Congenital Joint Contractures and Pterygia with Multiple Fractures: A Novel Mutation in the PLOD2 Gene
Veronica Arora1, K K Saxena2, Pratibha Bhai1, Renu Saxena1, I C Verma1, Ratna Dua Puri1 1Institute of Medical Genetics and Genomics, 2Department of Radiodiagnosis, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi 110060 Correspondence to: Dr Ratna D PuriEmail:ratnadpuri@yahoo.com
1 Abstract
Arthrogryposis multiplex congenita (AMC) or arthrogryposis describes congenital joint contracture in two or more joints.
The combination of fractures and pterygia with arthrogryposis is scantly reported in literature. Here we describe a case
with osteogenesis imperfecta (OI)- like bone fragility in association with congenital contractures and pterygia with normal
intellect. A novel mutation in the PLOD2 gene causing the above phenotype was identified in the proband. Such cases
are frequently mislabelled as OI. The aim is to alert clinicians to look for this rare syndrome in patients
with an OI-like phenotype. The differentials and most recent management and therapeutic options are also
discussed.
2 Introduction
Bruck syndrome is an autosomal recessive disorder consisting of increased bone fragility, congenital joint contractures and
pterygia (Breslau-Siderius et al.,1998). It is classified according to the causative gene into types 1 and 2. Mutations in the
FKBP10 gene which are localised to chromosome 17q21, have been identified to cause Bruck syndrome type 1
[MIM#259450] and this is more common. Type 2 Bruck syndrome [MIM# 609220] is caused by mutations in the PLOD2
gene on chromosome 3q24. Twenty seven patients with mutations in this gene causing Bruck syndrome type 2 have been
described worldwide (Ha-Vinh et al., 2004). We present an additional patient with this syndrome and a novel
mutation in the PLOD2 gene. The patient has frequent fractures, congenital joint contractures, kyphoscoliosis,
pterygia and pectus carinatum. The clinical and genetic features of all the previously reported cases are also
reviewed.
3 Case Summary
The proband is an eight-year-old boy, second born to non-consanguineously married Indian parents. He was born at term
by normal vaginal delivery at home after an uneventful antenatal period. Although the birth weight is not known, as per
given history he was of average weight. He cried immediately after birth. Contracture of both knees and elbows were
identified at birth. He had poor sucking and was never able to breastfeed. No facial dysmorphism was reported
at birth. In view of normal weight gain the child did not come to medical attention till two years of age.
He had the first fracture one week after birth in the humerus, and the second fracture was at two years
of age and these were treated conservatively. The third fracture was at three years of age involving the
ribs. His motor development was delayed and he started walking at 2 years of age. At five years of age, he
sustained multiple fractures in bilateral femurs, clavicles and humeri. All these fractures occurred with
trivial trauma. He also had progressive contractures involving both elbows, knees and ankle joints. He
became non-ambulatory at the age of five years due to the extensive contractures and fractures. There was
no history of seizures or any other prolonged illness. The family history was significant, with history of
death of a similarly affected sibling at the age of 3 days due to severe pneumonia also had contractures at
birth.
Examination of the proband at eight years of age revealed an alert child, responsive to surroundings. The head
circumference was 49 cms (50th centile) and weight was 9.9 kg (<3rd centile). Due to severe contractures the length could
not be measured. Contractures were present in all four limbs, bilateral knee joints, elbow joints, wrist joints
and fingers (Figure 1A). There was a flexion deformity at the right hip joint. Pterygia were present at
both elbow and knee joints (Figure 1C). He was not ambulatory in view of these deformities. There was
no facial dysmorphism. He had white sclera, overcrowded malformed teeth (Figure 1B), normal hearing,
pectus carinatum, severe kyphoscoliosis, mild bilateral clubfoot, and overriding of second and third digits of
the right foot. His intellect was normal. There was no organomegaly and other systemic examination was
normal. The radiological evaluation showed evidence of old fractures in bones of lower and upper limbs.
Wormian bones were present and a small sella turcica was seen (Figure 1E). The mandible was prominent.
Both lower limbs were flexed at the knee joints with very thin diaphysis and osteoporosis (Figure 1F).
Both upper limbs also had flexion deformities, diffuse osteopenia and thin bones. Pterygia were present at
all major joints. There was severe kyphoscoliotic deformity of the dorsolumbar spine and vertebra plana
of L3 (Figure 1D). Serum calcium (10.2 mg/dl) and phosphorus (4.8 mg/dl) were normal and alkaline
phosphatase (320 IU/ml) was mildly elevated. A phenotype of arthrogryposis with pterygia and fractures was
consistent with a clinical diagnosis of Bruck syndrome. Other differential diagnoses considered for this child
were osteogenesis imperfecta (OI), multiple pterygium syndrome and arthrogryposis multiplex congenita.
Molecular analysis by next generation sequencing to confirm the clinical diagnosis was performed for the
proband after informed consent. A novel, missense, homozygous variant in the PLOD2 gene was identified:
NM_182943.2: c.797 G>T, p.Gly266Val. This variant has not been described in the general population databases
(gnomAD and 1000 Genome databases). In silico tools (AlignGVGD, SIFT, MutationTaster, PolyPhen2)
predicted it to be deleterious. The variant is conserved across species and was confirmed to be present in
heterozygous form in both the mother and the father by Sanger sequencing (Figures 2A, 2B, 2C). The
variant is likely pathogenic according to the American College of Medical Genetics and Genomics (ACMG)
criteria.
Figure 1: A) Showing child affected with Bruck syndrome with multiple flexion contractures involving both
upper and lower limbs B) Showing overcrowded malformed teeth C) Elbow with pterygium and contractures D)
Radiograph of the thorax (anteroposterior view) showing severe kyphoscoliotic deformity of the dorsolumbar spine
and vertebra plana at L3 E) Radiograph of the skull showing Wormian bones with a small sella and protruding
mandible F) Radiograph of the left lower limb showing flexion contracture of the knee and the ankle joint.
Figure 2: A) Chromatograph of PLOD2 gene in the index child shows homozygous mutation present in the child
having Bruck syndrome. The arrow head indicates the position of the mutation. B) and C) The chromatograph
shows heterozygous mutation in both parents in the PLOD2 gene. The arrow head indicates the position of the
mutation.
4 Discussion
We describe a patient with a rare autosomal recessive disorder, Bruck syndrome that has few cases reported worldwide.
Our patient had the characteristic phenotype of multiple joint contractures, recurrent fragility fractures, pterygia and
progressive scoliosis. Bruck syndrome type 1 with mutations in FKBP10 gene and type 2 due to mutations in PLOD2
gene (Van der et al., 2003; Ha-Vin et al., 2004) cannot be distinguished on clinical and radiological features and testing for
both genes, as performed in this case, is required. In these patients, hydroxylation of lysine residues in the telopeptides of
skeletal type I collagen is reduced, whereas that in the triple helix of collagen I is normal. (Bank et al.,1999 and Schwarze
et al., 2013). PLOD2 gene codes for lysyl hydroxylase 2 (LH2), which is the enzyme responsible for hydroxylation
of type-I collagen telopeptide lysine residues. This is a key step in collagen biosynthesis as telopeptide
hydroxylysines are the precursors of a series of biochemical reactions, known as the hydroxyallysine route,
which finally form intermolecular lysylpyridinoline and hydroxylysylpyridinoline cross-links within collagen
fibrils. Collagen crosslinks provide stability and tensile properties to collagen fibrils. In keeping with this, BS
patients have reduced levels of hydroxyallysine-derived cross-links in type-I collagen from bone (Bank et
al.,1999).
Table 1 summarizes the characteristics of 29 patients from 16 families reported to have pathogenic variants in PLOD2
and we compare the findings with those seen in our patient. All patients presented with fractures at birth or in early
childhood and had normal intellect. None of the these have independent ambulation after the age of 7 years.
Kyphoscoliosis was found in 18/27 (68%) patients. with onset childhood adolescence and rapid progression.
Wormian bones were observed in 92%. Almost all patients with PLOD2 gene mutations had low bone mineral
density (BMD), although kyphoscoliosis and proximal femur deformity made it difficult to measure BMD
accurately.
Table 1: Phenotypic features of 29 reported patients with Bruck syndrome due to mutations in the PLOD2
gene.
FamilyNumber
Ageatonset
Intellect
Contractures
[K,A,H,E]
Fractures
Sclerae
Scoliosis [S]/Kyphosis [KY]
Otherabnormalphysicalfindings
RadiologicalFeatures
Treatment
Variantfound
Proteinchange
Ex, In
Reference
One
B
N
Congenital
K,
A,
H
+++
White
NA
-
-
NA
c.1886C>T
p.Thr629Ile
Ex18
Van
der
et
al.,
2003
Two
B
N
Congenital
K,
A
+++
Blue
Present
-
WB
NA
c.1865G>T
p.Gly622Val
Ex18
Breslau-
Siderius
et
al.,
1998
and
Van
der
et
al.,
2003
In our patient the phenotype was more severe compared to previously reported cases. Our patient had more number of
fractures and significant joint contractures affecting all major joints, with onset of kyphoscoliosis since birth. He also
exhibited camptodactyly and loss of ambulation at the age of five years. As the novel mutation identified in our patient in
exon 8 is away from the reported hotspot region on exon 17 (Puig-Hervas et al., 2012), it could be inferred that mutations
away from the N terminal domain may be associated with a more severe phenotype. However, this needs further
validation.
Bisphosphonates have been widely used to treat bone fragility in children with OI (Trejo et al., 2016). Only
eleven patients with PLOD2 mutations received treatment with bisphosphonates (Ha-Vinh et al., 2004;
Bank et al.,1999). Zoledronic acid was shown to reduce fracture incidence and increase the BMD with
good tolerance. In a study by Lv et al. (2017) the children received a relatively large dose of zoledronic
acid infusion and a significant increase in BMD after 6 months of treatment was noted. This indicated
that zoledronic acid could increase BMD through effectively inhibiting bone resorption, though further
studies are required to validate this. Release of contractures has been tried to improve ambulation, but
with little benefit (Leal et al., 2018). Bisphosphonate therapy was started for this child and he is on follow
up.
In summary, we report the first case of Bruck syndrome in India confirmed by molecular studies. This case report aims
to alert clinicians to consider Bruck syndrome in presence of recurrent fractures with contractures and other abnormalities
as a close differential diagnosis of osteogenesis imperfecta. Bisphosphonate therapy can improve the outcome with
decrease in fractures and improvement of bone density. It is important to suspect and confirm the diagnosis of Bruck
syndrome to appropriately counsel families for management and recurrence risks. Once the mutation is identified, prenatal
diagnosis is possible to prevent future recurrences.
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