acid mutations were reported once: p. dramnios (n ¼ 2), and decreased fetal (IdoA). This allows D4ST1 to catalyze (Arg29Gfs113), p.(Lys69), p.(Gln113 movement (n ¼ 2). No deliveries have the 4-O-sulfation of the adjacent Argfs14), p.(Arg135Gly), p.(Leu137Gln), been described in female patients with GalNAc, which then prevents back- p.(Cys152Leufs10), p.(Phe209Ser), p. EDS caused by D4ST1 deficiency. Two epimerization of the IdoA to GlcA. (Arg218Ser), p.(Gly228Leufs13), p. deliveries were described in a female Two homozygous missense muta- (Glu262Lys), p.(Arg274Pro), p.(Met280- patient with EDS caused by DSE tions (p.(Arg267Gly); p.(Ser268Leu)) Leu), p.(Cys289Ser), p.(Trp327Cfs29), deficiency, followed by uterine and have been detected [Muller€ et al., 2013; and p.(Glu334Glyfs107). bladder prolapse [Syx et al., 2015]. Syx et al., 2015]. Heterologous expres- DSE Craniofacial features sion of mutant full-length and soluble Two homozygous DSE1 missense mu- Characteristic craniofacial features in- recombinant DSE proteins harboring the tations (p.(Arg267Gly) and p.(Ser268- clude a large fontanelle (n ¼ 24), hyper- p.(Ser268Leu) substitution showed a loss Leu)) have been detected. telorism (n ¼ 36), downslanting of activity towards partially desulfated A registry with CHST14 and DSE palpebral fissures (n ¼ 35), blue sclerae DS, and patient-derived fibroblasts gene variants is available [Dalgleish, (n ¼ 28), short nose with hypoplastic also showed a significant reduction in 1998]. columella (n ¼ 17), ear deformities epimerase activity. The amount of DS (n ¼ 35) including low-set (n ¼ 22) and disaccharides was markedly decreased in posteriorly rotated (n ¼ 14) ears, high the conditioned medium and cell fraction palate (n ¼ 21), long philtrum and/or Clinical Description from cultured patient fibroblasts com- thin upper lip vermilion (n ¼ 24), and pared to control. No difference was seen At present, 39 patients (18 females, 21 small mouth and/or micro-retrognathia in CS chains from the conditioned males) from 26 families have been (n ¼ 16) at birth to early childhood. media, though the total amount of CS published with recessive CHST14 Slender facial shapes with protruding disaccharides in the cell fraction from the mutations (Table S1). The ages of jaws (n ¼ 11) and facial asymmetry patient was increased approximately patients with CHST14 mutations at (n ¼ 8) are evident from adolescence. 1.5-fold, consistent with increased syn- the latest publication ranged from 0 day Musculoskeletal system thesis or reduced conversion of CS chains to 59 years. [Dundar€ et al., 1997; Mild prenatal growth restriction was [Muller€ et al., 2013]. Sonoda and Kouno, 2000; Dundar€ suggested: Mean birth length 0.5 SD Syx et al. [2015] analyzed fibroblasts et al., 2001; Janecke et al., 2001; Yasui and median 0.6 SD (n ¼ 9; range, from from a patient harboring the p.(Arg267- et al., 2003; Kosho et al., 2005; Kosho 1.6 to þ1.3 SD); mean birth weight Gly) substitution and could show that a et al., 2010; Malfait et al., 2010; 0.6 SD and median 0.67 SD (n ¼ 11; minor fraction of decorin DS was Shimizu et al., 2011; Mendoza-Lon- range, from 2.0 to þ0.5 SD); and mean present, consisting of IdoA-containing dono et al., 2012; Winters et al., 2012; birth occipital frontal circumference 0.2 disaccharides, which could be attrib- Voermans et al., 2012; Syx et al., 2015; SD and median 0.5 SD (n ¼ 8; range, uted to residual DSE activity, or Janecke et al., 2016; Mochida et al., from 1.0 to þ1.0 SD) [Shimizu et al., compensating DSE2 activity. In this 2016]. 2011]. Mild postnatal growth restriction patient, no pronounced ultrastructural Three patients (one child, two adult was suggested with slenderness and abnormalities of dermal collagen fibrils women) from two families have been relative macrocephaly: Mean height were noted, but immunofluorescent published with recessive DSE1 muta- 0.9 SD and median 0.6 SD (14 data stainings of collagen types I, III, and V tions [Muller€ et al., 2013; Syx et al., points from 12 patients; range, from 3.9 and fibronectin showed evidence of 2015]. to þ1.2 SD); mean weight 1.5 SD and abnormal ECM assembly [Syx et al., The hallmarks of the disorder median 1.4 SD (11 data points from 9 2015]. include: (1) Characteristic craniofacial patients; range, from 2.4 to 0.4 SD); features, (2) congenital multiple contrac- and mean occipital frontal circumference tures, including adducted thumbs and 0.2SDandmedian0.0SD(10data talipes equinovarus, (3) characteristic points from 8 patients; range, from 1.2 Allelic Heterogeneity cutaneous features including fine palmar to >2.0 SD) [Shimizu et al., 2011]. creases, (4) peculiar finger shapes, (5) Multiple congenital contractures CHST14 progressive spinal and foot deformities, were cardinal features and typically Mutations have been detected through- (6) large subcutaneous hematomas, and included adduction-flexion contractures out the CHST14 gene. These include (7) ophtalmological and urogenital of the thumbs (n ¼ 32; no adducted RESEARCH REVIEW AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 101

palmar creases or wrinkles were char- acteristic and became evident with aging (n ¼ 29). Hyperalgesia to pressure was suggested (n ¼ 8) because patients disliked being hugged in infancy or disliked blood pressure measurement in the upper arms. Recurrent subcutane- ous infections with fistula formation were also observed (n ¼ 8). Ocular involvement Refractive errors, typically myopia (n ¼ 12) followed by astigmatism (n ¼ 5) and hyperopia (n ¼ 4), were described in 16 patients; strabismus in 13 patients; microcornea in 13; glau- coma or elevated intraocular pressure in eight; and retinal detachment in seven. Progressive visual field loss was described in a 31-year-old female [Kosho et al., 2010], deterioration in vision of the right eye because of the lacquer crack in Bruch’s membrane adjacent to right fovea in a 15-year-old male [Syx et al., 2015], and right-sided blindness because of retinal detach- ment in a 45-year-old female [Janecke et al., 2016]. Hearing Hearing impairment was described in nine patients (specified for high-pitched sounds in five). Cardiovascular system Recurrent large subcutaneous hema- tomas (skull, extremities, or hips) are a serious complication that can, even after minor trauma, progress acutely and massively to hemorrhagic shock Figure 7. A female patient with mcEDS-CHST14. Facial characteristics at age 23 requiring intensive treatment (hos- days (A) and 24 years (B). (A and C) Congenital contractures of fingers including pital admission, blood transfusion, or adducted thumbs (A) and cylindrical fingers at age 24 years (C). (D) Characteristic wrinkling palmar creases. (E) Left talipes equinovarus. (F) progressive foot deformities at surgical drainage) (n ¼ 21). Intranasal age 15 years. (G) A large subcutaneous hematoma at age 6 years (Images kindly provided administration of 1-desamino-8-D- by Dr. Tomoki Kosho, with permission. A and E, originally published in Kosho et al. arginine vasopressin (DDAVP) after [2010], in American Journal of Medical Genetics; G, originally published in Kosho et al. [2005], in American Journal of Medical Genetics). trauma effectively prevented large subcutaneous hematomas in three patients [Kosho et al., 2010; Janecke et al., 2016]. Congenital heart de- thumbs in seven and data not available in recurrent, chronic or easy joint dislocations fects, typically ASD, were detected in two) and talipes equinovarus (n ¼ 42). (n ¼ 19), and pectus deformities (flat and seven patients. Valve abnormalities Finger shapes were characteristically de- thin, excavatum, or carinatum) (n ¼ 18) and/or aortic root dilatation were scribed as “arachnodactyly,”“tapering,” were also noted. also detected in seven patients. “slender,” or “cylindrical” (n ¼ 36). Pro- Skin and integument Infectious endocarditis occurred in gressive talipes deformities (planus, valgus, Skin hyperextensibility (from child- two patients: One was successfully or severer) (n ¼ 27) and spinal deformities hood) and redundancy (from adoles- treated with surgical resection of the (decreased physiological curvature, scolio- cence) (n ¼ 24), bruisability (n ¼ 22), vegetation [Kosho et al., 2010] and sis, or kyphoscoliosis) (n ¼ 23) were and fragility with atrophic scars (n ¼ 23) the other expired [Janecke et al., observed. Marfanoid habitus (n ¼ 13); were common. Acrogeria-like fine 2016]. 102 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) RESEARCH REVIEW

Gastro-intestinal system of the forearm flexors, forearm extensors, hypoplasia of the cerebellar vermis Constipation was described in nine and quadriceps. Nerve conduction stud- (reminiscent of Dandy–Walker variant), patients. Two adults and one adolescent ies showed low compound muscle action and absence of the septum pellucidum patient had colonic diverticula perfora- potential amplitudes in the distal muscles. [Syx et al., 2015]. Spinal cord tethering tion, corrected surgically [Kosho et al., Needle electromyography showed an was noted in three patients, two of 2010; Kono et al., 2016]. One adoles- abnormal and mixed pattern of short- whom underwent corrective surgery. cent patient had a severe progressive duration, low-amplitude, polyphasic mo- Mild intellectual delay was suggested in gastric ulcer, treated with partial tor units, as well as polyphasic motor units three patients; one reportedly had gastrectomy [Kosho et al., 2010]. with a longer duration and higher global psychomotor delay in infancy, Complications associated with gastro- amplitude, reflecting an increase in fiber but his IQ was around 90 at the age of intestinal malformations included a size diameter. Muscle biopsy showed fiber 7 years 2 months [Dundar€ et al., 1997; common mesentery, spontaneous vol- type 1 predominance without fiber type Janecke et al., 2011]. vulus of the small intestine associated grouping, increased variation in the Other with absent gastrocolic omentum diameter of both type 1 and type 2 fibers, Poor breast development was noted in [Janecke et al., 2001], and duodenal and some type 1 fibers in close proximity seven female patients beyond adolescence. obstruction due to malrotation [Malfait to lobulated fibers. These findings were et al., 2010]. compatible with a myopathy, similar to Urogenital system other EDS types [Voermans et al., 2012]. Genotype–Phenotype Correlation Hydronephrosis was detected in eight Elevation of serum CK (creatine kinase) and Penetrance patients. It was caused by renal ptosis in level was described in four patients (277, one patient, who underwent laparo- 698, 1838, 3000 IU/L) [Janecke et al., Penetrance is complete, whereas differ- scopic placement of a ureteral stent, 2016]. ences in phenotypic severity among complicated by severe hemorrhage due Gross motor developmental delay was affected siblings have been suggested. to tissue fragility [Malfait et al., 2010]. described in 23 patients mainly because No apparent genotype–phenotype cor- Another patient had a pelviureteric of muscle hypotonia. The median age at relations have been described among junction obstruction requiring neph- which unassisted walking occurred in patients with EDS caused by D4ST1 rostomy in the neonatal period [Syx patients who accomplished it was 2 years deficiency. Phenotypic features in three et al., 2015]. Nephrolithiasis or cysto- 4months(n¼ 10; range, from 1 year 5 patients with EDS caused by DSE lithiasis was described in six patients, months to 4 years). One adult patient deficiency seemed to be milder than and recurrent urinary tract infection in could not walk unassisted because of those in patients with EDS caused by three. Cryptorchidism was observed in severe foot deformities and leg muscle D4ST1 deficiency, presumably associ- most male patients. One patient who weakness [Kosho et al., 2010]. ated with the glycobiological finding underwent orchidopexy developed hy- Neurological features and neuro- that some DS moieties were present in pogonadism in adulthood. development the decorin GAG in the fibroblasts Pulmonary Ventricular enlargement was described derived from patients with EDS caused Pneumothorax or pneumohemothorax in six patients and asymmetry in three by DSE deficiency, whereas DS was occurred in three adult patients, who on brain ultrasonography, computed completely replaced by CS in the were treated with chest tube drainage tomography, or magnetic resonance fibroblasts derived from patients with [Kosho et al., 2010]. imaging. Additional minor findings EDS caused by CHST14/D4ST1 defi- Neuromuscular features and motor were also recorded: Absence of the ciency [Syx et al., 2015]. development left septum pellucidum [Janecke et al., Muscle hypotonia or weakness was 2001], a short corpus callosum with lack Management described in 17 patients. A myopathic of an isthmus and well-defined rostrum, process was suggested as the cause of the mild prominence of the Sylvian fissures, Management should be comprehensive muscle weakness in a patient. Electro- and a few small gray matter heterotopias especially focusing on musculoskeletal, myographic examination demonstrated along the lateral walls of the temporal cutaneous, cardiovascular, visceral, and muscle action potentials with reduced horns of the lateral ventricles [Men- ocular complications [Shimizu et al., amplitude but with a normal distal doza-Londono et al., 2012], absence of 2011; Kosho, 2016]. No specific guide- latency time and nerve conduction the septum pellucidum, hypoplasia of lines for management of patients with velocity, and muscle biopsy revealed the inferior vermis with a normally D4ST1/DSE-deficient EDS are avail- no histological abnormalities [Dundar€ sized posterior fossa (Dandy–Walker able. Guidelines for management of et al., 1997]. In another patient, variant), hypoplasia of the hippocampi musculoskeletal problems, skin involve- quantitative muscle ultrasonography and splenium of the corpus callosum, ment, cardiovascular involvement, oph- showed increased echo intensity in the and hypoplasia of the optic nerves thalmologic and dental follow-up, and forearm extensors and anterior tibial (septo-optic dysplasia) [Winters et al., pregnancy should follow those formu- muscles as well as marked bilateral atrophy 2012] and mild cerebellar hypoplasia, lated for other forms of EDS (for RESEARCH REVIEW AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 103 reference: See “management guidelines Differential Diagnosis muscle ECM, its absence results in for the classical Ehlers–Danlos syn- disorganized patterning, abnormal force drome,” by Bowen et al., this issue). transmission, and other biomechanical Specific management guidelines Spndylodysplastic EDS alterations resulting in myopathy. Its may include: Kyphoscoliotic EDS(PLOD1, FKBP14) absence in skin and tendons would explain Freeman–Sheldon syndrome the overlapping EDS manifestations. At diagnosis: Loeys–Dietz syndrome – Screening for congenital heart defects Allelic Heterogeneity through a cardiac ultrasonography – Screening for ocular malformations To date, nine patients from five families MYOPATHIC EDS (mEDS) through an examination by a pediat- with myopathic EDS have been reported ric ophthalmologist Synonyms: EDS/Myopathy overlap [Hicks et al., 2014; Zou et al., 2014; – Screening for malformations in the syndrome Punetha et al., 2016]. The mutations renal system through a renal include four heterozygous missense muta- ultrasonography tions that have an autosomal dominant The History of Myopathic EDS – Screening for hearing impairment by mode of inheritance: c.7167 T>C, p. (mEDS) an automated auditory brainstem (Ile2334Thr), c.C5893T,p.(Arg1965Cys), response (aABR) as well as an The spectrum of diseases characterized 8329G>C, p.(Gly2777Arg), and c. examination of a pediatric otologist by muscle weakness, hypotonia, myop- G8357A, p.(Gly2786Asp), and one ho- Musculoskeletal: athy,and connective tissue symptoms was mozygous frameshift mutation, introduc- – Orthopedic intervention (e.g., serial first associated with mutations in the ing a PTC, associated with autosomal plaster casts or surgery) for talipes genes that code for collagen type VI. recessive inheritance (c.8006 þ1G>A, p. equinovarus and physical therapy for These conditions have a wide spectrum (2567Asp>Phefs2). motor developmental delay as the of severity that ranges from the most center of care for patients with the severe Ullrich congenital muscular dys- Clinical Description disorder trophy to the milder Bethlem myopathy. – After walking independently, special Zou et al. [2014] and Hicks et al. At present, nine patients from five attention to progressive foot defor- [2014] investigated groups of patients families have been reported (Table S1). mities and trauma that could cause that had some symptoms of these Their age at publication ranged from skin lacerations, joint dislocations, or myopathies but presented with a distinc- birth to 48 years (Table S1) [Hicks et al., large subcutaneous hematomas tive phenotype and did not have muta- 2014; Zou et al., 2014; Punetha et al., – Assessment of spinal deformities tions affecting type VI collagen. Through 2016]. The severity ranges from a severe (scoliosis, kyphoscoliosis) these studies they identified eight patients autosomal recessive neonatal form that Skin: A wrist-type sphygmomanometer in four families that presented with was described in two boys born to a for patients with hyperalgesia to autosomal recessive (two patients, one consanguineous couple, to a milder pressure family) and dominant (six patients, three autosomal dominant form that presents Ophtalmological: Regular check-ups families) forms of EDS/myopathy. Since in childhood with muscle weakness, for strabismus, refractive errors, then, one additional patient has been large joint contractures, and variable glaucoma described [Punetha et al., 2016]. Preva- degrees of joint hypermobility and ORL: Regular check-up for otitis media lence of this condition is unknown. hypertrophic scarring. The phenotype with effusion, hearing impairment may not be fully understood as there are Urological: Regular check-up for uri- so few reported cases. Mechanism of Disease nation problems, bladder enlargement. The hallmark of the disorder is Surgical fixation for cryptorchidism in Collagen XII is synthesized as a homo- muscle weakness that is present in infancy males trimer made up of three a1 collagen or childhood and is associated with Cardiovascular: Regular check-up for chains coded by COL12A1. It is found proximal large joint contractures and distal valve abnormalities, aortic root dilation along the surfaces of the fibers of joint hypermobility. Characteristically, Gastro-intestinal: Regular check-up for collagen type I in tissues that express the muscle weakness tends to get better constipation and evaluation for need of that collagen, and it is presumed to act as with age until young adulthood with laxatives and/or enemas a bridge between the collagen I fibers some deterioration in the 4th decade. Assessment of secondary sex character- and other extracellular components istics (breast development in females including decorin, fibromodulin, and Reproductive, including pregnancy and gonadal function in males) TNX [Zou et al., 2014]. Deficiency of One patient was born after a selective Emergent treatment for pneumothorax or this collagen results in lax tissues due to a caesarian section because of oligohy- pneumohemothorax, large subcutaneous mechanical problem with the ECM. dramnios, intrauterine growth restric- hematomas, and diverticular perforation Because collagen XII is expressed in the tion, and breech presentation. 104 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) RESEARCH REVIEW

Craniofacial features B1. CK was elevated in several, but not Classical EDS One patient displayed facial asymmetry all patients (of note: It was normal in the Classical-like EDS with skull flattening at birth, and mild siblings with the most severe, autosomal dysmorphic facial features, including recessive form). micrognathia, high palate, short nose, PERIODONTAL EDS (pEDS) big dysplastic ears. High arched palate was reported in two other patients. Synonyms: EDS type VIII, Ehlers– Genotype–Phenotype Correlation Musculoskeletal Danlos Syndrome periodontitis type, and Penetrance Congenital proximal joint contractures Ehlers–Danlos Syndrome periodontosis in combination with distal joint hyper- There appears to be a clear genotype– type. mobility were reported in three pa- phenotype correlation. In general, from tients. One patient was reported to have the five mutations described so far it seems The History of Periodontal EDS proximal contractures at birth without that missense mutations that affect critical mentioning of distal join hypermobility. residues in the molecule have a dominant- McKusick [1972] described a “unique At age 7 years, contractures had negative effect and result in variable condition” in a patient with EDS-like disappeared but she had joint hypermo- degrees of severity. There are no docu- features, that is, lesions on the shins, slow- bility in childhood. All patients tended mented instances of non-penetrance. healing breaks in the skin, atrophic scars, to have congenital kyphosis, in con- There is significant variability, within and absorptive periodontitis with early junction with torticollis in one, and and between families, with individuals loss of the teeth. Five years later, Stewart some developed scoliosis. The patients carrying the same mutation presenting et al. [1977] published a similar case and reported by Hicks et al. [2014] (n ¼ 5) with different degrees of severity. classified this new variant as EDS VIII. developed long finger flexions (n ¼ 4), The one family with the autosomal Since then, pEDS has been reported in rigid spine (n ¼ 2), flexion contractures recessive condition harbors a homozy- 32 case reports and seven pedigree of knee (n ¼ 2), elbow (n ¼ 1), and gous loss of function mutation. The analyses. Extensive periodontal destruc- wrist (n ¼ 1). Hip dislocation or sub- affected siblings have a more severe form tion with early onset is a core finding of luxation was reported in two patients. of the condition. Reportedly carrier periodontal EDS, mostly in combination One patient had a pectus excavatum. parents walked late (almost at 2 years of with striking pre-tibial plaques and tissue Skin and integument age); therefore there appears to be a mild fragility. There is greater variability in Reported skin features include hyper- phenotype (dominant) in the carriers other clinical features. trophic scars (n ¼ 3), atrophic scars and a severe phenotype (recessive) in the In the past, the delineation of pEDS (n ¼ 2), hyperkeratosis pilaris (n ¼ 1). individuals that are homozygous [Zou as a specific phenotype was hampered by Neuromuscular features and motor et al., 2014]. the relatively high prevalence of chronic development Penetrance is unknown. periodontitis, with an estimated range The siblings reported by Zou et al. from 19 to 83% depending on age and [2014] (homozygous mutation) had the severity [Demmer et al., 2010]. There- Management most severe phenotype with profound fore, periodontal disease in vascular and muscle hypotonia at birth, poor feeding There are no described treatments for other EDS types could be a coincidence and swallowing, and night-time hypo- this group of disorders. Anticipatory of two unrelated diseases. These histori- ventilation, with need for tube feeding guidance should focus on preventing cal overlaps between pEDS and other and non-invasive night-time ventilation. complications and improving the pre- EDS subtypes have confused the phe- They had a severe delay in motor senting symptoms. This may include notype. While the majority of pEDS development, and they eventually were physical therapy for the contractures patients had vEDS excluded through able to reach a sitting position, but were (since they tend to resolve over time), collagen protein analysis, this does not never able to stand or walk [Zou et al., and monitoring for any signs of feeding completely exclude a COL3A1 variant 2014]. All other patients had congenital or respiratory difficulties, in particular being causative in some of the older muscle hypotonia, with delayed gross nocturnal hypoventilation. If the latter is cases. motor development, but symptoms present, then assisted non-interventional Also, joint hypermobility is a com- seemed to improve over time. None of ventilation at night may be indicated. mon feature in the general population, these patients remained non-ambulatory. which complicates accurately ascertain- In one adult, muscle strength was reported ing co-segregation of these two traits. Differential Diagnosis to deteriorate again in his late 30s. The Villefranche EDS nosology group Reported abnormalities on muscle noted these difficulties in distinguishing biopsy include myopathy with variabil- Bethlem and Ullrich myopathies (Col- this rare disorder from other hereditary ity in fiber diameter, without overt sins lagen type VI-related disorders) disorders of connective tissue [Beighton of degeneration or regeneration. In one Kyphoscoliotic EDS et al., 1998]. In 2003, pEDS was mapped instance, there was decreased laminin Hypermobile EDS to a 7 cM (5.8 MB) interval on RESEARCH REVIEW AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 105 chromosome 12p13 in three families Moderate enlargement of the ER Clinical Description [Rahman et al., 2003], but no candidate cisterns documented in vitro in dermal In the review on clinical features, we gene was identified. In 2016, an interna- fibroblasts may reflect retention of distinguished between individuals with tional consortium published 19 indepen- malprocessed molecules but could also confirmed mutations in C1R or C1S dent families comprising 107 individuals reflect boosted expression/production and other case reports. See Table S1 for with pEDS to identify the genetic locus of collagen as a feed-back response to the prevalence of clinical features in the [Kapferer-Seebacher et al., 2016]. In- decreased deposition of mature collagen molecularly confirmed patients (Repre- cluded were samples of eight previous into the matrix. The exact pathome- sentative pictures of the phenotype are case reports and pedigree studies [Stewart chanism of pEDS remains to be clarified. given in Fig. 8). et al., 1977, Hartsfield and Kousseff, 1990, Rahman et al., 2003, Reinstein Allelic Heterogeneity et al., 2011, Reinstein et al., 2012, Craniofacial features Reinstein et al., 2013, Cıkla et al., Heterozygous missense or in-frame Stewart et al. [1977] included a photo- 2014, George et al., 2016]. In 17 of insertion/deletion variants in C1R graph of the reported patient with an these families, heterozygous missense or were detected in 15 families (comprising “aesthenic build.” Dysmorphic facial in-frame insertion/deletion mutations in 76 affected individuals), and heterozy- features were not described by Rahman C1R (15 families) or C1S (two families) gous missense or in-frame insertion/ et al. [2003]. In the dysmorphology were identified. C1R and C1S are deletion variants in C1S were detected literature, Cunniff and Williamson- contiguous genes in the previously in two families (comprising 16 affected Kruse [1995] described a triangular reported linkage region on chromosome individuals). These variants involve the face, prominent eyes, long nose, and 12p13, and encode subunits C1r and C1s C1r/C1s, C1r/C1r, or C1r/C1q inter- short philtrum. Biesecker described a of the first component of the classical faces or the hinges between interaction paucity of subcutaneous fat with prom- complement pathway. and catalytic domains of C1r and C1s. inent nose and larynx [Biesecker et al., The prevalence of pEDS is unknown. Variants never involved the catalytic 1991]. Hartsfield noted the phenotypic domain of C1r or C1s [Kapferer- overlap with vEDS [Hartsfield and Seebacher et al., 2016]. Kousseff, 1990]. The Mechanisms of Disease Complement is a major element of antimicrobial host defense through its ability to recognize pathogens and limit infection in the early phase after expo- sure to microorganisms. The classical pathway of complement is triggered by C1, a complex comprising a recognition subunit C1q and two modular serine proteases (SPs) C1r and C1s [Budayova- Spano et al., 2002]. C1r and C1s are assembled into a Ca(2þ)-dependent C1s─C1r─C1r─C1s tetramer which associates with the recognition protein C1q [Gaboriaud et al., 2014; Rossi et al., 2014]. After C1 binding to immune complexes, C1r auto-activates and then cleaves C1s which in turn cleaves C4 (into C4a and C4b) and C2 (into C2a and C2b) to form the classical pathway Figure 8. (A) Gingival tissues of a child affected with pEDS. The keratinized C3 convertase (C4b2a) [Patrick et al., gingiva is missing; the oral mucosa extends to the free gingival margin and the interdental papillae and is very fragile. (B) Gingival tissues of a non-affected child. The gingiva is 1970; Thielens et al., 1982; Amano keratinized and is tightly bound to the underlying periostum via collagen structures, and et al., 2008]. performs a protective function during mastication. The border between gingiva and One attractive hypothesis for the alveolar mucosa is the mucogingival junction (dotted line). The oral mucosa is non- keratinized and only loosely connected to the periostum; therefore, it is more fragile. (C) pathomechanism of pEDS is altered Dental radiograph of an affacted individual, at aged 29. Notice severe periodontal bone binding of the C1r─C1s tetramer or loss (asteriks). (D) Clinical picture of the same individual, at age 30. Premolars in the left prematurely cleaved fragments to C1q mandible have been lost in the meantime without periodontal pocketing and despite good oral hygiene. Notice the lack of keratinized gingiva and gingival recessions or soluble procollagens. This could (receeding gums) (Images kindly provided by Dr. Ines Kapferer-Seebacher, with affect C1 function or interfere with permission). procollagen processing within the ER. 106 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) RESEARCH REVIEW

Musculoskeletal system rupture (once duodenum, twice lung). had biopsy from pre-tibial lesions, In 93 individuals with C1R or C1S As pEDS patients are not routinely others at the standard site. There were mutations reported by Kapferer-See- checked for aneurisms, there might be no consistent findings, but evidence bacher et al. [2016] joint hypermobility also unrecorded cases. Additionally, of collagen fibril size, packing, mor- was reported in 56% of patients, mostly many of the reports describe pediatric phology, and ER dilatation are all affecting the fingers (30%), the elbows patients and there is a great need for reported. (19%), knees (11%), hips, wrist, and longterm follow-up. Electron microscopy examination of ankle (3%). Marfanoid habitus, scolio- Dental involvement skin reported in seven individuals sis, osteoarthritis, flat feet, and hernia Early-onset periodontitis with exten- with C1R/C1S mutations showed were not consistent features [Kapferer- sive periodontal destruction and loss of decreased collagen content, abnor- Seebacher et al., 2016]. teeth, starting in childhood or adoles- mal variation in collagen fibril Skin and integument cence, is one of the defining hallmarks diameter and some abnormally Pretibial plaques with or without of pEDS, and was present in all reported shaped fibrils [Rahman et al., haemosiderosis are a consistent feature cases and in 99% of individuals with 2003; Reinstein et al., 2012, 2013; in most reports. Clinically, the lesions confirmed C1R/C1S mutations. A Kapferer-Seebacher et al., 2016], resemble necrobiosis lipoidica, but clear demarcation to the diagnosis of which is in line with further reports generally differ histologically. Fibrosis chronic or aggressive periodontitis is [Kobayasi, 2004; Mataix et al., and haemosiderin deposits were re- essential. Typically, periodontal de- 2008]. Dermal collagen fibers ported, as opposed to interstitial and struction in pEDS is not accompanied showed some variability in the palisade granulomas and/or microangi- by periodontal pocket formation but by density of the packing and a opathy 19. Buckel and Zaenglein receding gums (personal observation few areas of kinking. The size [2007] confirmed similar findings. IK). Prior to periodontitis, affected uniformity does not support Easy bruising, skin fragility, and (mild) individuals may present with extensive vEDS, while the kinking is non- hyperelasticity of the skin have been gingival inflammation in response to specific. Additionally, patients’ reported in the majority of cases. There mild dental plaque accumulation. A fibroblasts showed an increased is a single report of an associated characteristic recently described feature proportion of dilated rough ER vasculitis in the absence of pretibial is a striking lack of attached gingiva (RER) cisternae [Reinstein et al., lesions [Hoffman et al., 1991]. In 93 causing oral tissue fragility (Fig. 1) 2012; Kapferer-Seebacher et al., individuals with C1R or C1S mutations [Kapferer-Seebacher et al., 2016]. 2016]. reported by Kapferer-Seebacher et al. Additional laboratory findings Dyne et al. [1993] reported collagen [2016], consistent cutaneous findings – Biochemistry: depletion and a larger number of were pretibial discolorations (83%), Biochemical analysis of collagen in small elastin fibrils; ultrastructure easy bruising (96%), skin fragility cultured skin fibroblasts did not show showed occasional serrated collagen (83%), and (mild) hyperelasticity of abnormalities in the production and fibrils, with normal fibril diameter. the skin (73%). Atrophic scars were secretion of type I, III, and V collagens – Immunology: present in 50% of cases [Kapferer- in several case reports and also in eight Hoffman et al. [1991] reported a Seebacher et al., 2016]. individuals with confirmed mutations patient with severe periodontitis, Cardiovascular involvement in C1S/C1R [Biesecker et al., 1991; valvular heart disease, osteocondylar Until recent, pEDS has not been Cunniff and Williamson-Kruse, 1995; and phalangeal osteolysis in the associated with catastrophic vascular Kapferer-Seebacher et al., 2016]. In absence of pretibial hyperpigmenta- complications or hollow visceral rup- contrast, Mataix et al. [2008] reported tion. This patient had intractable ture that arise in vEDS. It is of note that a reduced rate of collagen (I) and vasculitis and had a T cell response the father of the case reported by collagen (III) synthesis compared to to type I collagen. Other patients Stewart et al. [1977] had duodenal control samples. Lapiere and Nusgens have not had evidence of vasculitis. rupture and subsequent collagen pro- [1981] initially reported a family with The case has some similarities to tein analysis showed a normal collagen pEDS and reduced collagen III pro- patients described with Singleton (I:III) ratio. Recently, a 42-year-old tein from skin, but later reported that a Merton syndrome, (premature dental woman was reported with pEDS and a repeat analysis had not been able to loss, aortic calcification, and osteo- ruptured “blood blister” shaped aneu- replicate this. porosis, OMIM 182250). It is doubt- rysm of her left middle cerebral artery – Skin histology and ultrastructure: ful whether this patient had true [Cıkla et al., 2014]. It is of note that there is variation in pEDS. Kapferer-Seebacher et al. [2016] collagen ultrastructure depending on Kapferer-Seebacher et al. [2016] reported a prevalence of 16% for the site of biopsy in the general reported a prevalence of 40% for vascular complications (cerebral aneur- population (Pope and Vandersteen, recurrent infections like otitis media, isms or aortic dissection), and one personal observations). Many pa- herpes zoster, bladder infections, individual with three events of organ tients with pEDS in the literature empyema, kidney infections, or RESEARCH REVIEW AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 107

pneumonia. There were single pa- interdentally. Gingival recession might adhesion deficiencies types I, II, and III tients with autoimmunologic disor- also present only on the buccal or (OMIM 116920; OMIM 266265; ders like Sjogren€ syndrome, rosacea, lingual aspects of the tooth. In this OMIM 612840), WHIM (OMIM and Crohn’s disease [Kapferer- case, it can, for example, be associated 193670), Cohen Syndrome (OMIM Seebacher et al., 2016]. with a thin gingival biotype and 216550), and agranulocytosis (OMIM intencse tooth brushing, but not 610738). with periodontitis. Conditions with more complex “Chronic periodontitis” prevalence dermatological phenotypes include estimates ranged from 19 to 83% Kindler syndrome (hereditary acroker- Management depending on age and severity atotic poikiloderma OMIM 173650), Thereisnocurativetreatmentforthis [Demmer et al., 2010]. Severe peri- Papillon–Lefevre syndrome and cathep- disorder. A recent review of the dental odontitis with a mean prevalence of sin C associated phenotypes (602635), management of EDS recommended 11.2% is the sixth-most prevalent con- hypotrichosis osteolysis periodontitis special care regarding mucosal fragil- dition in the world [Kassebaum et al., (OMIM 607658). Multiple loci associ- ity, bleeding, temporomandibular 2014]. The typical patient is over ated with an aggressive periodontitis joint hypermobility, and local anaes- 30 years of age, and the amount of have been reported (OMIM 170650) thetic resistance [Tulika and Kiran, bone destruction is consistent with [Hart and Atkinson, 2007]. The 2015]. Management of periodontal the presence of plaque and calculus Singleton–Merten syndrome (OMIM disease requires lifelong biofilm man- [Armitage, 2004]. In general, the 182250) with periodontal destruction agement including intense oral hy- disease progresses slowly but there and aortic calcification has recently been giene instructions and nonsurgical may be bursts of destruction. In shown to result from dominant muta- debridement about every 3 months. addition, the rate of disease progression tions in the IF1H1 gene [Rutsch et al., Systemic antibiotics may be indicated. can be modified by local factors, 2015]. Conservative surgical management is systemic diseases, and extrinsic Hypophosphatasia (OMIM recommended because of difficulties factors such as smoking or emotional 146300) is a highly variable autosomal with fragile periosteal skin flaps and stress. dominant disorder associated with suture tears. “Aggressive periodontitis” preva- enamel hypoplasia, early loss of primary lence estimates range from 0.1% in dentition, bowed long bones, and Caucasians residing in north and mid osteopenia. Odontohypophosphatasia Differential Diagnosis Europeto5%inAfricanpopulations is the least severe form of hypophos- [Albandar, 2014]. The primary phatasia, characterized by premature Vascular EDS features are rapid attachment loss in exfoliation of primary and/or perma- Classical EDS otherwise healthy individuals and nent teeth in the absence of skeletal Hypermobile EDS familial aggregation, usually affecting system abnormalities. It is associated Periodontal diseases persons under 30 years of age [Alban- with a low circulating alkaline dar, 2014]. Some types of aggressive phosphatase. Periodontal diseases range from periodontitis seem to be inherited mild and reversible gingivitis to irre- in a Mendelian manner, and both FUTURE RESEARCH AND versible loss of periodontal attachment autosomal modes and X-linked GAPS resulting in tooth loss. “(Plaque-in- transmission have been proposed duced) gingivitis” is an inflammation [Meng et al., 2011]. However, review During the last decade, there has been solely of the gums in response to of pedigree analysis, linkage and an explosion of diverse but overlap- bacterial biofilms, and is characterized linkage disequilibrium studies have so ping novel EDS or EDS-like pheno- by bleeding on probing. “Periodontitis” farbeeninconclusive[Mengetal., types for which molecular defects have is characterized by inflammation of the 2011]. been identified in an array of new gingiva and destruction of the peri- There are several “monogenic syn- genes, as illustrated above. The geno- odontal tissues, which are the gingiva, dromes with significant periodontitis” as mic era promises to shed additional the cementum, the periodontal liga- part of the clinical phenotype. The light on unsolved forms of Ehlers– ment, and the alveolar bone. Periodon- majority of syndromes with severe Danlos syndrome. However, while our tal bone loss is diagnosed radiologically periodontal destruction in childhood knowledge of the molecular basis of or clinically with a periodontal probe. are inherited as autosomal recessive or EDS has greatly progressed since the “Gingival recession” (receding gums) in X-linked traits and are associated with Villefranche Nosology, our under- general is the exposure of the tooth neutrophil dysfunction, for example, standing of the pathophysiological roots. It might be an accompanying congenital and cyclic neutropenia mechanisms underlying these condi- feature of periodontitis, and in this (OMIM 202700), Chediak–Higashi tions remains very limited, and eluci- case the tooth root is exposed also syndrome (OMIM 214500), leukocyte dation of the genetic basis has not 108 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) RESEARCH REVIEW translated to improved clinical man- of unknown significance are being iden- Aldahmesh MA, Mohamed JY,Alkuraya FS. 2012. A novel mutation in PRDM5 in brittle agement strategies. tified. As such there is a need for the cornea syndrome. Clin Genet 81:198–199. development of functional tests to study Aldeeri AA, Alazami AM, Hijazi H, Alzahrani F, the pathogenic nature of these variants Alkuraya FS. 2014. Excessively redundant umbilical skin as a potential early clinical Identification of therapeutic targets feature of Morquio syndrome and FKBP14- However, while our related Ehlers–Danlos syndrome. Clin Genet 86:469–472. knowledge of the molecular Amano MT, Ferriani VP, Florido MP, Reis ES, basis of EDS has greatly Delcolli MI, Azzolini AE, Assis-Pandochi ACKNOWLEDGEMENTS AI, Sjoholm€ AG, Farah CS, Jensenius JC, progressed since the Isaac L. 2008. Genetic analysis of comple- We are very grateful for the cooperation ment C1s deficiency associated with sys- Villefranche Nosology, our of many patients and their families all temic lupus erythematosus highlights over the world. We also wish to alternative splicing of normal C1s gene. – understanding of the acknowledge the invaluable discussions Mol Immunol 45:1693 1702. Armitage GC. 2004. Periodontal diagnoses and pathophysiological with many professionals and lay persons. classification of periodontal diseases. Perio- – mechanisms underlying these We would like to thank our generous dontol 2000 34:9 21. sponsors including, but not limited to, Arunrut T, Sabbadini M, Jain M, Machol K, Scaglia F, Slavotinek A. 2016. Corneal conditions remains very The Ehlers–Danlos National Founda- clouding, cataract, and colobomas with a limited, and elucidation of the tion, the Ehlers–Danlos Support UK, novel missense mutation in B4GALT7—A and the Ehlers–Danlos Society. Fran- review of eye anomalies in the linkeropathy genetic basis has not syndromes. Am J Med Genet Part A siska Malfait is Senior Clinical Investi- 170A:2711–2718. translated to improved clinical gator at the Fund for Scientific Research Avgitidou G, Siebelmann S, Bachmann B, Flanders. Kohlhase J, Heindl LM, Cursiefen C. management strategies. 2015a. Brittle cornea syndrome: Case report with novel mutation in the PRDM5 gene and review of the literature. Case Rep REFERENCES Ophthalmol Med 2015:5. 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