The Ehlers–Danlos syndromes, rare types

In the paper

“In addition, two other arginine-to-cysteine (Arg-to-Cys) substitutions in the proa1(I) chain of type I collagen, c.1720C>T, p.(Arg574Cys) and c.3277C>T, p.(Arg1093Cys°), were identified in two other adults with vascular rupture, but without EDS-signs [Malfait et al., 2007].”

What the sources say

• Partly supported

  The Abstract identifies the two substitutions in Patients 2 and 3, and Results: Clinical Description says the two had osteopenia rather than classic EDS signs. However, Results and Table 2 describe their vascular events as arterial dissections and aneurysms, not documented vascular ruptures; the paper describes rupture as a propensity or future risk. (LLM, conf=0.85)

  cites Malfait et al., 2007 sourceExperimental — accuracy not yet measured

In the paper

“The p.(Arg312Cys) mutation has subsequently been identified in two other individuals with EDS and complications of vascular fragility [Ritelli et al., 2013;Gaines et al., 2015].”

What the sources say

• Supported

  The Discussion (page unavailable) reports that Ritelli et al. detected COL1A1 p.(Arg312Cys) in one patient with vascular involvement and describes the associated phenotype as vascular-like cEDS. This supports the individual attributable to Ritelli et al. in the sentence’s two-citation claim; it does not establish the second individual attributed to Gaines et al. (LLM, conf=0.90)

  cites Ritelli et al., 2013 source
• ?Not checked — no full text of the sourcecites Gaines et al., 2015 source

In the paper

“They detected a complete TNX deficiency in five EDS patients and three affected siblings (one of which with the contiguous gene syndrome).”

What the sources say

• Supported

  Table 2 identifies five tenascin-X-deficient patients and three affected siblings; the Figure 3 caption describes complete tenascin-X deficiency and identifies the three additional affected family members. Mutation Detection states that Patient 3 had the contiguous-gene syndrome. Page numbers are not provided in our copy. (LLM, conf=0.93)

  cites Schalkwijk et al. [2001] source

In the paper

“Malfait et al. [2007] identified the same mutation in an adult who suffered from a rupture of medium-sized arteries, reminiscent of vascular EDS.”

What the sources say

• Partly supported

  The Mutation Detection section identifies COL1A1 p.R312C in Patient 1, and Table 2 records a right iliac artery event at age 37. But Table 2 and the Results describe that event as a dissection, not a rupture. The Discussion compares the arterial phenotype with vascular EDS, so the resemblance is supported. (LLM, conf=0.87)

  cites Malfait et al. [2007] sourceExperimental — accuracy not yet measured

In the paper

“Patients with the p.(Arg312Cys) mutation are particularly at risk for vascular events, highlighting the benefit of molecular confirmation in classical EDS patients for management purposes.”

What the sources say

• Supported

  Mutation Detection identifies R134C as p.R312C in Patient 1. The Results report an iliac artery dissection in that patient, and the Discussion advises awareness of vascular aneurysm or rupture in patients with these substitutions. Page numbers were not available in our copy. (LLM, conf=0.90)

  cites Malfait et al. [2007] source
• Supported

  The Discussion states that patients and relatives carrying COL1A1 p.(Arg312Cys) showed severe vascular involvement and a propensity for arterial rupture in young adulthood. The Background also describes arterial-rupture risk in vascular-like classical EDS. The management implication in the citing sentence is its authors’ framing, not a separate finding needed to support the risk claim. (LLM, conf=0.93)

  cites Ritelli et al., 2013 source
• ?Not checked — no full text of the sourcecites Gaines et al., 2015 source

In the paper

“The authors concluded that pregnancy is without major complications in TNX-deficient patients, apart from one incident of postpartum hemorrhage.”

What the sources say

• Supported

  The Discussion explicitly concludes that pregnancy is generally without major complications in TNX-deficient patients, apart from one incident of postpartum hemorrhage. The Results report one such incident in 12 childbirths; the authors caution that their patient group was small. (LLM, conf=0.95)

  cites Egging et al. [2008] source

In the paper

“The authors concluded that TNXB haploinsufficiency is associated with hEDS [Zweers et al., 2003].”

What the sources say

• Supported

  The paper’s title states the association, and its Abstract reports that unusually low TNX levels were significantly more frequent in patients with hypermobility-type EDS than expected. The body text also reports joint hypermobility among family members with TNXB haploinsufficiency. The claim describes an association, not a universal cause. (LLM, conf=0.93)

  cites Zweers et al., 2003 source

In the paper

“The absence of TNX throughout the body leads to a phenotype resembling the classical type of EDS.”

What the sources say

• Partly supported

  The Discussion states that tenascin-X-deficient patients had clinical findings similar to classic EDS. It documents complete absence of tenascin-X in serum, skin, and fibroblast-conditioned medium, but does not establish its absence throughout the body. (LLM, conf=0.86)

  cites Schalkwijk et al., 2001 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites Peeters et al., 2004
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Demirdas et al., 2016

In the paper

“Family members with a haploinsufficient mutation in the TNXB gene have been described to have symptoms of joint hypermobility in 60% of the cases, but more research is needed to confirm this [Zweers et al., 2003].”

What the sources say

• Partly supported

  The clinical-examination passage (section labeled “1 … Show more Show less”; page unavailable) reports joint hypermobility in 9 of 20 heterozygous family members (45%). A separate passage in the same section reports 9 of 14 females (64%) meeting clinical criteria. Thus, approximately 60% applies to the female subgroup, not to family members overall. (LLM, conf=0.88)

  cites Zweers et al., 2003 sourceExperimental — accuracy not yet measured

In the paper

“The condition was shown to be caused by biallelic mutations in FKBP14 [Baumann et al., 2012].”

What the sources say

• Supported

  The Discussion concludes that this autosomal-recessive EDS variant is caused by FKBP14 mutations. The Abstract reports affected individuals with either homozygous or compound heterozygous FKBP14 mutations, supporting the claim that the mutations are biallelic. (LLM, conf=0.94)

  cites Baumann et al., 2012 source

In the paper

“To date, 10 patients with kEDS-FKBP14 from nine independent families have been described: Five pediatric (<12 years), three adolescents (16 years), and two adults (42-and 48-year-old) (Table S1) [Baumann et al., 2012, Aldeeri et al., 2014, Murray et al., 2014, Alazami et al., 2016, Dordoni et al., 2016].”

What the sources say

• Partly supported

  The Subjects and Methods section describes two affected people in family I and four additional people from other families; Molecular Analysis identifies those additional families as II–V. Baumann et al. therefore support six patients from five families, but do not establish the cited cumulative total of 10 patients from nine families. (LLM, conf=0.88)

  cites Baumann et al., 2012 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites Aldeeri et al., 2014 source
• ?Not checked — no full text of the sourcecites Murray et al., 2014 source

In the paper

“The mutations result in decreased activity of ADAMTS-2, which leads to defects in processing of type I procollagen to mature type I collagen [Colige et al., 1999;Colige et al., 2004;Van Damme et al., 2016].”

What the sources say

• ?Not checked — no full text of the sourcecites Colige et al., 1999 source
• Supported

  The Abstract states that ADAMTS2 mutations inactivate ADAMTS-2, the enzyme that removes the aminopropeptide from type I procollagen. It also reports that the mutations studied strongly impaired aminoprocollagen processing; the Discussion describes a near absence of fully processed type I collagen chains in affected patients. Page numbers were not supplied. (LLM, conf=0.94)

  cites Colige et al., 2004 source
• ?Not checked — no full text of the sourcecites Van Damme et al., 2016 source

In the paper

“Baumann et al. [2012] reported five families with an autosomal recessive variant of EDS, characterized by severe congenital muscle hypotonia, joint hypermobility, skin hyperextensibility, progressive kyphoscoliosis, and sensorineural hearing loss.”

What the sources say

• Supported

  The Introduction reports six affected individuals from five unrelated families with an autosomal-recessive EDS variant. The Discussion describes severe hypotonia at birth, joint hypermobility, hyperelastic skin, progressive kyphoscoliosis, and predominantly sensorineural hearing impairment. Page numbers are not provided in the supplied passages. (LLM, conf=0.94)

  cites Baumann et al., 2012 source

In the paper

“A range of clinical severity is observed in individuals with kEDS-PLOD1 for each of the systems discussed as detailed in the above section [Steinmann et al., 2002;Rohrbach et al., 2011].”

What the sources say

• ?Not checked — no full text of the sourcecites Steinmann et al., 2002 source
• Supported

  The Discussion (page not provided) reports variability in the severity and onset of kyphoscoliosis among people with EDS VIA and describes a less severe presentation without skeletal involvement. This supports the citing sentence’s point that clinical severity varies among individuals with kEDS-PLOD1. (LLM, conf=0.88)

  cites Rohrbach et al., 2011 source

In the paper

“Four different FKBP14 mutations have been identified to date [Baumann et al., 2012;Aldeeri et al., 2014;Murray et al., 2014;Dordoni et al., 2016].”

What the sources say

• Partly supported

  The Molecular Analysis section identifies two distinct FKBP14 mutations, c.362dup and c.42_60del. Baumann et al. therefore supports the existence of FKBP14 mutations but does not establish the sentence’s total of four; the sentence also cites later papers for that cumulative claim. (LLM, conf=0.88)

  cites Baumann et al., 2012 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites Aldeeri et al., 2014 source
• ?Not checked — no full text of the sourcecites Murray et al., 2014 source

In the paper

“kEDS-PLOD1 is caused by deficiency of the collagen-modifying enzyme procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1 (PLOD1 or LH1 [lysylhydroxylase1]) due to homozygosity or compound heterozygosity for mutated PLOD1 alleles.”

What the sources say

• Supported

  The Background states that kyphoscoliotic EDS is caused by deficiency of the collagen-modifying enzyme LH1 (also called PLOD1), due to homozygosity or compound heterozygosity for mutant PLOD1 alleles. This directly supports the attributed claim. (LLM, conf=0.95)

  cites Rohrbach et al., 2011 source

In the paper

“Its involvement in vertebrate development has been addressed in zebrafish studies; prdm5 was shown to be essential for convergent extension movements through regulation of Wnt signaling [Meani et al., 2009].”

What the sources say

• Partly supported

  The Results section, “prdm5 modulates CE movements during embryogenesis” (page not provided), links prdm5 depletion to disrupted convergent extension movements and altered Wnt signaling. The paper describes prdm5 as modulating these movements, but does not establish that it is essential for them; that word overstates the finding. (LLM, conf=0.82)

  cites Meani et al., 2009 sourceExperimental — accuracy not yet measured

In the paper

“More specifically, it regulates collagen transcription and fibrillogenesis by binding collagen genes and maintaining RNA polymerase II occupancy [Galli et al., 2012].”

What the sources say

• Supported

  The Introduction states that Prdm5 binds collagen genes, maintains RNA polymerase II occupancy along Col1a1, and sustains collagen I transcription. It also reports that loss of Prdm5 reduces collagen I fiber assembly, supporting the fibrillogenesis part of the claim. (LLM, conf=0.93)

  cites Galli et al., 2012 source

In the paper

“In line with its role in BCS, PRDM5 was shown to regulate transcription of ECM genes, including several collagen genes and small leucine-rich proteoglycans (SLRP) in pre-osteoblastic mouse cells.”

What the sources say

• Supported

  The Discussion (page not supplied) says Prdm5 promotes transcription of ECM genes in osteoblastic cells, targets collagens and small leucine-rich proteoglycans, and regulates collagen I and Decorin expression. It also identifies genome-wide mapping in a pre-osteoblastic cell line and describes the findings as consistent with ECM defects in brittle cornea syndrome. (LLM, conf=0.91)

  cites Galli et al., 2012 source

In the paper

“The ages at publication ranged from 2 years to 33 years [Kresse et al., 1987, Faiyaz-Ul-Haque et al., 2004, Guo et al., 2013, Arunrut et al., 2016, Salter et al., 2016].”

What the sources say

• ?Not checked — no full text of the sourcecites Kresse et al., 1987
• ?Not checked — no full text of the sourcecites Faiyaz-Ul-Haque et al., 2004 source
• Partly supported

  The Results (Clinical Report; page unavailable) describe this paper’s patient at age 10, which falls within the claimed range. The Discussion (Comparison with Previous Reports; page unavailable) identifies other B4GALT7-deficient patients, but our copy does not establish that their ages at publication—or the ages across the cited reports—ranged from 2 to 33 years. (LLM, conf=0.81)

  cites Guo et al., 2013 sourceExperimental — accuracy not yet measured

In the paper

“The second mutation, a homozygous missense variant c.221G>A, p.(Gly64Asp) [Bin et al., 2011] has been identified in two siblings from Portugal”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Bin et al., 2011
• Partly supported

  The Results report that both affected siblings were homozygous for SLC39A13 c.221G>A, and the Case reports say their parents came from Portugal. However, the Results identify the predicted substitution as Gly74Asp (G74D), not Gly64Asp. (LLM, conf=0.90)

  cites Fukada et al., 2008 sourceExperimental — accuracy not yet measured

In the paper

“To date, eight patients with spEDS-SLC39A13 from three independent families have been described: Three pediatric (<12 years), two adolescents (12.5 and 14.5 years), and three adults (>20 years)”

What the sources say

• Partly supported

  The Case reports section (page unavailable) describes two affected adult siblings in one family, and the Discussion (page unavailable) reports two additional families described by Giunta et al. Our copy does not give a total of eight patients or the claimed breakdown of three pediatric patients, two adolescents, and three adults. (LLM, conf=0.86)

  cites Fukada et al., 2008 sourceExperimental — accuracy not yet measured
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Giunta et al., 2008b

In the paper

“Subsequently, Fukada et al. [2008] reported a third family with two affected siblings presenting with similar clinical findings who were homozygous for a missense mutation in SCL39A13”

What the sources say

• Supported

  The Results section reports two affected siblings who were homozygous for a SLC39A13 substitution, G74D. The Introduction and Discussion describe two previously reported families with a similar EDS variant, supporting the description of this as a third family. The claim prints the gene name as “SCL39A13,” rather than “SLC39A13.” Page numbers are not provided in our copy. (LLM, conf=0.93)

  cites Fukada et al., 2008 source

In the paper

“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 detachment in a 45-year-old female [Janecke et al., 2016].”

What the sources say

• Supported

  The Results (Clinical Findings) state that the female patient experienced retinal detachment in both eyes at age 45, causing right-sided blindness. The claim accurately reports the affected side and age without implying that the detachment was limited to the right eye. (LLM, conf=0.94)

  cites Janecke et al., 2016 source

In the paper

“Intranasal administration of 1-desamino-8-Darginine vasopressin (DDAVP) after trauma effectively prevented large subcutaneous hematomas in three patients [Kosho et al., 2010;Janecke et al., 2016].”

What the sources say

• ?Not checked — no full text of the sourcecites Kosho et al., 2010 source
• Partly supported

  The Discussion (page not provided) says intranasal DDAVP after injury has been reported to prevent further hematoma formation and notes the same outcome in the paper’s patient P3/II. It does not establish that this occurred in three patients; the nearby reference to three patients concerns bleeding-test results, not DDAVP treatment. (LLM, conf=0.86)

  cites Janecke et al., 2016 sourceExperimental — accuracy not yet measured

In the paper

“These findings were compatible with a myopathy, similar to other EDS types [Voermans et al., 2012].”

What the sources say

• Supported

  The Discussion states that muscle ultrasound, electromyography, and biopsy findings in the patient pointed to a myopathy, similarly to findings in other EDS types. This directly supports the citing sentence. (LLM, conf=0.95)

  cites Voermans et al., 2012 source

In the paper

“To date, nine patients from five families with myopathic EDS have been reported [Hicks et al., 2014;Zou et al., 2014;Punetha et al., 2016]”

What the sources say

• ?Not checked — no full text of the sourcecites Hicks et al., 2014 source
• Partly supported

  The Clinical findings section reports two affected brothers in family A and one affected boy in family B. This supports three patients from two families as part of the cited reports, but this paper does not establish the sentence’s total of nine patients from five families. (LLM, conf=0.88)

  cites Zou et al., 2014 sourceExperimental — accuracy not yet measured
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Punetha et al., 2016

In the paper

“Elevation of serum CK (creatine kinase) level was described in four patients (277, 698, 1838, 3000 IU/L) [Janecke et al., 2016].”

What the sources say

• Partly supported

  The Results (Clinical Findings; page unavailable) report elevated CK values of 698, 1,838, and 3,000 U/L in three patients. The Discussion says one earlier case had elevated CK, supporting a total of four, but the supplied passages and targeted searches do not verify the claimed 277 IU/L value. (LLM, conf=0.87)

  cites Janecke et al., 2016 sourceExperimental — accuracy not yet measured

In the paper

“Atrophic scars were present in 50% of cases [Kapferer-Seebacher et al., 2016].”

What the sources say

• Partly supported

  The Results section (Clinical Characteristics of Periodontal EDS; page unavailable) reports that 50% of affected individuals had abnormal scars, defined as atrophic or wide. It does not report that 50% had atrophic scars specifically. (LLM, conf=0.90)

  cites Kapferer-Seebacher et al., 2016 sourceExperimental — accuracy not yet measured

In the paper

“In 17 of these families, heterozygous missense or in-frame insertion/deletion mutations in C1R (15 families) or C1S (two families) were identified.”

What the sources say

• Supported

  The Introduction reports heterozygous C1R mutations in 15 of 19 families and C1S mutations in two. The Discussion identifies the alterations as mono-allelic missense or in-frame insertion/deletions. Together, these passages support the claim. (LLM, conf=0.95)

  cites Kapferer-Seebacher et al., 2016 source

In the paper

“Variants never involved the catalytic domain of C1r or C1s [Kapferer-Seebacher et al., 2016].”

What the sources say

• Supported

  The Results section (Protein Variant Modeling) states that the C-terminal catalytic serine-protease domains of C1r and C1s were unaffected by the identified alterations. This directly supports the claim about the variants studied in this paper. (LLM, conf=0.94)

  cites Kapferer-Seebacher et al., 2016 source

In the paper

“A characteristic recently described feature is a striking lack of attached gingiva causing oral tissue fragility (Fig. 1) [Kapferer-Seebacher et al., 2016].”

What the sources say

• Supported

  The Results section (Clinical Characteristics of Periodontal EDS) describes a striking lack of attached gingiva causing oral tissue fragility as a unique structural anomaly in affected individuals who were specifically examined. The Discussion also explains how the absence of attached gingiva causes that fragility. (LLM, conf=0.95)

  cites Kapferer-Seebacher et al., 2016 source

In the paper

“In 2016, an international consortium published 19 independent families comprising 107 individuals with pEDS to identify the genetic locus [Kapferer-Seebacher et al., 2016].”

What the sources say

• Supported

  The Abstract states that an international consortium recruited 19 independent families comprising 107 individuals with pEDS. The Genetic Results section confirms the same family and individual counts and describes the molecular investigations used to identify the genetic cause. (LLM, conf=0.95)

  cites Kapferer-Seebacher et al., 2016 source

In the paper

“In the past, the delineation of pEDS as a specific phenotype was hampered by the relatively high prevalence of chronic periodontitis, with an estimated range from 19 to 83% depending on age and severity [Demmer et al., 2010].”

What the sources say

• ?Could not verify

  The Results (page unavailable) report periodontal pocket-depth measurements in INVEST participants, not a 19–83% prevalence range for chronic periodontitis. A search for that range and for pEDS phenotype delineation found no passage addressing either point. (LLM, conf=0.72)

  cites Demmer et al., 2010 sourceExperimental — accuracy not yet measured

In the paper

“Biochemical analysis of collagen in cultured skin fibroblasts did not show abnormalities in the production and secretion of type I, III, and V collagens in several case reports and also in eight individuals with confirmed mutations in C1S/C1R [Biesecker et al., 1991;Cunniff and Williamson-Kruse, 1995;Kapferer-Seebacher et al., 2016].”

What the sources say

• ?Not checked — no full text of the sourcecites Biesecker et al., 1991 source
• ?Not checked — no full text of the sourcecites Cunniff and Williamson-Kruse, 1995 source
• Supported

  The Results section (Clinical Laboratory Studies; page unavailable) reports no abnormalities in production or secretion of type I, III, and V collagens in cultured skin fibroblasts from family 1. It also reports normal collagen analyses for two named individuals and the probands of six other families, matching the eight individuals attributed to this source. (LLM, conf=0.92)

  cites Kapferer-Seebacher et al., 2016 source

In the paper

“Additionally, patients' fibroblasts showed an increased proportion of dilated rough ER (RER) cisternae [Reinstein et al., 2012;Kapferer-Seebacher et al., 2016].”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Reinstein et al., 2012
• Partly supported

  The Results (Expression Studies; page unavailable) report increased dilated RER cisternae in HEK293 cells transfected with a patient-associated C1R mutation, compared with controls—not in patients’ fibroblasts. The Discussion says the finding was similar to that seen in skin in situ, but does not establish the claimed finding in patients’ fibroblasts. (LLM, conf=0.88)

  cites Kapferer-Seebacher et al., 2016 sourceExperimental — accuracy not yet measured

In the paper

“Electron microscopy examination of skin reported in seven individuals with C1R/C1S mutations showed decreased collagen content, abnormal variation in collagen fibril diameter and some abnormally shaped fibrils [Rahman et al., 2003;Reinstein et al., 2012Reinstein et al., , 2013;;Kapferer-Seebacher et al., 2016], which is in line with further reports [Kobayasi, 2004;Mataix et al., 2008].”

What the sources say

• ?Not checked — no full text of the sourcecites Rahman et al., 2003 source
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Reinstein et al., 2012
• Supported

  The Results section (Clinical Laboratory Studies; page unavailable) reports all three collagen abnormalities in skin examined by electron microscopy in families 4 and 5, with similar findings in three people from family 1 and two other named individuals. It does not explicitly state a total of seven, but the individuals it describes are consistent with that count. (LLM, conf=0.86)

  cites Kapferer-Seebacher et al., 2016 source

In the paper

“All three adults had severe cardiovascular complications.”

In the paper

“Generalized joint hypermobility was reported in four patients.”

In the paper

“Easy bruising was reported in all patients (n ¼ 6).”

In the paper

“To date, six patients from five families have been reported with the p. (Arg312Cys) (Table S1).”

In the paper

“There are no reported genotype-phenotype correlations.”

In the paper

“In 19 of these patients (15 families), the molecular diagnosis is known.”

In the paper

“The atrophic scars typical for classical EDS were not observed.”

In the paper

“It is noted that all reported patients had hyperextensible skin, frequently described to be soft and velvety of structure.”

In the paper

“Obligate carriers displayed no overt symptoms.”

In the paper

“All four reported adults had severe cardiac-valvular problems, resulting in valve replacement surgery.”

In the paper

“Congenital bilateral hip dislocation was described in all reported patients (n ¼ 41).”

In the paper

“In five out of the 24 reported patients, no genetic confirmation of the clinical diagnosis after TNX serum measurement was performed.”

In the paper

“A total of 24 patients with a complete TNX-deficiency without involvement of the CYP21B gene have been reported.”

In the paper

“The patients harboring the c.2927_2928delCT and the c.2751-2A>T mutations have a relatively milder phenotype compared to the others.”

In the paper

“Skin abnormalities are almost universally described.”

In the paper

“To date 15 patients from 14 independent families have been reported.”

In the paper

“In contrast, open reductions with an iliac osteotomy, with or without femoral osteotomy, were favorable in some patients.”

In the paper

“One of the most consistent clinical findings was an umbilical hernia at birth (n ¼ 14).”

In the paper

“Sufficient clinical data are available for nine patients.”

In the paper

“No specific work has been carried out looking at genotype-phenotype correlations.”

In the paper

“Almost all patients have joint hypermobility (n ¼ 69).”

In the paper

“Kyphoscoliotic EDS was the first inborn error of human collagen metabolism to be defined at the biochemical level, as early as 1972.”

What the sources say

• ?Not checked — no full text of the sourcecites Krane et al., 1972 source
• ?Not checked — no full text of the sourcecites Pinnell et al., 1972 source

In the paper

“The outcome was very variable and the final ability to walk ranged from myopathic gait, impossibility of walking without aids, to a motor self-sufficiency from 200 m to 1 km.”

In the paper

“Most patients were born with a severe and recognizable facial gestalt, including prominent and protuberant eyes with puffy, edematous eyelids and excessive periorbital skin, large fontanels and/or wide cranial sutures, a hypoplastic chin and bluish or greyish discoloration of the sclerae (n ¼ 12).”

In the paper

“Approximately, one third was affected with hearing loss (n ¼ 19).”

In the paper

“Their age ranged between 6 months and 48 years.”

In the paper

“Secondary glaucoma was reported in several patients (n ¼ 5), particularly those with extensive corneal damage following rupture.”

In the paper

“Soft connective tissue herniations were reported in five patients.”

In the paper

“The combined hearing loss and decreased visual acuity often led to severe sensorineural disability.”

In the paper

“Both inter-and intrafamilial variability with respect to age of onset and progression of deafness were observed.”

In the paper

“The most consistent ophthalmic feature was blue sclerae (n ¼ 49).”

In the paper

“Keratoconus has also been diagnosed in a young adult, heterozygous for a PRDM5 mutation [Burkitt Wright et al., 2011].”

What the sources say

• ?Not checked — no full text of the sourcecites Burkitt Wright et al., 2011 source

In the paper

“To provide a comprehensive overview of the clinical phenotype of BCS, we reviewed the data on 51 patients (ZNF469: n¼ 32; PRDM5: n ¼ 19) (Table S1) [Al-Hussain et al., 2004;Abu et al., 2008;Christensen et al., 2010;Khan et al., 2010;Burkitt Wright et al., 2011;Al-Owain et al., 2012;Aldahmesh et al., 2012;Rohrbach et al., 2013;Ramappa et al., 2014;Avgitidou et al., 2015b;Porter et al., 2015].”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Al-Hussain et al., 2004
• ?Not checked — no full text of the sourcecites Abu et al., 2008 source
• ?Not checked — no full text of the sourcecites Burkitt Wright et al., 2011 source

In the paper

“Fractures (n ¼ 5) and osteopenia/osteoporosis (n ¼ 2) have been reported in a limited number of patients.”

In the paper

“Notably and in contrast to kEDS, vascular and visceral fragility has not been described in the context of BCS.”

In the paper

“Prior to rupture, visual acuity in BCS patients was often affected by keratoconus and/or keratoglobus (n ¼ 27) and high myopia (n ¼ 17).”

In the paper

“Heterozygous carriers may have very mild corneal thinning (e.g., CCT around 500 mm).”

In the paper

“There is currently no evidence of a clear genotype-phenotype correlation: All types of mutations scattered across both genes appear to cause indistinguishable clinical phenotypes.”

In the paper

“Four highly deleterious mutations are found outside the catalytic domain, one mutant lacking the initiation Met codon (p.(Met1?), one mutant in the cytoplasmic tail (p.(Arg6Trp)), and two in the stem region (p.(Ser65Gly) and p. (Pro67Leu)).”

In the paper

“Arunrut et al. [2016] reported a patient with congenital cloudy cornea, bilateral high hypermetropia, pendular nystagmus, coloboma of iris and optic nerves, and posterior subcapsular cataracts.”

What the sources say

• ?Not checked — no full text of the sourcecites Arunrut et al., 2016 source

In the paper

“At present, 47 patients from 36 families with molecularly confirmed spEDS-B3GALT6 have been identified”

In the paper

“The ages at publication ranged from birth to 33 years”

In the paper

“The hallmarks of the disorder include: (1) Characteristic craniofacial features”

In the paper

“The hallmarks of the disorder include: (1) Characteristic craniofacial features, (2) kyphoscoliosis”

In the paper

“Of note, none of the patients was described to have progeroid features.”

In the paper

“Obligate carriers display no overt clinical symptoms.”

In the paper

“The hallmarks of the disorder include: (1) Characteristic craniofacial features, (2) kyphoscoliosis, (3) joint hypermobility, mostly of distal joint, (4) joint contractures”

In the paper

“Other mutations are located in the luminal catalytic domain.”

In the paper

“The hallmarks of the disorder include: (1) Characteristic craniofacial features, (2) kyphoscoliosis, (3) joint hypermobility, mostly of distal joint, (4) joint contractures, (5) short stature, (6) muscle hypotonia”

In the paper

“The hallmarks of the disorder include: (1) Characteristic craniofacial features, (2) kyphoscoliosis, (3) joint hypermobility, mostly of distal joint, (4) joint contractures, (5) short stature, (6) muscle hypotonia, (7) osteoporosis with multiple fractures”

In the paper

“Except for the homozygous p. (Arg179_Arg180dup), compound heterozygosity always included a missense mutation on one of the two alleles.”

In the paper

“Detailed clinical data are available for 36 patients.”

In the paper

“The hallmarks of the disorder include: (1) Characteristic craniofacial features, (2) kyphoscoliosis, (3) joint hypermobility, mostly of distal joint”

In the paper

“The hallmarks of the disorder include: (1) Characteristic craniofacial features, (2) kyphoscoliosis, (3) joint hypermobility, mostly of distal joint, (4) joint contractures, (5) short stature”

In the paper

“The hallmarks of the disorder include: (1) Characteristic craniofacial features, (2) kyphoscoliosis, (3) joint hypermobility, mostly of distal joint, (4) joint contractures, (5) short stature, (6) muscle hypotonia, (7) osteoporosis with multiple fractures, (8) radiographic skeletal abnormalities compatible with SEMD”

In the paper

“At present seven patients from six families with molecularly confirmed spEDS-B4GALT7 have been identified (Table S1).”

In the paper

“One patient with low-impact rib and vertebral fractures in infancy received bisphosphonate treatment, with improvement of bone pain and muscle function [Salter et al., 2016].”

What the sources say

• ?Not checked — no full text of the sourcecites Salter et al., 2016 source

In the paper

“The hallmarks of the disorder include: (1) Characteristic craniofacial features, (2) kyphoscoliosis, (3) joint hypermobility, mostly of distal joint, (4) joint contractures, (5) short stature, (6) muscle hypotonia, (7) osteoporosis with multiple fractures, (8) radiographic skeletal abnormalities compatible with SEMD, and (9) intellectual disability”

In the paper

“Joint contractures were frequent (n ¼ 21)”

In the paper

“Slender tapering fingers were also reported in the majority of the affected.”

In the paper

“Short stature with height at the third centile or below was reported for all patients but one, whose height was at the 10th centile at age 8.5 years.”

In the paper

“Three mutations have been identified so far in a total of eight patients from three independent families.”

In the paper

“The adult patients presented with mildly shortened truck.”

In the paper

“No pregnancies have been reported in the affected individuals.”

In the paper

“Protuberant eyes and down-slanting palpebral fissures were described in the majority of affected from the three families.”

In the paper

“All affected individuals were born at term from uncomplicated pregnancies.”

In the paper

“Severe short stature was frequently reported (n ¼ 26).”

In the paper

“Refractive errors, typically myopia (n ¼ 12) followed by astigmatism (n ¼ 5) and hyperopia (n ¼ 4), were described in 16 patients;”

In the paper

“Skin hyperextensibility (from childhood) and redundancy (from adolescence) (n ¼ 24), bruisability (n ¼ 22), and fragility with atrophic scars (n ¼ 23) were common.”

In the paper

“Three patients (one child, two adult women) from two families have been published with recessive DSE1 mutations”

In the paper

“Valve abnormalities and/or aortic root dilatation were also detected in seven patients.”

In the paper

“Acrogeria-like fine palmar creases or wrinkles were characteristic and became evident with aging (n ¼ 29).”

In the paper

“Recurrent subcutaneous infections with fistula formation were also observed (n ¼ 8).”

In the paper

“Hyperalgesia to pressure was suggested (n ¼ 8) because patients disliked being hugged in infancy or disliked blood pressure measurement in the upper arms.”

In the paper

“Skin hyperextensibility (from childhood) and redundancy (from adolescence) (n ¼ 24), bruisability (n ¼ 22), and fragility with atrophic scars (n ¼ 23) were common.”

In the paper

“Recurrent large subcutaneous hematomas (skull, extremities, or hips) are a serious complication that can, even after minor trauma, progress acutely and massively to hemorrhagic shock requiring intensive treatment (hospital admission, blood transfusion, or surgical drainage) (n ¼ 21).”

In the paper

“described in 16 patients; strabismus in 13 patients; microcornea in 13; glaucoma or elevated intraocular pressure in eight; and retinal detachment in seven.”

In the paper

“Progressive talipes deformities (planus, valgus, or severer) (n ¼ 27) and spinal deformities (decreased physiological curvature, scoliosis, or kyphoscoliosis) (n ¼ 23) were observed.”

In the paper

“Congenital heart defects, typically ASD, were detected in seven patients.”

In the paper

“Marfanoid habitus (n ¼ 13); recurrent, chronic or easy joint dislocations (n ¼ 19), and pectus deformities (flat and thin, excavatum, or carinatum) (n ¼ 18) were also noted.”

In the paper

“Marfanoid habitus (n ¼ 13); recurrent, chronic or easy joint dislocations (n ¼ 19), and pectus deformities (flat and thin, excavatum, or carinatum) (n ¼ 18) were also noted.”

In the paper

“Marfanoid habitus (n ¼ 13); recurrent, chronic or easy joint dislocations (n ¼ 19), and pectus deformities (flat and thin, excavatum, or carinatum) (n ¼ 18) were also noted.”

In the paper

“Skin hyperextensibility (from childhood) and redundancy (from adolescence) (n ¼ 24), bruisability (n ¼ 22), and fragility with atrophic scars (n ¼ 23) were common.”

In the paper

“strabismus in 13 patients; microcornea in 13; glaucoma or elevated intraocular pressure in eight; and retinal detachment in”

In the paper

“Finger shapes were characteristically described as “arachnodactyly, ” “tapering,” “slender,” or “cylindrical” (n ¼ 36).”

In the paper

“Progressive talipes deformities (planus, valgus, or severer) (n ¼ 27) and spinal deformities (decreased physiological curvature, scoliosis, or kyphoscoliosis) (n ¼ 23) were observed.”

In the paper

“Characteristically, the muscle weakness tends to get better with age until young adulthood with some deterioration in the 4th decade.”

In the paper

“Infectious endocarditis occurred in two patients: One was successfully treated with surgical resection of the vegetation [Kosho et al., 2010] and the other expired [Janecke et al., 2016].”

In the paper

“No apparent genotype-phenotype correlations have been described among patients with EDS caused by D4ST1 deficiency.”

In the paper

“Penetrance is complete, whereas differences in phenotypic severity among affected siblings have been suggested.”

In the paper

“The median age at which unassisted walking occurred in patients who accomplished it was 2 years 4 months (n ¼ 10; range, from 1 year 5 months to 4 years).”

In the paper

“Gross motor developmental delay was described in 23 patients mainly because of muscle hypotonia.”

In the paper

“Muscle hypotonia or weakness was described in 17 patients.”

In the paper

“There is significant variability, within and between families, with individuals carrying the same mutation presenting with different degrees of severity.”

In the paper

“There are no documented instances of non-penetrance.”

In the paper

“Extensive periodontal destruction with early onset is a core finding of periodontal EDS, mostly in combination with striking pre-tibial plaques and tissue fragility.”

In the paper

“Prior to periodontitis, affected individuals may present with extensive gingival inflammation in response to mild dental plaque accumulation.”

In the paper

“Until recent, pEDS has not been associated with catastrophic vascular complications or hollow visceral rupture that arise in vEDS.”

In the paper

“Pretibial plaques with or without haemosiderosis are a consistent feature in most reports.”

In the paper

“(F) progressive foot deformities at age 15 years.”

In the paper

“(B and C) Abnormal scar formation in two patients.”

In the paper

“(D) Abnormal dentition and hypodontia.”

In the paper

“(C) Severe kyphoscoliosis in a patient homozygous for a causative mutation in FKBP14”

In the paper

“(D) Characteristic wrinkling palmar creases.”

In the paper

“There is no curative treatment for this disorder.”

In the paper

“a mother and her two sons (H-J) with a c.279þ2T>C in COL1A2.”

In the paper

“(A and B) Kyphoscoliosis in two unrelated patients homozygous for causative mutations in PLOD1.”

In the paper

“Other patients have not had evidence of vasculitis.”

In the paper

“The p.(Pro281Leu) was most frequent (n ¼ 9)”

In the paper

“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.”

In the paper

“(A and C) Congenital contractures of fingers including adducted thumbs (A) and cylindrical fingers at age 24 years (C).”

In the paper

“(C) Dental radiograph of an affacted individual, at aged 29.Notice severe periodontal bone loss (asteriks).”

In the paper

“PCR of the patients DNA revealed a 30 kb deletion in chromosome 6 overlapping both the CYP21B gene and the TNXB gene.”

What the sources say

• ?Not checked — no full text of the sourcecites Burch et al. [1997] source

In the paper

“Nuytinck et al. [2000] reported two children with a classical EDS phenotype, including skin hyperextensibility, easy bruising, atrophic scarring, and joint hypermobility, with a c.934C>T, p.(Arg312Cys) mutation.”

What the sources say

• ?Not checked — no full text of the sourcecites Nuytinck et al. [2000] source

In the paper

“Burch et al. [1997] first described the TNX-deficient pheno-and genotype in a male patient (26 years old) with hyperextensible skin, hypermobile joints, easy bruising and 21-hydroxylase deficiency.”

What the sources say

• ?Not checked — no full text of the sourcecites Burch et al. [1997] source

In the paper

“Other Arg-to-Cys substitutions that lead to vascular fragility EDS-like signs have only been observed in association with the p.(Arg312Cys) mutation.”

In the paper

“c.3040C>T,p.(Arg1014Cys) is associated with autosomal dominant Caffey disease [Gensure et al., 2005]”

What the sources say

• ?Not checked — no full text of the sourcecites Gensure et al., 2005 source

In the paper

“TNXB haploinsufficiency, here termed CAH-X syndrome, was present in 13 patients (and two sibs).”

What the sources say

• ?Not checked — no full text of the sourcecites Merke et al., 2013 source

In the paper

“All papers conclude that there is some degree of muscle weakness in patients with TNX-deficiency.”

What the sources say

• ?Not checked — no full text of the sourcecites Voermans et al., 2007 source
• ?Not checked — no full text of the sourcecites Ottenheijm et al., 2012 source
• ?Not checked — no full text of the sourcecites Gerrits et al., 2013 source

In the paper

“Cells from affected individuals produce type I collagen molecules that contain only proa1(I) chains.”

What the sources say

• ?Not checked — no full text of the sourcecites Schwarze et al., 2004 source

In the paper

“Although the precise function of TNX is unknown, it is known to play a role in the ECM as it is highly expressed in connective tissue of muscle, around tendons, ligaments, and in skin [Mao and Bristow, 2001].”

What the sources say

• ?Not checked — no full text of the sourcecites Mao and Bristow, 2001 source

In the paper

“Heterozygous mutations that lead to entire or partial loss of exon 6 of either COL1A1 or COL1A2 determines lack of the Ntelopeptide linking the N-propeptide to the major triple helical domain of the a1(I) or the a2(I) chain.”

What the sources say

• ?Not checked — no full text of the sourcecites Giunta et al., 1999 source

In the paper

“Arthrochalasia EDS is caused by heterozygous mutations in either COL1A1 (previously EDS type VIIA) or COL1A2 (previously EDS type VIIB).”

What the sources say

• ?Not checked — no full text of the sourcecites Giunta et al., 1999 source

In the paper

“Given that proa(I) homotrimer formation alone does not lead to OI, the OI phenotype in the latter patient suggests that the intracellular accumulation of mutant proa2(I) chains and the cellular alterations, resulting from a high rate of degradation of these chains, contributes to the skeletal phenotype.”

In the paper

“The stiffening of titin most likely compensates for the muscle weakness [Ottenheijm et al., 2012].”

What the sources say

• ?Not checked — no full text of the sourcecites Ottenheijm et al., 2012 source

In the paper

“Seven different mutations have been reported in five independent cardiacvalvular EDS patients.”

What the sources say

• ?Not checked — no full text of the sourcecites Schwarze et al., 2004 source

In the paper

“Twelve of 13 patients with CAH-X had EDS clinical features.”

What the sources say

• ?Not checked — no full text of the sourcecites Merke et al., 2013 source

In the paper

“Three of the seven patients were found to have mitral valve abnormalities (billowing of the mitral valve in two patients of the same family and a severe mitral valve prolapse (MVP) in another patient).”

What the sources say

• ?Not checked — no full text of the sourcecites Peeters et al. [2004]

In the paper

“In contrast, the EDS phenotype that results from unstable mRNA and no proa2(I) chains reflects what appears to be a more limited response in the ECM.”

In the paper

“Classical-like EDS is caused by a complete lack of TNX due to homozygous or compound heterozygous TNXB mutations, that lead to nonsense-mediated mRNA decay (NMD), or biallelic deletion of TNXB.”

What the sources say

• ?Not checked — no full text of the sourcecites Mao and Bristow, 2001 source

In the paper

“The biallelic COL1A2 mutations result in the complete absence of proa2(I)chains.”

What the sources say

• ?Not checked — no full text of the sourcecites Schwarze et al., 2004 source

In the paper

“The c.362dup, p.(Glu122Argfs à 7) has been identified in homozygous state in five independent families.”

In the paper

“Because the number of patients with a COL1A1 mutation is small, it is uncertain whether this correlation holds true [Giunta et al., 2008a].”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Giunta et al., 2008a

In the paper

“The milder phenotype could be due to the fact that NMD might be only partially efficient for these alleles and some transcripts can escape NMD.”

In the paper

“FKBP14 encodes FKBP22, a member of the F506-binding family of peptidylprolyl cis-trans isomerases found in the lumen of the endoplasmic reticulum (ER)”

What the sources say

• ?Not checked — no full text of the sourcecites Galat, 2003 source

In the paper

“This difference in the stoichiometry suggests that COL1A1-associated aEDS might be more severe than COL1A2-assiated aEDS.”

In the paper

“Dermatosparaxis EDS (dEDS) is caused by homozygous or compound heterozygous mutations in ADAMTS2, the gene that encodes ADAMTS-2.”

What the sources say

• ?Not checked — no full text of the sourcecites Colige et al., 1999 source

In the paper

“In view of the major clinical overlap of this phenotype with kEDS-PLOD1, both conditions are grouped within the same clinical entity (”

In the paper

“Brittle cornea syndrome is a rare autosomal recessive generalized HCTD, hallmarked by a thin and fragile cornea that tends to perforate spontaneously or after minor trauma.”

What the sources say

• ?Not checked — no full text of the sourcecites Ticho et al., 1980 source
• ?Not checked — no full text of the sourcecites Cameron, 1993 source

In the paper

“A homozygous deletion of four amino acids was recently reported: c.197þ5_197þ8delGTAA [Alazami et al., 2016].”

What the sources say

• ?Not checked — no full text of the sourcecites Alazami et al., 2016 source

In the paper

“In view of the major clinical overlap of EDS caused by B4GALT7 mutations with the phenotypes caused by B3GALT6 and by SLC39A13 mutations, these three conditions are now grouped within the same clinical entity (”

In the paper

“Genome-wide association studies have consistently associated single nucleotide polymorphisms (SNPs) in the vicinity of the ZNF469 locus with central corneal thickness (CTT) [Lu et al., 2010;Vitart et al., 2010;Vithana et al., 2011;Hoehn et al., 2012;Ulmer et al., 2012]”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Lu et al., 2010
• ?Not checked — no full text of the sourcecites Vitart et al., 2010 source
• ?Not checked — no full text of the sourcecites Vithana et al., 2011 source

In the paper

“This suggests that recessive mutations in ZNF469 and PRDM5 could be a rare cause of isolated keratoconus or corneal rupture.”

In the paper

“Hernandez et al. [1979Hernandez et al. [ , 1981Hernandez et al. [ , 1986] ] reported five patients with EDS-features and features of early aging, including wrinkled facies, significant growth failure, fine/curly hair, periodontitis, bilateral cryptorchidism, apparent intellectual deficit.”

What the sources say

• ?Not checked — no full text of the sourcecites Hernandez et al., 1979 source
• ?Not checked — no full text of the sourcecites Hernandez et al., 1981 source
• ?Not checked — no full text of the sourcecites Hernandez et al., 1986 source

In the paper

“This defective proteoglycan biosynthesis was shown to result from biallelic mutations in B4GALT7, encoding galactosyltransferase I [Quentin et al., 1990;Okajima et al., 1999].”

What the sources say

• ?Not checked — no full text of the sourcecites Quentin et al., 1990 source
• ?Not checked — no full text of the sourcecites Okajima et al., 1999 source

In the paper

“pathogenic ZNF469 alleles have been identified as the single most significant genetic risk factor in the development of keratoconus (relative risk of 12) [Lechner et al., 2014].”

What the sources say

• ?Not checked — no full text of the sourcecites Lechner et al., 2014 source

In the paper

“Expression of both HS and CS GAG chains was affected in these patients.”

What the sources say

• ?Not checked — no full text of the sourcecites Malfait et al., 2013 source

In the paper

“In view of the major clinical overlap of EDS caused B3GALT6 mutations, with the phenotypes caused by B4GALT7 and by SLC39A13 mutations, these three conditions are grouped within the same clinical entity (”

In the paper

“In 2013, two independent research studies identified biallelic mutations in B3GALT6, encoding b3GalT6 (galactosyltransferase II or b1,3-galactosyltransferase 6), in two different conditions.”

In the paper

“Coincidently, Malfait et al. [2013] identified B3GALT6 mutations in three unrelated families with a pleiotropic EDS-like connective tissue disorder, characterized by severe kyphoscoliosis, joint hypermobility and contractures, multiple early-onset fractures, SEMD, skin fragility, and intellectual disability.”

What the sources say

• ?Not checked — no full text of the sourcecites Malfait et al., 2013 source

In the paper

“Finally the b4GalT7deficient cells showed reduced proliferation rates compared to controls.”

What the sources say