Clinical Vignette

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 (50^th centile) and weight was 9.9 kg (<3^rd 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.

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.