Ni et al. BMC Medical Genetics(2020) 21:214
https://doi.org/10.1186/s12881-020-01154-3

CASE REPORTOpen Access

The first case report of Kyphoscoliotic
Ehlers-Danlos syndrome of chinese origin
with a novel PLOD1 gene mutation
Xiaolin Ni, Chenxi Jin, Yan Jiang, Ou Wang, Mei Li, Xiaoping Xing and Weibo Xia*

Abstract
Background: Kyphoscoliotic Ehlers-Danlos syndrome (kEDS) is a rare autosomal recessive connective tissue disordercharacterized by progressive kyphoscoliosis, congenital muscular hypotonia, marked joint hypermobility, and severe
skin hyperextensibility and fragility. Deficiency of lysyl hydroxylase 1 (LH1) due to mutations of PLOD1 (procollagenlysine, 2-oxoglutarate 5-dioxygenase 1) gene has been identified as the pathogenic cause of kEDS (kEDS-PLOD1).
Up to now, kEDS-PLOD1 has not been reported among Chinese population.
Case presentation: A 17-year-old Chinese male patient presenting with hypotonia, joint hypermobility andscoliosis was referred to our hospital. After birth, he was found to have severe hypotonia leading to delayed motor
development. Subsequently, joint hypermobility, kyphoscoliosis and amblyopia were found. Inguinal hernia wasfound at age 5 years and closed by surgery. At the same time, he presented with hyperextensible and bruisable
velvety skin with widened atrophic scarring after minor trauma. Dislocation of elbow joint was noted at age of
6 years. Orthopedic surgery for correction of kyphoscoliosis was performed at age 10 years. His family history was
unremarkable. Physical examination revealed elevated blood pressure. Slight facial dysmorphologies including highpalate, epicanthal folds, and down-slanting palpebral fissures were found. He also had blue sclerae with normal
hearing. X-rays revealed severe degree of scoliosis and osteopenia. The Echocardiography findings were normal.
Laboratory examination revealed a slightly elevated bone turnover. Based on the clinical manifestations presented
by our patient, kEDS was suspected. Genetic analysis revealed a novel homozygous missense mutation of PLOD1(c.1697 G > A, p.C566Y), confirming the diagnosis of kEDS-PLOD1. The patient was treated with alfacalcidol andnifedipine. Improved physical strength and normal blood pressure were reported after 12-month follow-up.
Conclusions: This is the first case of kEDS-PLOD1 of Chinese origin. We identified one novel mutation of PLOD1,
extending the mutation spectrum of PLOD1. Diagnosis of kEDS-PLOD1 should be considered in patients withcongenital hypotonia, progressive kyphoscoliosis, joint hypermobility, and skin hyperextensibility and confirmed bymutation analysis of PLOD1.
Keyword: Kyphoscoliotic ehlers-danlos syndrome; PLOD1 gene; mutation; case report* Correspondence: xiawb@pumch.cn
Department of Endocrinology, Key Laboratory of Endocrinology National
Commission of Health Peking Union College Hospital, Chinese Academy ofMedical Sciences, Shuaifuyuan No. 1, Wangfujing street Dongcheng District,
Beijing 100730, China© The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License,
which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give
appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate ifchanges were made. The images or other third party material in this article are included in the article's Creative Commonslicence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commonslicence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain
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The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to thedata made available in this article, unless otherwise stated in a credit line to the data.

Ni et al. BMC Medical Genetics(2020) 21:214

Background
Kyphoscoliotic Ehlers-Danlos syndrome (kEDS) (OMIM
225,400, previously EDS type VIA) is a rare autosomal
recessive connective tissue disorder characterized byprogressive kyphoscoliosis, congenital muscular hypotonia, severe skin hyperextensibility, and marked joint
hypermobility and dislocation [1]. In addition, fragility ofthe skin with abnormal scarring, Marfanoid habitus, hernia, microcornea, facial dysmorphology, blue sclerae, refractive errors, osteopenia, and arterial rupture could
also be presented in patients with kEDS [2]. Estimatedprevalence is approximately 1 in 100,000 live births [3].
Deficiency of procollagen-lysine, 2-oxoglutarate 5dioxygenase 1 (PLOD1) or lysyl hydroxylase 1 (LH1) due
to mutations of PLOD1 was identified as pathogenic causeof kEDS [4]. As an enzyme, LH1 plays an important rolein hydroxylation of lysyl residuel in Xaa-Lys-Gly. The
hydroxylysine residues serve as sites of attachment for
carbohydrate units which are essential for the formationof intra- and intermolecular collagen crosslinks [5]. As aresult, LH1 deficiency results in underhydroxylation oflysyl residues and underglycosylation of hydroxylysyl residues, leading to impaired collagen crosslinks formation
with consequent mechanical instability of the affected tissues [6]. Abnormal urinary excretion pattern of lysylpyridinolines (LP) and hydroxylysyl-pyridinolines (HP)cross-links (LP/HP) is a highly sensitive and specific testfor LH1 deficiency [6]. In 2012, mutations of a second
gene, FK506 binding protein 14 (FKBP14), was identified
as another cause of kEDS (kEDS-FKBP14) [7]. Althoughpatients with kEDS-FKBP14 present a clinically overlapping phenotype with PLOD1-related kEDS (kEDSPLOD1), they can still be distinguished by normal LP/HP,
presence of myopathy, and hearing impairment [7].
Although more than 40 different mutations have been
identified in the PLOD1 leading to kEDS, only seven different missense disease associated variants have been described (according to the LOVD Gene Homepage for
PLOD1 at https://eds.gene.le.ac.uk/home.php?select_db=
PLOD1). In addition, mutation of PLOD1 has not beenreported among Chinese population.
In this report, we present the clinical, biochemical, andmolecular data of the first Chinese patient diagnosed
with kEDS-PLOD1 due to a novel PLOD1 missense
mutation.
Case presentation
On October 15, 2019, a 17-year-old patient was referredto our department because of hypotonia, joint hypermobility and scoliosis from childhood. He was the second
child of non-consanguineous parents (Fig. 1a), born atterm with normal weight (3500 g) and height (55 cm) bynormal vaginal delivery. After birth, he was found to havesevere hypotonia and did not open his eyes until he wasPage 2 of 8

20 days old. The severe hypotonia led to delayed motor
development. He was not able to walk independently until
2 years of age and joint hypermobility was found at thattime. Kyphoscoliosis and amblyopia were found at age
3 years. Inguinal hernia was found at age 5 years andclosed by surgery. At the same time, he presented withhyperextensible and bruisable velvety skin with widened
atrophic scarring after minor trauma. Dislocation of elbow
joint has been noted to happen frequently since age of
6 years. Orthopedic surgery for correction of kyphoscoliosis was performed at age 10 years. Kyphoscoliosis reappeared two years after surgery and progressed gradually,
but remained stable in the past three years. His
intelligence was normal. The patient denied any fracture
history. His family history was unremarkable.
On physical examination at age 17 years, his height
and weight were 165 cm (-0.5 SD) and 82.5 kg (+ 1.9SD), respectively. Blood pressure was 138/94 mmHg
without renal artery vascular murmur. He presented
with generalized hypotonia, protruding abdomen andkyphoscoliosis (Fig. 2a). He had joint hypermobility(Beighton score 6/9), multiple atrophic scars on the legs
(Fig. 2b) and back due to the surgery for correction of
kyphoscoliosis (Fig. 2c), and skin hyperextensibility(Fig. 2d). Slight facial dysmorphologies were found, including high palate, epicanthal folds, and down-slanting
palpebral fissures (Fig. 2e). He also had blue sclerae.
Hearing was normal.
In order to evaluate bone morphology, X-ray photographs were taken at the age of 17 years old when hevisited our hospital. Radiographs of the vertebral column
revealed severe degree of scoliosis, concave to the left in
the thoracic spine and to the right in the lumbar spinewith severe kyphosis (Fig. 3a-d). Radiograph of skull andhands showed copper-beaten appearance and osteopenia, respectively (Fig. 3e and f). The Echocardiography
findings were normal, while electrocardiogram revealed
sinus tachycardia with 121 bmp. Color Doppler ultrasound of renal artery did not show stenosis. Serum levelsof alkaline phosphatase (ALP), N-aminoterminal propeptide of type I procollagen (P1NP), β-isomerized Cterminal telopeptide of type 1 collagen (β-CTX), as well
as serum levels of 25-hydroxyvitamin D and intact parathyroid hormone (PTH) were measured. He had both aslightly activated bone resorption (β-CTX 0.96 ng/l, normal range: 0.26 ~ 0.512 ng/ mL) and an activated boneformation (P1NP 89.0 ng/ml, normal range: 15.1 ~58.6 ng/ml). Results of regular biochemical analyses revealed high level of uric acid (618 μmol/L, normal range:
210 ~ 416 μmol/L), and free fatty acids (1672 μmol/L,
normal range: 129 ~ 769 μmol/L).
Based on the clinical manifestations presented by ourpatient, kEDS was suspected. Hence, blood samples wereobtained from the patient and his parents for genetic

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Fig. 1 Pedigree and molecular analysis of the family with kEDS-PLOD1. a Pedigree of the family of kEDS of Chinese origin. b A homozygous mutationof PLOD1 (c.1697 G > A) in patient (II-2) is a novel missense mutation (p.C566Y). His parents (I-1 and I-2) were heterozygous carriers of corresponding
mutation. Black symbols present affected individuals, white symbols with black dots present carriers of the mutation

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Fig. 2 Clinical features of patient at the age of 17 years old. a Kyphoscoliosis. b Atrophic scars on leg. c Scar after surgery on the back. d Skin
hyperextensibility. e Epicanthal folds and down-slanting palpebral fissures

analysis. Genomic DNA was extracted from 0.2 ml peripheral blood using QIAamp DNA Blood mini kit (Qiagen, Germany) according to the manufacturer’s protocol.
Exons included in coding sequence (CDS) and > 50 bp ofexon–intron boundaries of the PLOD1 and FKBP14 gene
were amplified respectively by polymerase chain reaction(PCR). The amplified products were sequenced by ABI
3730XL sequencer (Applied Biosystems, Foster City,
CA). A homozygous mutation involving a G to A transition of PLOD1 (c.1697 G > A) (NM_000302.4) was detected, resulting in a cysteine to tyrosine substitution atamino acid (p.C566Y) (Fig. 1b). Corresponding heterozygous mutation was detected in his parents. Therefore,
the diagnosis of kEDS-PLOD1 was confirmed.
Due to the lack of curative treatment, this patient
could only be managed by regular evaluation of musculoskeletal, skin, cardiovascular and ophthalmologic system. Alfacalcidol (0.25ug qd) has been used in ourpatient to try to improve bone mass and muscle strengthwith good adherence for 12 months. Diet control andweigh loss had been tried to control the blood pressure.
Under the circumstances of COVID-19 pandemic, thepatient was followed up regularly by telephone since detailed follow-up to hospital was limited. Due to the poor
control of weight reported by patient, nifedipine has
been used since September 1, 2020. Recently, the patientreported improved physical strength without adverse
events and normal blood pressure with treatment of alfacaicidol and nifedipine by telephone.

Discussion and conclusions
We describe a 17-year-old patient who presented withcongenital muscular hypotonia, progressive kyphoscoliosis, severe skin hyperextensibility and fragility, marked
joint hypermobility and dislocation, facial dysmorphology, blue sclerae, refractive errors, and osteopenia. According to the latest revised International EDS criteria,

minimal criteria suggestive for kEDS includes the first(congenital muscle hypotonia) and second major criteria(congenital or early-onset kyphoscoliosis), plus third
major criteria (Generalized joint hypermobility) or threeminor criteria (Table 1) [8]. Our patients met threemajor criteria and six minor criteria. The diagnosis of
kEDS was confirmed by detection of a novel mutation of
PLOD1 gene. To our knowledge, this is the first case of
kEDS-PLOD1 of Chinese origin.
Kyphoscoliosisis, mostly accompanied with hypotonia
and ligamentous laxity, is usually present at birth or develops in infancy. Although congenital or early onset
kyphoscoliosis is obligatory for the diagnosis in the criteria
for kEDS, not all of reported patients with kEDS presented
with kyphoscoliosis at birth or in infancy [8]. Rohrbach
et al. reported that 1 of 12 patients with kEDS did not develop kyphoscoliosis until the age of 27 years. The absenceof hypotonia at birth could indicate a more favorable
prognosis of not developing spine deformity later in life[6]. Indeed, data from PLOD1−/− mice suggested a direct
correlation between lack of spine deformity and absenceof hypotonia at birth [9]. However, recent study reported
two patients who presented to be hypotonic at birth while
did not develop congenital or early onset kyphoscoliosis[10]. So, kyphoscoliosis is not necessarily existent in patients with kEDS, and the association between occurrenceof kyphoscoliosis and hypotonia at birth is still controversial. It should be noted that the main differences of diagnostic criteria between kEDS and classic EDS (cEDS) are
the presence of kyphoscoliosis and hypotonia at birth,while hypotonia could also exist in cEDS [11]. In this condition, patients with kEDS could be easily misdiagnosed as
cEDS. In patients who satisfy the main criteria of cEDS
without mutataion of COL5A1 and COL5A2, the possibility of PLOD1 mutation should be considered. In ourstudy, the patient presented to be hypotonic at birth, but
kyphoscoliosis was not noted until 3 years of age.

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Fig. 3 Radiographic findings of the patient at 17 years old. a X-ray of spine showing scoliosis and b kyphosis of thoracic vertebra, c scoliosis andd kyphosis of lumbar vertebra. e X-ray of skull showing copper-beaten appearance. f X-ray of hands showing osteopenia

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Table 1 Criteria of kEDS from 2017 International EDS
Classification and clinical manifestations of the patient
Criteria

Patient

Major criteria
Congenital muscle hypotonia+

Congenital or early onset kyphoscoliosis(progressive or nonprogressive)+

Generalized joint hypermobility withdislocations/subluxations(shoulders, hips, and knees in particular)+

Minor criteria
Skin hyperextensibility+

Easy bruisable skin+Rupture/aneurysm of a medium-sized artery-

Osteopenia/osteoporosis+

Blue sclerae+

Hernia (umbilical or inguinal)+

Pectus deformity-

Marfanoid habitus-

Talipes equinovarus-

Refractive errors (myopia, hypermetropia)+

Gene-specific minor criteria
PLOD1
Skin fragility (easy bruising, friable skin,poor wound healing, widened atrophic scarring)+

Scleral and ocular fragility/rupture+

Microcornea-

Facial dysmorphology+

FKBP14
Congenital hearing impairment (sensorineural,
conductive, or mixed)-

Follicular hyperkeratosis-

Muscle atrophy-

Bladder diverticula-

kEDS: Kyphoscoliotic Ehlers-Danlos syndrome; PLOD1: procollagen-lysine, 2oxoglutarate 5-dioxygenase 1; FKBP14: FK506 binding protein 14
Minimal criteria suggestive for kEDS: major criterion (1): congenital muscle
hypotonia and major criterion (2): congenital or early-onset kyphoscoliosis plus
either major criterion (3): GJH and/or three minor criteria (either general or
gene-specific criteria)

Although vascular incidents are more common in vascular EDS (vEDS), eight cases with antenatal or neonatal
vascular incidents have also been reported in kEDS [2, 6,
12–17]. In addition, as a major life-threatening complication in this disorder, vascular incidents such as aortic
dilation/dissection and rupture of medium-sized arteries
often occurs during transition period from youth toadulthood [14, 15]. Yeowell et al. reported a patient withkEDS who presented with aortic root dilatation and diedfrom arterial rupture [14]. Echocardiography in our patient was normal. Orthostatic intolerance was reported

to be prevalent in hypermobile EDS (hEDS) and wasmost frequently expressed as postural orthostatic tachycardia. Although we did not perform autonomic function testing on our patient, consistent with previous
study [18], relatively high resting systolic and diastolicblood pressure and heart rate were found, suggesting increased resting cardiac sympathetic activity. Although
the underlying mechanism of vascular incidents has notbeen well established, the abnormal collagen structure isa facilitating factor. Control of blood pressure was suggested to reduce the risk of arterial rupture [3]. Although nifedipine used in our patient normalized bloodpressure successfully, evaluation of cardiovascular structure and function by echocardiography should be
followed up regularly [3].
At present, 44 different mutations of PLOD1 (Ehlers
Danlos Syndrome Variant Database) has been reported,
including missense, nonsense, insertion, duplication, deletion, splicing mutations. Among them, the 8.9 kb duplication of 7 exons (exons 10–16; c.1067_1846 dup) is
the most common mutation [19], followed by nonsense
mutation (p.Arg319*), while missense mutations are
relatively rare. The patient harbored a homozygous missense mutation (c.1697 G > A, p.C566Y) resulting in a
cysteine to tyrosine substitution, and his parents were
heterozygous carriers of the corresponding mutation.
The substituted cysteine was highly conserved in human,rat, mouse, chicken and chimpanzee (Fig. 4). This variant was not reported in several global human genome
databases, including the Human Gene Mutation Database (HGMD) (https://www.hgmd.cf.ac.uk/ac/), dbSNP(https://www.ncbi.nlm.nih.gov/SNP), ClinVar database(https://www.ncbi.nlm.nih.gov/clinvar/), 1000 Genomes(https://www.1000genomes.org), the Exome Aggregation
Consortium (ExAC) (https://exac.broadinstitute.org).
This variant is possibly causative for kEDS because it
was predicted to be “PROBABLY DAMAGING” with ascore 0.999 by Polymorphism Phenotyping version 2(PolyPhen-2) (https://genetics.bwh.harvard.edu/pph2/),“AFFECT PROTEIN FUNCTION” with a score 0.00 by
Sorting Intolerant From Tolerant (SIFT) (https://sift.bii.
a-star.edu.sg), and “disease causing” by Mutation Taster(https://www.mutationtaster.org/). Clinical severity wasobserved to be variable in individuals with kEDSPLOD1, even in patients with same mutation [5, 6]. No
specific work has been carried out to analyze genotype–phenotype correlations to date [5, 15, 19].
One major limitation of our study is the incomplete
follow-up. We will keep evaluating the structure andfunction of relevant organs and monitoring the development of existed symptoms of our patient regularly.
In conclusion, this is the first case with kEDS-PLOD1
in China. We identified one novel mutation of PLOD1,
extending the mutation spectrum of PLOD1. Diagnosis

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Fig. 4 Sequence alignment of human PLOD1 with other species. Number and black box indicates the mutant residue in human PLOD1. The
amino acid cysteine at position 566 is highly conserved among different speciesof kEDS-PLOD1 should be considered in patients withcongenital hypotonia, progressive kyphoscoliosis, joint
hypermobility, and skin hyperextensibility. The suspected diagnosis could be confirmed by mutation analysis of PLOD1. All of these will help avoid unnecessary
examination and increase early detection rate.
Abbreviations
kEDS: Kyphoscoliotic Ehlers-Danlos syndrome; cEDS: Classic EDS;vEDS: Vascular EDS; hEDS: Hypermobile EDS; PLOD1: Procollagen-lysine, 2oxoglutarate 5-dioxygenase 1; FKBP14: FK506 binding protein 14; LH1: Lysylhydroxylase 1; LP: Lysyl-pyridinolines; HP: Hydroxylysyl-pyridinolines;
ALP: Alkaline phosphatase; P1NP: N-aminoterminal prepeptide of type I
procollagen; β-CTX: β-Isomerized C-terminal telopeptide of type 1 collagen;
PTH: Parathyroid hormone
Acknowledgements
Not applicable.
Authors’ contributions
WBX designed the study. XLN, WBX prepared the first draft of the paper. XL
Ni, CXJ and YJ collected clinical information and performed genetic analysis.
OW, XPX, ML, YJ and WBX revised the manuscript. All authors revised thepaper critically for intellectual content and approved the final version. All
authors agree to be accountable for the work and to ensure that anyquestions relating to the accuracy and integrity of the paper are investigatedand properly resolved.
Funding
This study was supported by the National Natural Science Foundation ofChina (No.81970757) for covering the expense of mutation analysis.
Availability of data and materials
The datasets generated during the current study are available in the Mendeley
repository, https://dx.doi.org/10.17632/85x3f8r789.1 (https://doi.org/10.17632/85
x3f8r789.1).
Ethics approval and consent to participate
This study was approved by the Local Ethics Committee of the Departmentof Scientific Research at Peking Union Medical College Hospital (PUMCH).
Written informed consent was obtained from all of participants before
entering the study.
Consent for publication
Written consent for publication was obtained from the patient and his
parents.
Competing interests
The authors declare that they have no competing interests.

Received: 14 August 2020 Accepted: 20 October 2020

References
1. Abdalla EM, Rohrbach M, Burer C, Kraenzlin M, El-Tayeby H, Elbelbesy MF,
Nabil A, Giunta C. Kyphoscoliotic type of Ehlers-Danlos Syndrome (EDS VIA)
in six Egyptian patients presenting with a homogeneous clinical phenotype.
Eur J Pediatr. 2015;174(1):105–12. .
2. Tosun A, Kurtgoz S, Dursun S, Bozkurt G. A case of Ehlers-Danlos syndrome
type VIA with a novel PLOD1 gene mutation. Pediatr Neurol. 2014;51(4):566–9. .
3. Yeowell HN, Steinmann B: PLOD1-Related Kyphoscoliotic Ehlers-Danlos
Syndrome. In: GeneReviews((R)). edn. Edited by Adam MP, Ardinger HH,
Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A. Seattle (WA):
University of Washington, Seattle University of Washington, Seattle.
GeneReviews is a registered trademark of the University of Washington,
Seattle. All rights reserved.; 1993.
4. Krane SM, Pinnell SR, Erbe RW. Lysyl-protocollagen hydroxylase deficiency infibroblasts from siblings with hydroxylysine-deficient collagen. Proc Natl
Acad Sci U S A. 1972;69(10):2899–903. .
5. Hyland J, Ala-Kokko L, Royce P, Steinmann B, Kivirikko KI, Myllyla R. A
homozygous stop codon in the lysyl hydroxylase gene in two siblings with
Ehlers-Danlos syndrome type VI. Nat Genet. 1992;2(3):228–31. .
6. Rohrbach M, Vandersteen A, Yis U, Serdaroglu G, Ataman E, Chopra M,
Garcia S, Jones K, Kariminejad A, Kraenzlin M, et al. Phenotypic variability of
the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA): clinical,
molecular and biochemical delineation. Orphanet J Rare Dis. 2011;6:46. .
7. Baumann M, Giunta C, Krabichler B, Ruschendorf F, Zoppi N, Colombi M,
Bittner RE, Quijano-Roy S, Muntoni F, Cirak S, et al. Mutations in FKBP14
cause a variant of Ehlers-Danlos syndrome with progressive kyphoscoliosis,
myopathy, and hearing loss. Am J Hum Genet. 2012;90(2):201–16.
8. Malfait F, Francomano C, Byers P, Belmont J, Berglund B, Black J, Bloom L,
Bowen JM, Brady AF, Burrows NP, et al. The 2017 international classificationof the Ehlers-Danlos syndromes. Am J Med Genet C Semin Med Genet.
2017;175(1):8–26. .
9. Takaluoma K, Hyry M, Lantto J, Sormunen R, Bank RA, Kivirikko KI, Myllyharju
J, Soininen R. Tissue-specific changes in the hydroxylysine content andcross-links of collagens and alterations in fibril morphology in lysylhydroxylase 1 knock-out mice. J Biol Chem. 2007;282(9):6588–96. .
10. van Dijk FS, Mancini GMS, Maugeri A, Cobben JM. Ehlers Danlos syndrome,
kyphoscoliotic type due to Lysyl Hydroxylase 1 deficiency in two children
without congenital or early onset kyphoscoliosis. Eur J Med Genet. 2017;60(10):536–40. .
11. Malfait F, Wenstrup R, De Paepe A: Classic Ehlers-Danlos Syndrome. In:
GeneReviews((R)). edn. Edited by Adam MP, Ardinger HH, Pagon RA, Wallace
SE, Bean LJH, Stephens K, Amemiya A. Seattle (WA): University ofWashington, Seattle University of Washington, Seattle. GeneReviews is a
registered trademark of the University of Washington, Seattle. All rights
reserved.; 1993.
12. Wenstrup RJ, Murad S, Pinnell SR. Ehlers-Danlos syndrome type VI: clinicalmanifestations of collagen lysyl hydroxylase deficiency. J Pediatr. 1989;
115(3):405–9. .

Ni et al. BMC Medical Genetics(2020) 21:214

13. Yeowell HN, Walker LC. Ehlers-Danlos syndrome type VI results from a
nonsense mutation and a splice site-mediated exon-skipping mutation in
the lysyl hydroxylase gene. Proc Assoc Am Physicians. 1997;109(4):383–96. .
14. Yeowell HN, Allen JD, Walker LC, Overstreet MA, Murad S, Thai SF. Deletionof cysteine 369 in lysyl hydroxylase 1 eliminates enzyme activity and causes
Ehlers-Danlos syndrome type VI. Matrix Biol. 2000;19(1):37–46. .
15. Giunta C, Randolph A, Steinmann B. Mutation analysis of the PLOD1 gene:an efficient multistep approach to the molecular diagnosis of the
kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA). Mol Genet Metab.
2005;86(1–2):269–76. .
16. Shin YL, Park YN, Jang MA. Rare Cases of PLOD1-Related Kyphoscoliotic
Ehlers-Danlos Syndrome in a Korean Family Identified by Next Generation
Sequencing. J Korean Med Sci. 2020;35(10):e96. .
17. Yeowell HN, Walker LC, Neumann LM. An Ehlers-Danlos syndrome type VIA
patient with cystic malformations of the meninges. Eur J Dermatol. 2005;
15(5):353–8. .
18. De Wandele I, Rombaut L, Leybaert L, Van de Borne P, De Backer T, Malfait
F, De Paepe A, Calders P. Dysautonomia and its underlying mechanisms in
the hypermobility type of Ehlers-Danlos syndrome. Semin Arthritis Rheum.
2014;44(1):93–100. .
19. Brady AF, Demirdas S, Fournel-Gigleux S, Ghali N, Giunta C, KapfererSeebacher I, Kosho T, Mendoza-Londono R, Pope MF, Rohrbach M, et al.
The Ehlers-Danlos syndromes, rare types. Am J Med Genet C Semin Med
Genet. 2017;175(1):70–115. .

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