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Abstract
A female toddler presented with short stature and hypermobility of limbs. She had sustained five long bone fractures following minor trauma since early infancy. Skeletal survey was consistent with osteogenesis imperfecta. This was genetically proven on clinical exome analysis, which revealed a pathogenic homozygous autosomal recessive P3H1 nonsense mutation. She has been started on cyclical pamidronate infusion therapy. We have demonstrated an extremely rare case of non-lethal osteogenesis imperfecta VIII due to P3H1 mutation.
- Paediatrics
- Endocrinology
- Calcium and bone
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Background
Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous skeletal dysplasia that occurs in approximately 1 in 10 000–20 000 births.1 It is characterised by multiple fractures caused by skeletal fragility and extra skeletal findings such as blue sclera, dentinogenesis imperfecta, hearing loss, joint hypermobility and hyperlaxity.1
OI consists of I–XIX types: I–V are autosomal dominant and VI–XIII are autosomal recessive. The most common types of OI are the autosomal dominant cases, which are associated by mutations in the collagen type I alpha 1 (COL1A1) and collagen type I alpha 2 (COL1A2) genes. Homozygous truncating mutations in P3H1 (LEPRE1) are responsible for OI type VIII.2 The P3H1 encodes propyl-3-hydroxylase 1, which forms a molecular complex with cyclophilin B, encoded by the cartilage-associated protein and peptidyl propyl isomerase. The P3H1 is involved in the post-translational modification of collagen in the endoplasmic reticulum and prolly 3-hydroxylation of specific proline residues.3 4 OI due to P3H1 mutation is rare and was first reported in 2007.2 There are only a handful of case reports and series, which have described OI due to this rare mutation. In this report, we have discussed the case of a toddler who presented to us at a tertiary paediatric endocrine unit with multiple fractures and was subsequently diagnosed to have OI due to P3H1 gene homozygous mutation.
Case presentation
Our patient was a female toddler, first by birth order, born of a non-consanguineous marriage by caesarean section due to breech presentation. She was born in good condition with a birth weight of 3 kg with no evidence of respiratory distress or birth injury. There was also no history of previous abortion or intrauterine deaths.
She has had five long bone fractures since early infancy, all of which were following minor trauma like handling or massaging of limbs. This was noticed by parents in the form of swelling of the limb and excessive crying on movement of the involved limb. From mid infancy to toddler age, she had serially sustained left humerus fracture, right femoral fracture, right humerus fracture, left femoral fracture and right femoral fracture. All the fractures were managed conservatively, according to the relatives, as per the advice from the orthopaedic doctor from an outside hospital. She was referred to us at a tertiary paediatric endocrine department, from the orthopaedic department, for further evaluation of recurrent non-accidental atraumatic fractures. Due to multiple fractures and subsequent immobilisation due to fractures, along with muscle weakness, joint laxity and deformities, the child had significant gross motor delay; she was not able to roll over and unable to sit. There was no history of fragility fractures in any other member of the family.
On presentation she was haemodynamically stable. On anthropometry, she weighed 5.5 kg (−5.21 SD), her length was 53 cm (−9.86 SD) and the head circumference was 48 cm (+1.02 SD). On examination she had relatively large head, short and curved limbs with hypermobility of the joints (figure 1). Her dental examination was normal, and she did not have blue sclera. Systemic examination revealed no other significant abnormality. She did not have any respiratory complaints.
Clinical picture showing large head, curved bilateral upper and lower limbs, rhizomelia.
Investigations
The blood investigations of the child are enumerated in table 1. Skeletal survey showed generalised osteopaenia, thin calvaria, thinning along the anterior aspect of all ribs, scoliosis, thinned out cornices of long bones, with bowing and deformity of bilateral femora, tibiae, fibulae and humeri (figures 2 and 3). Fractures were noted in the shaft of bilateral humeri and femora in different stages of healing with callus formation. Scoliosis was present, but there was no evidence of vertebral fracture. Ultrasonographic examination of the abdomen and kidneys showed normal renal and hepatic morphology. Echocardiography and fundus examination were normal. Clinical exome analysis showed a pathogenic homozygous P3H1 gene mutation on exon 3 (c.640C>T) (p.Arg214Ter) consistent with the genetic diagnosis of autosomal recessive OI type VIII. Parents have been advised regarding their own genetic testing and prenatal counselling, which they plan to do so before the next pregnancy.
Laboratory investigations in our patient with OI VIII
Skeletal survey showing bowing, deformity and fractures with callus formation of ribs, both humeri and generalised osteopenia.
Skeletal survey showing bowing, deformity and fractures with callus formation of both femora, curved bilateral tibiae and fibulae and generalised osteopenia.
Differential diagnosis
The differential diagnosis includes hypophosphatemic rickets and skeletal dysplasias such as metaphyseal dysplasia. However, rickets was ruled out, as there were no radiographic signs of rickets and the metabolic bone profile (calcium, phosphorus, 25(OH) vitamin D, PTH levels) was normal. The presence of multiple fractures following minor trauma ruled out skeletal dysplasias and/or non-accidental injuries. The skeletal survey with multiple fractures following minor trauma in a child was more indicative of osteogenesis imperfecta which was confirmed by genetic testing.
Treatment
The child was admitted and started on cyclical pamidronate infusions after confirming that the calcium and vitamin D levels were within normal limits. Intravenous cyclical pamidronate therapy was started for the child. A full cycle consists of three infusions over 3 days. The first cycle was given at a total dose of 1.25 mg/kg, of which 0.25 mg/kg was given on the first day and 0.5 mg/kg on the second and third days of the cycle. Subsequent cycles were given at a dose of 1.5 mg/kg/cycle with 0.5 mg/kg daily on all 3 days, at an interval of 6 weeks.
Outcome and follow-up
Our plan is to give cycles of pamidronate infusion every 2 months until 3 years of age and then shift to cyclical zoledronate infusion therapy. The child has finished three cycles of pamidronate infusion and has had no further fractures since then.
Discussion
We have presented the case of a female toddler with a history of five long bone fractures with significant motor delay. On examination she had rhizomelia and hypermobile joints, white sclera, normal dentition with skeletal survey suggestive of multiple fractures in different stages of healing. Clinical exome analysis showed a pathogenic homozygous P3H1 gene mutation. To the best of our knowledge, this is one of the only few cases of non-lethal osteogenesis imperfecta type VIII due to P3H1 mutation to be reported from India.
Type VIII OI, a rare autosomal recessive disorder characterised by white sclera, rhizomelia, severe growth deficiency and bone fragility, was added to the classification of OI in 2007 as a severe and lethal type.2 It accounts for less than 10% of all the patients with OI. Most affected individuals die early in infancy due to respiratory causes. Those who survive into childhood often experience extreme short stature, extremely low bone mineral density, significant bony deformities with physical restrictions, pain, recurrent fractures and activity limitations.
In humans, about one-third of the reported P3H1 mutant alleles are splice site variants. These splice site variants are also known as the West African allele, which is the most common disease-associated variant of P3H1.5 The P3H1 (c.628C>T/p.Arg210 Ter) was first reported by Willaert et al in a consanguineous Turkish family.6 The mother had two pregnancies in which the fetuses were found to have genetic mutations, and elective termination was performed at the 20th and 18th gestational week, respectively. The previous reported cases of OI due to P3H1 mutation are enumerated in table 2 along with their clinical presentation. All the reported cases of P3H1-related OI had normal white sclera with normal dentition . Therefore, blue sclera and dentinogenesis imperfecta are not consistent with this phenotype.
Previously reported cases of P3H1-related OI in the medical literature (NR, not reported; (+) present; (−) not present)
Usually type VIII OI due to P3H1 gene mutations are lethal and severe, and affected individuals die in the perinatal period from respiratory causes. Our case is rare and unusual in the fact that it is a milder form as she did not present with intrauterine fractures or intrauterine death. She has survived till toddler age although with multiple long bone fractures. Based on our patient’s milder, non-lethal presentation, we speculate that missense variants in the catalytic domain of P3H1 leads to decreased, but not absent, prolly 3-hydroxylation, not completely affecting the post-translational modification in the endoplasmic reticulum.7
Intravenous bisphosphonate therapy is now regarded as the cornerstone of medical management of OI. Intravenous pamidronate therapy is administered at an annual dose of maximum 12 mg/kg in cycles. A full cycle consists of three infusions over 3 days. The dose of pamidronate varies according to the age of patients. Children less than 2 years of age receive an initial dose of 0.25 mg/kg on the first day of the first cycle and then 0.5 mg/kg on the second and third days of the first cycle. Once they are shown to tolerate the higher dose, they receive 0.5 mg/kg daily on all 3 days of subsequent cycles. Cycles are repeated every 6 weeks for the first year. Children who are 2–3 years old receive 0.33 mg/kg on the first day of the first cycle and 0.66 mg/kg on the second and third days of the first cycle. Once they are shown to tolerate the higher doses, they receive 0.66 mg/kg daily on all 3 days of subsequent cycles. Cycles are repeated every 8 weeks for that year. Children ≥3 years of age receive 0.5 mg/kg on the first day of the first cycle and 1 mg/kg on the second and third days of the first cycle, and subsequently receive a dose escalation to 1 mg/kg for all 3 days. Cycles are repeated every 3 months for that year. The dosing interval after the first year of treatment is decreased to every 4–6 months for all ages based on the patient’s bone density response. Intravenous zoledronate therapy is a relatively new, heterocyclic nitrogen containing intravenous bisphosphonate. It is given at a dose of 0.05 mg/kg every 6 months.8 It has superior potency, a long-lasting effect in suppressing bone turnover and a more rapid intravenous infusion, allowing lesser frequency of administration and more convenient. Presently data available for use of zoledronate in children less than 3 years of age is scarce, hence limiting its use.
Bisphosphonate therapy in infants and young children with moderate-to-severe OI is well tolerated and associated with an increase in bone density, reduced fracture frequency, normal growth and vertebral remodelling.9 It also improves motor function with attainment of motor milestones at a more age appropriate age.9 However, there is a lack of literature showing effectiveness of bisphosphonate therapy in different forms of OI. Hence, clinical trials of bisphosphonate therapy for each type of OI are warranted. In the absence of specific molecular pathology-driven clinical trials, the use of bisphosphonate is largely based on theory and extrapolation from other forms of disease, and this must be borne in mind when starting treatment in these rare OI subtypes.
Finally, it is important to reiterate that early referral is the key in the management of OI. The management involves a multidisciplinary team of specialists including paediatrician, paedatric endocrinologist, orthopaedic, physical and occupational therapist, otolaryngorhinologist, dentist, geneticist and psychologist. This includes medical treatment (as discussed above), rehabilitation and orthosis application, surgical intervention for the fractures, genetic and prenatal counselling.10
There is a paucity of data on children with OI type VIII due to P3H1 gene mutation, let alone those surviving beyond the perinatal period, making our case report even more relevant. With our case report we have highlighted the identification of P3H1 gene mutation on exon three causing a milder non lethal phenotype of OI type VIII in a child with multiple long bone fractures, severe growth restriction and normal dentition and white sclera.
Patient’s perspective
We were happy when we had our daughter. She was alright at birth with good weight and was fine for a few months of age when she started having fractures. At first we thought it was a single fracture post some trauma but we were frightened when she started having multiple fractures. Doctors told us that our child has a bone disease which is genetically inherited and that she will need lifelong medical support. We would like to thank the team of doctors for diagnosing our child’s rare disease. We are happy that there are medicines to prevent fractures in the future. We shall keep a regular follow-up.
Learning points
In a child with multiple long bone fractures following minor trauma, with or without family history, one always has to consider the possibility of osteogenesis imperfecta.
Genetic testing could be offered in all cases of osteogenesis imperfecta to know the type of mutation as this helps in prognostication, monitoring for other systemic involvements like auditory, dental, ophthalmic monitoring and genetic counselling.
P3H1 mutation is a rare cause of OI, which usually presents as a severe and lethal form, but can rarely present as a non lethal form.
Ethics statements
Patient consent for publication
Footnotes
Contributors The following authors were responsible for drafting the text, sourcing and editing clinical images, investigating results, drawing original diagrams and algorithms and critically revising important intellectual content: PS, NS and SK. NS is the guarantor. The following authors gave final approval of the manuscript: RG.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.