The Ehlers–Danlos syndromes, rare types

Two other 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 adults with vascular rupture but without EDS signs.

“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].”

• cites Malfait et al., 2007 sourcePartly 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)

  Experimental — accuracy not yet measured

The COL1A1 p.(Arg312Cys) mutation has subsequently been identified in two other individuals with EDS and complications of vascular fragility.

“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].”

• cites Ritelli et al., 2013 sourceSupported
• cites Gaines et al., 2015 sourceNot checked — no full text of the source

Schalkwijk et al. detected a complete TNX deficiency in five EDS patients and three affected siblings, one of whom had the contiguous gene syndrome.

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

• cites Schalkwijk et al. [2001] sourceSupported

The COL1A1 p.(Arg312Cys) mutation was identified in an adult who suffered a rupture of medium-sized arteries reminiscent of vascular EDS.

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

• cites Malfait et al. [2007] sourcePartly 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)

  Experimental — accuracy not yet measured

Patients with the COL1A1 p.(Arg312Cys) mutation are particularly at risk for vascular events.

“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.”

• cites Malfait et al. [2007] sourceSupported
• cites Ritelli et al., 2013 sourceSupported
• cites Gaines et al., 2015 sourceNot checked — no full text of the source

Pregnancy is without major complications in TNX-deficient patients, apart from one incident of postpartum hemorrhage.

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

• cites Egging et al. [2008] sourceSupported

TNXB haploinsufficiency is associated with hypermobile EDS.

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

• cites Zweers et al., 2003 sourceSupported

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

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

• cites Schalkwijk et al., 2001 sourcePartly 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)

  Experimental — accuracy not yet measured
• cites Peeters et al., 2004Not checked — no full text of the source
• cites Demirdas et al., 2016Not matched

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

Family members with a haploinsufficient mutation in the TNXB gene have been described to have symptoms of joint hypermobility in 60% of cases.

“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].”

• cites Zweers et al., 2003 sourcePartly 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)

  Experimental — accuracy not yet measured

The kEDS-FKBP14 condition is caused by biallelic mutations in FKBP14.

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

• cites Baumann et al., 2012 sourceSupported

To date, 10 patients with kEDS-FKBP14 from nine independent families have been described.

“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].”

• cites Baumann et al., 2012 sourcePartly 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)

  Experimental — accuracy not yet measured
• cites Aldeeri et al., 2014 sourceNot checked — no full text of the source
• cites Murray et al., 2014 sourceNot checked — no full text of the source

Mutations in ADAMTS2 result in decreased activity of ADAMTS-2, leading to defects in processing of type I procollagen to mature type I collagen.

“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].”

• cites Colige et al., 1999 sourceNot checked — no full text of the source
• cites Colige et al., 2004 sourceSupported
• cites Van Damme et al., 2016 sourceNot checked — no full text of the source

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.

“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.”

• cites Baumann et al., 2012 sourceSupported

A range of clinical severity is observed in individuals with kEDS-PLOD1 for each of the systems discussed.

“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].”

• cites Steinmann et al., 2002 sourceNot checked — no full text of the source
• cites Rohrbach et al., 2011 sourceSupported

Four different FKBP14 mutations have been identified to date.

“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].”

• cites Baumann et al., 2012 sourcePartly 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)

  Experimental — accuracy not yet measured
• cites Aldeeri et al., 2014 sourceNot checked — no full text of the source
• cites Murray et al., 2014 sourceNot checked — no full text of the source

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

“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.”

• cites Rohrbach et al., 2011 sourceSupported

In zebrafish studies, prdm5 was shown to be essential for convergent extension movements through regulation of Wnt signaling.

“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].”

• cites Meani et al., 2009 sourcePartly 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)

  Experimental — accuracy not yet measured

PRDM5 regulates collagen transcription and fibrillogenesis by binding collagen genes and maintaining RNA polymerase II occupancy.

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

• cites Galli et al., 2012 sourceSupported

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.

“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.”

• cites Galli et al., 2012 sourceSupported

The ages at publication of spEDS-B4GALT7 patients ranged from 2 years to 33 years.

“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].”

• cites Kresse et al., 1987Not checked — no full text of the source
• cites Faiyaz-Ul-Haque et al., 2004 sourceNot checked — no full text of the source
• cites Guo et al., 2013 sourcePartly 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)

  Experimental — accuracy not yet measured

The second SLC39A13 mutation, homozygous missense c.221G>A, p.(Gly64Asp), has been identified in two siblings from Portugal.

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

• cites Bin et al., 2011Not matched

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

• cites Fukada et al., 2008 sourcePartly 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)

  Experimental — accuracy not yet measured

To date, eight patients with spEDS-SLC39A13 from three independent families have been described: three pediatric, two adolescents, and three adults.

“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)”

• cites Fukada et al., 2008 sourcePartly 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)

  Experimental — accuracy not yet measured
• cites Giunta et al., 2008bNot matched

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

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

“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”

• cites Fukada et al., 2008 sourceSupported

Right-sided blindness because of retinal detachment was described in a 45-year-old female.

“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].”

• cites Janecke et al., 2016 sourceSupported

Intranasal administration of DDAVP after trauma effectively prevented large subcutaneous hematomas in three patients.

“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].”

• cites Kosho et al., 2010 sourceNot checked — no full text of the source
• cites Janecke et al., 2016 sourcePartly 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)

  Experimental — accuracy not yet measured

These findings were compatible with a myopathy, similar to other EDS types.

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

• cites Voermans et al., 2012 sourceSupported

To date, nine patients from five families with myopathic EDS have been reported.

“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]”

• cites Hicks et al., 2014 sourceNot checked — no full text of the source
• cites Zou et al., 2014 sourcePartly 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)

  Experimental — accuracy not yet measured
• cites Punetha et al., 2016Not matched

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

Elevation of serum CK level was described in four patients (277, 698, 1838, 3000 IU/L).

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

• cites Janecke et al., 2016 sourcePartly 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)

  Experimental — accuracy not yet measured

Atrophic scars were present in 50% of pEDS cases with C1R or C1S mutations.

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

• cites Kapferer-Seebacher et al., 2016 sourcePartly 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)

  Experimental — accuracy not yet measured

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

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

• cites Kapferer-Seebacher et al., 2016 sourceSupported

Variants never involved the catalytic domain of C1r or C1s.

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

• cites Kapferer-Seebacher et al., 2016 sourceSupported

A characteristic recently described feature of pEDS is a striking lack of attached gingiva causing oral tissue fragility.

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

• cites Kapferer-Seebacher et al., 2016 sourceSupported

In 2016, an international consortium published 19 independent families comprising 107 individuals with pEDS to identify the genetic locus.

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

• cites Kapferer-Seebacher et al., 2016 sourceSupported

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.

“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].”

• cites Demmer et al., 2010 sourceCould 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)

  Experimental — accuracy not yet measured

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.

“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].”

• cites Biesecker et al., 1991 sourceNot checked — no full text of the source
• cites Cunniff and Williamson-Kruse, 1995 sourceNot checked — no full text of the source
• cites Kapferer-Seebacher et al., 2016 sourceSupported

Patients' fibroblasts showed an increased proportion of dilated rough ER (RER) cisternae.

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

• cites Reinstein et al., 2012Not matched

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

• cites Kapferer-Seebacher et al., 2016 sourcePartly 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)

  Experimental — accuracy not yet measured

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.

“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].”

• cites Rahman et al., 2003 sourceNot checked — no full text of the source
• cites Reinstein et al., 2012Not matched

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

• cites Kapferer-Seebacher et al., 2016 sourceSupported

All three adults with the COL1A1 p.(Arg312Cys) substitution had severe cardiovascular complications.

“All three adults had severe cardiovascular complications.”

Generalized joint hypermobility was reported in four patients with the COL1A1 p.(Arg312Cys) substitution.

“Generalized joint hypermobility was reported in four patients.”

Easy bruising was reported in all six patients with the COL1A1 p.(Arg312Cys) substitution.

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

To date, six patients from five families have been reported with the COL1A1 p.(Arg312Cys) substitution.

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

There are no reported genotype-phenotype correlations for the condition under discussion.

“There are no reported genotype-phenotype correlations.”

In 19 of these 24 patients (15 families), the molecular diagnosis is known.

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

The atrophic scars typical for classical EDS were not observed in TNX-deficient patients.

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

All reported TNX-deficient patients had hyperextensible skin, frequently described to be soft and velvety of structure.

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

Obligate carriers of the condition under discussion displayed no overt symptoms.

“Obligate carriers displayed no overt symptoms.”

All four reported adults with cardiac-valvular EDS had severe cardiac-valvular problems resulting in valve replacement surgery.

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

Congenital bilateral hip dislocation was described in all reported patients with arthrochalasia EDS (n=41).

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

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

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

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

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

Patients with dermatosparaxis EDS harboring the c.2927_2928delCT and c.2751-2A>T mutations have a relatively milder phenotype compared to others.

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

Skin abnormalities are almost universally described in kEDS-PLOD1.

“Skin abnormalities are almost universally described.”

To date, 15 patients from 14 independent families with dermatosparaxis EDS have been reported.

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

Open reductions with an iliac osteotomy, with or without femoral osteotomy, were favorable in some patients with arthrochalasia EDS.

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

One of the most consistent clinical findings in dermatosparaxis EDS was an umbilical hernia at birth (n=14).

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

Sufficient clinical data are available for nine patients with kEDS-FKBP14.

“Sufficient clinical data are available for nine patients.”

No specific work has been carried out looking at genotype-phenotype correlations in kEDS-PLOD1.

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

Almost all patients with kEDS-PLOD1 have joint hypermobility (n=69).

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

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

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

• cites Krane et al., 1972 sourceNot checked — no full text of the source
• cites Pinnell et al., 1972 sourceNot checked — no full text of the source

The outcome in kEDS-FKBP14 was very variable; final ability to walk ranged from myopathic gait, impossibility of walking without aids, to motor self-sufficiency from 200 m to 1 km.

“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.”

Most patients with dermatosparaxis EDS 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=12).

“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).”

Approximately one third of BCS patients was affected with hearing loss (n=19).

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

The age of reviewed BCS patients ranged between 6 months and 48 years.

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

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

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

Soft connective tissue herniations were reported in five BCS patients.

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

The combined hearing loss and decreased visual acuity often led to severe sensorineural disability in BCS.

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

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

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

The most consistent ophthalmic feature in BCS was blue sclerae (n=49).

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

Keratoconus has also been diagnosed in a young adult heterozygous for a PRDM5 mutation.

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

• cites Burkitt Wright et al., 2011 sourceNot checked — no full text of the source

To provide a comprehensive overview of the clinical phenotype of BCS, the authors reviewed data on 51 patients (ZNF469: n=32; PRDM5: n=19).

“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].”

• cites Al-Hussain et al., 2004Not matched

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

• cites Abu et al., 2008 sourceNot checked — no full text of the source
• cites Burkitt Wright et al., 2011 sourceNot checked — no full text of the source

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

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

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

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

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

“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).”

Heterozygous carriers of BCS-associated mutations may have very mild corneal thinning (e.g., CCT around 500 mm).

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

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

“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.”

Four highly deleterious B3GALT6 mutations are found outside the catalytic domain: p.(Met1?), p.(Arg6Trp), p.(Ser65Gly), and p.(Pro67Leu).

“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)).”

Arunrut et al. [2016] reported a spEDS-B4GALT7 patient with congenital cloudy cornea, bilateral high hypermetropia, pendular nystagmus, coloboma of iris and optic nerves, and posterior subcapsular cataracts.

“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.”

• cites Arunrut et al., 2016 sourceNot checked — no full text of the source

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

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

The ages at publication of spEDS-B3GALT6 patients ranged from birth to 33 years.

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

The hallmarks of spEDS-B3GALT6 include characteristic craniofacial features.

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

The hallmarks of spEDS-B3GALT6 include kyphoscoliosis.

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

None of the spEDS-B4GALT7 patients was described to have progeroid features.

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

Obligate carriers of spEDS-B4GALT7 display no overt clinical symptoms.

“Obligate carriers display no overt clinical symptoms.”

The hallmarks of spEDS-B3GALT6 include joint contractures.

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

Other B3GALT6 mutations are located in the luminal catalytic domain.

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

The hallmarks of spEDS-B3GALT6 include muscle hypotonia.

“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”

The hallmarks of spEDS-B3GALT6 include osteoporosis with multiple fractures.

“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”

Except for the homozygous p.(Arg179_Arg180dup), compound heterozygosity for B3GALT6 always included a missense mutation on one of the two alleles.

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

Detailed clinical data are available for 36 spEDS-B3GALT6 patients.

“Detailed clinical data are available for 36 patients.”

The hallmarks of spEDS-B3GALT6 include joint hypermobility, mostly of distal joint.

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

The hallmarks of spEDS-B3GALT6 include short stature.

“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”

The hallmarks of spEDS-B3GALT6 include radiographic skeletal abnormalities compatible with SEMD.

“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”

At present seven patients from six families with molecularly confirmed spEDS-B4GALT7 have been identified.

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

One spEDS-B4GALT7 patient with low-impact rib and vertebral fractures in infancy received bisphosphonate treatment, with improvement of bone pain and muscle function.

“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].”

• cites Salter et al., 2016 sourceNot checked — no full text of the source

The hallmarks of spEDS-B3GALT6 include intellectual disability.

“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”

Joint contractures were frequent in spEDS-B3GALT6 (n=21).

“Joint contractures were frequent (n ¼ 21)”

Slender tapering fingers were reported in the majority of affected individuals with spEDS-SLC39A13.

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

Short stature with height at the third centile or below was reported for all spEDS-SLC39A13 patients but one, whose height was at the 10th centile at age 8.5 years.

“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.”

Three SLC39A13 mutations have been identified in a total of eight patients from three independent families.

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

Adult spEDS-SLC39A13 patients presented with mildly shortened trunk.

“The adult patients presented with mildly shortened truck.”

No pregnancies have been reported in affected individuals with spEDS-SLC39A13.

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

Protuberant eyes and down-slanting palpebral fissures were described in the majority of affected individuals from the three spEDS-SLC39A13 families.

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

All affected individuals with spEDS-SLC39A13 were born at term from uncomplicated pregnancies.

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

Severe short stature was frequently reported in spEDS-B3GALT6 (n=26).

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

Refractive errors, typically myopia (n=12), followed by astigmatism (n=5) and hyperopia (n=4), were described in 16 patients.

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

Skin fragility with atrophic scars was common (n=23).

“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.”

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

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

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

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

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

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

Recurrent subcutaneous infections with fistula formation were observed (n=8).

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

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

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

Bruisability was common (n=22).

“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.”

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 (n=21).

“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).”

Retinal detachment was described in seven patients.

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

Spinal deformities (decreased physiological curvature, scoliosis, or kyphoscoliosis) were observed in 23 patients.

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

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

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

Marfanoid habitus was noted in 13 patients.

“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.”

Recurrent, chronic or easy joint dislocations were noted in 19 patients.

“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.”

Pectus deformities (flat and thin, excavatum, or carinatum) were noted in 18 patients.

“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.”

Skin hyperextensibility (from childhood) and redundancy (from adolescence) were common (n=24).

“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.”

Glaucoma or elevated intraocular pressure was described in eight patients.

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

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

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

Progressive talipes deformities (planus, valgus, or severer) were observed in 27 patients.

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

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

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

Infectious endocarditis occurred in two patients.

“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].”

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

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

Differences in phenotypic severity among affected siblings have been suggested in EDS caused by D4ST1 deficiency.

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

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

“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).”

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

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

Muscle hypotonia or weakness was described in 17 patients.

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

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

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

There are no documented instances of non-penetrance in myopathic EDS.

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

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

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

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

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

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

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

Pretibial plaques with or without haemosiderosis are a consistent feature in most reports of pEDS.

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

The mcEDS-CHST14 patient has progressive foot deformities at age 15 years.

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

Abnormal scar formation is present in two patients with spEDS-SLC39A13.

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

Abnormal dentition and hypodontia are present in patients with spEDS-SLC39A13.

“(D) Abnormal dentition and hypodontia.”

Severe kyphoscoliosis is present in a patient homozygous for a causative mutation in FKBP14.

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

The mcEDS-CHST14 patient has characteristic wrinkling palmar creases.

“(D) Characteristic wrinkling palmar creases.”

There is no curative treatment for pEDS.

“There is no curative treatment for this disorder.”

A mother and her two sons have a c.279+2T>C in COL1A2.

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

Kyphoscoliosis is present in two unrelated patients homozygous for causative mutations in PLOD1.

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

Other patients have not had evidence of vasculitis.

“Other patients have not had evidence of vasculitis.”

The p.(Pro281Leu) was most frequent (n=9) among CHST14 mutations.

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

Patients with spEDS-B3GALT6 have facial characteristics including long face with mild micrognatia in infancy, proptotic eyes with shallow orbits and blue tint to the sclerae.

“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 mcEDS-CHST14 patient has congenital contractures of fingers including adducted thumbs and cylindrical fingers at age 24 years.

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

Dental radiograph of an affected individual, at aged 29, shows severe periodontal bone loss.

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

PCR of the patient's DNA revealed a 30 kb deletion in chromosome 6 overlapping both the CYP21B gene and the TNXB gene.

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

• cites Burch et al. [1997] sourceNot checked — no full text of the source

Two children with a classical EDS phenotype including skin hyperextensibility, easy bruising, atrophic scarring, and joint hypermobility had the COL1A1 c.934C>T, p.(Arg312Cys) mutation.

“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.”

• cites Nuytinck et al. [2000] sourceNot checked — no full text of the source

Burch et al. first described a 26-year-old male patient with congenital adrenal hyperplasia due to 21-hydroxylase deficiency as well as hyperextensible skin, hypermobile joints, easy bruising, and poor wound healing.

“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.”

• cites Burch et al. [1997] sourceNot checked — no full text of the source

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

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

COL1A1 c.3040C>T, p.(Arg1014Cys) is associated with autosomal dominant Caffey disease.

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

• cites Gensure et al., 2005 sourceNot checked — no full text of the source

TNXB haploinsufficiency, termed CAH-X syndrome, was present in 13 patients and two siblings in a cohort of 192 consecutive unrelated CAH patients.

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

• cites Merke et al., 2013 sourceNot checked — no full text of the source

All papers describing research concerning muscular function in TNX-deficiency or their muscle tissue conclude that there is some degree of muscle weakness in patients with TNX-deficiency.

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

• cites Voermans et al., 2007 sourceNot checked — no full text of the source
• cites Ottenheijm et al., 2012 sourceNot checked — no full text of the source
• cites Gerrits et al., 2013 sourceNot checked — no full text of the source

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

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

• cites Schwarze et al., 2004 sourceNot checked — no full text of the source

TNX is highly expressed in connective tissue of muscle, around tendons, ligaments, and in skin.

“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].”

• cites Mao and Bristow, 2001 sourceNot checked — no full text of the source

Heterozygous mutations causing entire or partial loss of exon 6 of COL1A1 or COL1A2 determine lack of the N-telopeptide linking the N-propeptide to the major triple helical domain of the a1(I) or a2(I) chain.

“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.”

• cites Giunta et al., 1999 sourceNot checked — no full text of the source

Arthrochalasia EDS is caused by heterozygous mutations in either COL1A1 or COL1A2.

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

• cites Giunta et al., 1999 sourceNot checked — no full text of the source

Given that proa(I) homotrimer formation alone does not lead to OI, the OI phenotype in the patient with a stable mutant mRNA suggests that intracellular accumulation of mutant proa2(I) chains and cellular alterations from their high degradation rate contribute to the skeletal phenotype.

“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.”

The stiffening of titin most likely compensates for the muscle weakness in TNX-deficient EDS.

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

• cites Ottenheijm et al., 2012 sourceNot checked — no full text of the source

Seven different mutations have been reported in five independent cardiac-valvular EDS patients.

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

• cites Schwarze et al., 2004 sourceNot checked — no full text of the source

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

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

• cites Merke et al., 2013 sourceNot checked — no full text of the source

Three of seven TNX-deficient patients investigated by Peeters et al. had mitral valve abnormalities, including billowing of the mitral valve in two patients of the same family and a severe mitral valve prolapse in another patient.

“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).”

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

The EDS phenotype that results from unstable mRNA and no proa2(I) chains reflects a more limited response in the extracellular matrix.

“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.”

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, or biallelic deletion of TNXB.

“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.”

• cites Mao and Bristow, 2001 sourceNot checked — no full text of the source

Biallelic COL1A2 mutations result in the complete absence of proa2(I) chains.

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

• cites Schwarze et al., 2004 sourceNot checked — no full text of the source

The c.362dup, p.(Glu122Argfs*7) FKBP14 mutation has been identified in homozygous state in five independent families.

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

Because the number of patients with a COL1A1 mutation is small, it is uncertain whether the correlation between COL1A1 mutation and more severe arthrochalasia EDS holds true.

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

• cites Giunta et al., 2008aNot matched

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

The milder phenotype in dermatosparaxis EDS associated with c.2927_2928delCT and c.2751-2A>T could be due to NMD being only partially efficient for these alleles, allowing some transcripts to escape NMD.

“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.”

FKBP14 encodes FKBP22, a member of the F506-binding family of peptidylprolyl cis-trans isomerases found in the lumen of the endoplasmic reticulum.

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

• cites Galat, 2003 sourceNot checked — no full text of the source

The difference in stoichiometry suggests that COL1A1-associated arthrochalasia EDS might be more severe than COL1A2-associated arthrochalasia EDS.

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

Dermatosparaxis EDS is caused by homozygous or compound heterozygous mutations in ADAMTS2, the gene encoding ADAMTS-2.

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

• cites Colige et al., 1999 sourceNot checked — no full text of the source

Because of major clinical overlap between kEDS-FKBP14 and kEDS-PLOD1, both conditions are grouped within the same clinical entity, Kyphoscoliotic EDS, in the new EDS classification.

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

Brittle cornea syndrome (BCS) is a rare autosomal recessive generalized hereditary connective tissue disorder, hallmarked by a thin and fragile cornea that tends to perforate spontaneously or after minor trauma.

“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.”

• cites Ticho et al., 1980 sourceNot checked — no full text of the source
• cites Cameron, 1993 sourceNot checked — no full text of the source

A homozygous deletion of four amino acids, c.197+5_197+8delGTAA, has been reported in FKBP14.

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

• cites Alazami et al., 2016 sourceNot checked — no full text of the source

Because of major clinical overlap of EDS caused by B4GALT7 mutations with phenotypes caused by B3GALT6 and SLC39A13 mutations, these three conditions are grouped within the same clinical entity, Spondylodysplastic EDS, in the new EDS classification.

“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 (”

Genome-wide association studies have consistently associated single nucleotide polymorphisms (SNPs) in the vicinity of the ZNF469 locus with central corneal thickness (CCT).

“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]”

• cites Lu et al., 2010Not matched

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

• cites Vitart et al., 2010 sourceNot checked — no full text of the source
• cites Vithana et al., 2011 sourceNot checked — no full text of the source

Recessive mutations in ZNF469 and PRDM5 could be a rare cause of isolated keratoconus or corneal rupture.

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

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

“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.”

• cites Hernandez et al., 1979 sourceNot checked — no full text of the source
• cites Hernandez et al., 1981 sourceNot checked — no full text of the source
• cites Hernandez et al., 1986 sourceNot checked — no full text of the source

This defective proteoglycan biosynthesis was shown to result from biallelic mutations in B4GALT7, encoding galactosyltransferase I.

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

• cites Quentin et al., 1990 sourceNot checked — no full text of the source
• cites Okajima et al., 1999 sourceNot checked — no full text of the source

Pathogenic ZNF469 alleles have been identified as the single most significant genetic risk factor in the development of keratoconus (relative risk of 12).

“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].”

• cites Lechner et al., 2014 sourceNot checked — no full text of the source

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

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

• cites Malfait et al., 2013 sourceNot checked — no full text of the source

Because of major clinical overlap of EDS caused by B3GALT6 mutations with phenotypes caused by B4GALT7 and SLC39A13 mutations, these three conditions are grouped within the same clinical entity, Spondylodysplastic EDS, in the new EDS classification.

“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 2013, two independent research studies identified biallelic mutations in B3GALT6, encoding β3GalT6, in two different conditions.

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

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.

“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.”

• cites Malfait et al., 2013 sourceNot checked — no full text of the source

The β4GalT7-deficient cells showed reduced proliferation rates compared to controls.

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

• cites Seidler et al., 2006 sourceNot checked — no full text of the source

In three other families with a phenotype resembling β4GalT7-deficient EDS, targeted B3GALT6 sequencing subsequently identified causal mutations in all of them.

“In three other families with a phenotype resembling b4GalT7-deficient EDS, targeted B3GALT6 sequencing subsequently identified causal mutations in all of them.”

• cites Nakajima et al., 2013 sourceNot checked — no full text of the source

Following the identification of B3GALT6 as the causal gene for SEMD-JL1, Vorster et al. [2015] identified the same mutations and a novel p.(Thr79Ala) mutation, all located in or in the vicinity of the stem region, in eight prototype South African families.

“Following the identification of B3GALT6 as the causal gene for SEMD-JL1, Vorster et al. [2015] identified the same mutations and a novel p.(Thr79Ala) mutations, all located in or in the vicinity of the stem region, in eight prototype South African families.”

• cites Vorster et al., 2015 sourceNot checked — no full text of the source

Nakajima et al. [2013] identified B3GALT6 mutations in seven Japanese families with spondyloepimetaphyseal dysplasia with joint laxity type 1 (SEMD-JL1) by whole exome sequencing.

“Nakajima et al. [2013] identified B3GALT6 mutations in seven Japanese families with spondyloepimetaphyseal dysplasia with joint laxity type 1 (SEMD-JL1 or SEMD-JL Beighton type) by whole exome sequencing.”

• cites Nakajima et al., 2013 sourceNot checked — no full text of the source

The c.808C>T, p.(Arg270Cys) is the most frequent B4GALT7 mutation.

“The c.808C>T, p.(Arg270Cys) is most frequent.”

EDS caused by D4ST1 deficiency results from recessive mutations in CHST14, localized at 15q14.

“EDS caused by D4ST1-deficiency results from recessive mutations in the carbohydrate sulfotransferase 14 gene (CHST14), localized at 15q14.”

Malfait et al. [2010] found mutations in CHST14 through homozygosity mapping in two Turkish sisters and an Indian girl, both with parental consanguinity.

“Malfait et al. [2010] found mutations in CHST14 through homozygosity mapping in two Turkish sisters and an Indian girl, both with parental consanguinity.”

• cites Malfait et al., 2010 sourceNot checked — no full text of the source

The hallmarks of spEDS-SLC39A13 include distal joint hypermobility which later results in contractures.

“The hallmarks of the disorder include: (1) Moderate short stature; (2) hyperelastic, velvety, thin skin with an easily visible venous pattern, and bruisability which leads to atrophic scars; (3) slender, tapering fingers, wrinkled palms, and considerable thenar (and hypothenar) atrophy; (4) distal joint hypermobility which later results in contractures”

• cites Giunta et al., 2008bNot matched

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

Dündar et al. [2009] reported that loss-of-function mutations in CHST14 were causal for ATCS.

“D€ undar et al. [2009] reported that loss-of-function mutations in CHST14 was causal for the syndrome”

• cites D€ undar et al., 2009Not matched

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

A homozygous 9-bp in-frame deletion in exon 4, c.483_491del9, was found in two unrelated consanguineous families from North-Western Iraq and Southeastern Turkey.

“A homozygous 9-bp in-frame deletion in exon 4, c.483_491del9 was found in two unrelated consanguineous families originating from North-Western Iraq and the Southeastern part of Turkey, respectively.”

• cites Giunta et al., 2008bNot matched

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

Giunta et al. [2008b] reported a new clinical entity caused by a mutation in the zinc transporter gene SLC39A13.

“Giunta et al. [2008b] reported a “new” clinical entity caused by a mutation in the zinc transporter gene SLC39A13.”

• cites Giunta et al., 2008bNot matched

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

SpEDS-SLC39A13 is caused by homozygous loss-of-function mutations in the zinc transporter gene SLC39A13.

“SpEDS-SLC39A13 is caused by homozygous loss-of-function mutations in the zinc transporter gene SLC39A13.”

Dündar et al. [1997] originally reported two cousins from a consanguineous Turkish family with developmental delay, ocular abnormalities, characteristic facial features, generalized joint laxity, arachnodactyly, camptodactyly, and distal arthrogryposis with adducted thumbs and clubfeet.

“D€ undar et al. [1997] originally reported on two cousins from consanguineous Turkish family, both having developmental delay, ocular abnormalities, characteristic facial features, generalized joint laxity, arachnodactyly, camptodactyly, and distal arthrogryposis with adducted thumbs and clubfeet.”

• cites D€ undar et al., 1997Not matched

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

Malfait et al. [2010] concluded that patients with ATCS or EDS Kosho type had a single clinical condition, termed Musculocontractural EDS (MCEDS).

“The authors concluded that these patients and those diagnosed with ATCS or EDS, Kosho type had a single clinical condition, which they termed “Musculocontractural EDS (MCEDS)””

• cites Malfait et al., 2010 sourceNot checked — no full text of the source

At the protein level, c.483_491del9 leads to deletion of the highly conserved residues Phe-Leu-Ala from the third transmembrane domain of ZIP13.

“At the protein level, the c.483_491del9 mutation leads to the deletion of the highly conserved amino acid residues Phe-Leu-Ala from the third transmembrane domain of ZIP13”

• cites Giunta et al., 2008bNot matched

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

The hallmarks of spEDS-SLC39A13 include moderate short stature.

“The hallmarks of the disorder include: (1) Moderate short stature”

• cites Giunta et al., 2008bNot matched

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

ZIP13 loss-of-function leads to a generalized disturbed hydroxylation of lysyl and prolyl residues in collagen alpha chains.

“It has been shown that ZIP13 loss-of-function leads to a generalized disturbed hydroxylation of lysyl and prolyl residues in collagen a chains”

• cites Giunta et al., 2008bNot matched

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

EDS caused by D4ST1 deficiency was initially reported as three independent conditions, ATCS, EDS Kosho Type, and musculocontractural EDS, all now concluded to be a single clinical entity.

“EDS caused by D4ST1 deficiency has initially been reported as three independent conditions: A rare type of arthrogryposis syndrome, “adducted thumbclubfoot syndrome (ATCS)”; a specific type of EDS, “EDS, Kosho Type (EDSKT)”; and a subset of kEDS without lysyl hydroxylase deficiency, “musculocontractural EDS (MCEDS),” all of which are now concluded to be a single clinical entity”

• cites Kosho et al., 2005 sourceNot checked — no full text of the source
• cites Malfait et al., 2010 sourceNot checked — no full text of the source
• cites Janecke et al., 2011 sourceNot checked — no full text of the source

The hallmarks of spEDS-SLC39A13 include a ratio of urinary pyridinolines, LP/HP, of ≥1.0.

“The hallmarks of the disorder include: (1) Moderate short stature; (2) hyperelastic, velvety, thin skin with an easily visible venous pattern, and bruisability which leads to atrophic scars; (3) slender, tapering fingers, wrinkled palms, and considerable thenar (and hypothenar) atrophy; (4) distal joint hypermobility which later results in contractures; (5) characteristic radiographic abnormaliti”

• cites Giunta et al., 2008bNot matched

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

Miyake et al. [2010] identified CHST14 as the causal gene for EDS Kosho type through homozygosity mapping using two consanguineous families.

“Miyake et al. [2010] identified CHST14 as the causal gene for this condition through homozygosity mapping using the two consanguineous families.”

• cites Miyake et al., 2010 sourceNot checked — no full text of the source

The hallmarks of spEDS-SLC39A13 include characteristic radiographic abnormalities.

“The hallmarks of the disorder include: (1) Moderate short stature; (2) hyperelastic, velvety, thin skin with an easily visible venous pattern, and bruisability which leads to atrophic scars; (3) slender, tapering fingers, wrinkled palms, and considerable thenar (and hypothenar) atrophy; (4) distal joint hypermobility which later results in contractures; (5) characteristic radiographic abnormaliti”

• cites Giunta et al., 2008bNot matched

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

The amount of DS disaccharides was markedly decreased in conditioned medium and cell fraction from cultured patient fibroblasts compared to control.

“The amount of DS disaccharides was markedly decreased in the conditioned medium and cell fraction from cultured patient fibroblasts compared to control.”

• cites M€ uller et al., 2013Not matched

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

Two deliveries were described in a female patient with EDS caused by DSE deficiency, followed by uterine and bladder prolapse.

“Two deliveries were described in a female patient with EDS caused by DSE deficiency, followed by uterine and bladder prolapse”

• cites Syx et al., 2015 sourceNot checked — no full text of the source

The hallmarks of mcEDS include progressive spinal and foot deformities.

“The hallmarks of the disorder include: (1) Characteristic craniofacial features, (2) congenital multiple contractures, including adducted thumbs and talipes equinovarus, (3) characteristic cutaneous features including fine palmar creases, (4) peculiar finger shapes, (5) progressive spinal and foot deformities”

Two homozygous missense DSE mutations, p.(Arg267Gly) and p.(Ser268Leu), have been detected in DSE-deficient EDS.

“Two homozygous missense mutations (p.(Arg267Gly); p.( Ser268Leu)) have been detected”

• cites M€ uller et al., 2013Not matched

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

• cites Syx et al., 2015 sourceNot checked — no full text of the source

Skin fragility in patients with EDS caused by D4ST1 deficiency is postulated to result from impaired assembly of collagen fibrils caused by replacement of a DS with a CS chain of decorin through alterations in electrostatic binding of decorin to collagen fibrils followed by a difference in the spatial relationship between collagen fibrils and decorin.

“In view of these findings, skin fragility in patients with EDS caused by D4ST1 deficiency is postulated to result from impaired assembly of collagen fibrils caused by the replacement of a DS with a CS chain of decorin through alterations in the electrostatic binding of decorin to collagen fibrils followed by difference in the spatial relationship between collagen fibrils and decorin”

• cites Kosho, 2013 sourceNot checked — no full text of the source
• cites Kosho et al., 2014 sourceNot checked — no full text of the source
• cites Kosho, 2016 sourceNot checked — no full text of the source

The hallmarks of mcEDS include ophtalmological and urogenital involvement.

“The hallmarks of the disorder include: (1) Characteristic craniofacial features, (2) congenital multiple contractures, including adducted thumbs and talipes equinovarus, (3) characteristic cutaneous features including fine palmar creases, (4) peculiar finger shapes, (5) progressive spinal and foot deformities, (6) large subcutaneous hematomas, and (7) ophtalmological and urogenital involvement”

The hallmarks of mcEDS include congenital multiple contractures, including adducted thumbs and talipes equinovarus.

“The hallmarks of the disorder include: (1) Characteristic craniofacial features, (2) congenital multiple contractures, including adducted thumbs and talipes equinovarus”

The hallmarks of mcEDS include large subcutaneous hematomas.

“The hallmarks of the disorder include: (1) Characteristic craniofacial features, (2) congenital multiple contractures, including adducted thumbs and talipes equinovarus, (3) characteristic cutaneous features including fine palmar creases, (4) peculiar finger shapes, (5) progressive spinal and foot deformities, (6) large subcutaneous hematomas”

The hallmarks of mcEDS include peculiar finger shapes.

“The hallmarks of the disorder include: (1) Characteristic craniofacial features, (2) congenital multiple contractures, including adducted thumbs and talipes equinovarus, (3) characteristic cutaneous features including fine palmar creases, (4) peculiar finger shapes”

Deterioration in vision of the right eye because of a lacquer crack in Bruch's membrane adjacent to the right fovea was described in a 15-year-old male.

“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].”

• cites Syx et al., 2015 sourceNot checked — no full text of the source

Light microscopy of affected skin specimens showed fine collagen fibers predominantly in the reticular to papillary dermis with marked reduction of normally thick collagen bundles.

“Light microscopy of the affected skin specimens using hematoxylin and eosin staining showed that fine collagen fibers were predominantly present in the reticular to papillary dermis with marked reduction of normally thick collagen bundles”

• cites Miyake et al., 2010 sourceNot checked — no full text of the source

Progressive visual field loss was described in a 31-year-old female.

“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].”

• cites Kosho et al., 2010 sourceNot checked — no full text of the source

The hallmarks of mcEDS include characteristic cutaneous features including fine palmar creases.

“The hallmarks of the disorder include: (1) Characteristic craniofacial features, (2) congenital multiple contractures, including adducted thumbs and talipes equinovarus, (3) characteristic cutaneous features including fine palmar creases”

Collagen XII is synthesized as a homotrimer made up of three a1 collagen chains coded by COL12A1.

“Collagen XII is synthesized as a homotrimer made up of three a1 collagen chains coded by COL12A1.”

Nerve conduction studies showed low compound muscle action potential amplitudes in the distal muscles.

“Nerve conduction studies showed low compound muscle action potential amplitudes in the distal muscles.”

Pneumothorax or pneumohemothorax occurred in three adult patients, who were treated with chest tube drainage.

“Pneumothorax or pneumohemothorax occurred in three adult patients, who were treated with chest tube drainage [Kosho et al., 2010].”

• cites Kosho et al., 2010 sourceNot checked — no full text of the source

Penetrance is complete in EDS caused by D4ST1 deficiency.

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

Phenotypic features in three patients with EDS caused by DSE deficiency seemed to be milder than those in patients with EDS caused by D4ST1 deficiency.

“Phenotypic features in three patients with EDS caused by DSE deficiency seemed to be milder than those in patients with EDS caused by D4ST1 deficiency, presumably associated with the glycobiological finding that some DS moieties were present in the decorin GAG in the fibroblasts derived from patients with EDS caused by DSE deficiency, whereas DS was completely replaced by CS in the fibroblasts”

• cites Syx et al., 2015 sourceNot checked — no full text of the source

Because collagen XII is expressed in the muscle ECM, its absence results in disorganized patterning, abnormal force transmission, and other biomechanical alterations resulting in myopathy.

“Because collagen XII is expressed in the muscle ECM, its absence results in disorganized patterning, abnormal force transmission, and other biomechanical alterations resulting in myopathy.”

One adult patient could not walk unassisted because of severe foot deformities and leg muscle weakness.

“One adult patient could not walk unassisted because of severe foot deformities and leg muscle weakness [Kosho et al., 2010].”

• cites Kosho et al., 2010 sourceNot checked — no full text of the source

In another patient, quantitative muscle ultrasonography showed increased echo intensity in the forearm extensors and anterior tibial muscles as well as marked bilateral atrophy of the forearm flexors, forearm extensors, and quadriceps.

“In another patient, quantitative muscle ultrasonography showed increased echo intensity in the forearm extensors and anterior tibial muscles as well as marked bilateral atrophy of the forearm flexors, forearm extensors, and quadriceps.”

Two adults and one adolescent patient had colonic diverticula perforation, corrected surgically.

“Two adults and one adolescent patient had colonic diverticula perforation, corrected surgically [Kosho et al., 2010;Kono et al., 2016].”

• cites Kosho et al., 2010 sourceNot checked — no full text of the source
• cites Kono et al., 2016Not matched

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

Absence of collagen XII in skin and tendons would explain the overlapping EDS manifestations.

“Its absence in skin and tendons would explain the overlapping EDS manifestations.”

One adolescent patient had a severe progressive gastric ulcer, treated with partial gastrectomy.

“One adolescent patient had a severe progressive gastric ulcer, treated with partial gastrectomy [Kosho et al., 2010].”

• cites Kosho et al., 2010 sourceNot checked — no full text of the source

Deficiency of collagen XII results in lax tissues due to a mechanical problem with the ECM.

“Deficiency of this collagen results in lax tissues due to a mechanical problem with the ECM.”

Historical overlaps between pEDS and other EDS subtypes have confused the phenotype.

“These historical overlaps between pEDS and other EDS subtypes have confused the phenotype.”

Fibrosis and haemosiderin deposits were reported in pEDS, as opposed to interstitial and palisade granulomas and/or microangiopathy.

“Fibrosis and haemosiderin deposits were reported, as opposed to interstitial and palisade granulomas and/or microangiopathy 19.”

There appears to be a clear genotype-phenotype correlation in myopathic EDS.

“There appears to be a clear genotypephenotype correlation.”

In contrast, Mataix et al. [2008] reported a reduced rate of collagen (I) and collagen (III) synthesis compared to control samples.

“In contrast, Mataix et al. [2008] reported a reduced rate of collagen (I) and collagen (III) synthesis compared to control samples.”

• cites Mataix et al., 2008 sourceNot checked — no full text of the source

[1972] described a unique condition in a patient with EDS-like features, that is, lesions on the shins, slow-healing breaks in the skin, atrophic scars, and absorptive periodontitis with early loss of the teeth.

“[1972] described a “unique condition” in a patient with EDS-like features, that is, lesions on the shins, slowhealing breaks in the skin, atrophic scars, and absorptive periodontitis with early loss of the teeth.”

• cites [1972]Not matched

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

Reported abnormalities on muscle biopsy in myopathic EDS include myopathy with variability in fiber diameter, without overt signs of degeneration or regeneration.

“Reported abnormalities on muscle biopsy include myopathy with variability in fiber diameter, without overt sins of degeneration or regeneration.”

None of the other patients with myopathic EDS remained non-ambulatory.

“None of these patients remained non-ambulatory.”

The one family with the autosomal recessive condition harbors a homozygous loss of function mutation.

“The one family with the autosomal recessive condition harbors a homozygous loss of function mutation.”

The affected siblings with the autosomal recessive condition have a more severe form of the condition.

“The affected siblings have a more severe form of the condition.”

Easy bruising, skin fragility, and (mild) hyperelasticity of the skin have been reported in the majority of pEDS cases.

“Easy bruising, skin fragility, and (mild) hyperelasticity of the skin have been reported in the majority of cases.”

Defects in the initiation and modification of the GAG chains are associated with different EDS subtypes.

“Defects in the initiation and modification of the GAG chains are associated with different EDS subtypes (indicated in black boxes).”