This Case Series by Shrivastava, et al. [1] from Gandhi Medical College, Bhopal, presented 7 cases of OI among 16 members of two unrelated families. Through this article, the authors attempted to study the familial pattern of inheritance of OI. In the first family, the index case (case 1) was a 2-year-old girl, fourth in birth order, who presented with inability to walk and lower limb bony deformity. She had a history of recurrent fractures since day 5 of life. She had blue sclera, and her hearing was normal. The serum levels of calcium, inorganic phosphate and alkaline phosphatase were normal while the skiagram of bones revealed osteoporosis with deformity. On eliciting the family history, her elder brother (8 years; case 2) had blue sclera and deafness secondary to otosclerosis, while the elder sister (6 years; case 3) had only blue sclera. There was no evidence of fracture or deformity in either of the siblings. The parents and one of the siblings (4½-year-old) in this family were unaffected. In the second family, the index case (case 4) was a 12-year-old boy with progressively worsening deafness, blue sclera and past history of recurrent fractures. His mother (case 5) died at the age of 22 years during childbirth, and the female offspring (case 6) who apparently had deformities at birth, succumbed on 5th day of life. Both had blue sclera. The father was healthy. The maternal uncle (16 years; case 7) also had blue sclera but no evidence of fractures, deformity or deafness. The exact mode of transmission could not be elicited in both families as complete family history was not available, but a strong familial tendency of the disease was suggested. The cardinal triad (blue sclera, deafness and brittle bones) was not seen in all cases, while the blue sclera was reported as consistent finding. The combination of blue sclera and fracture was more common as compared to deafness. Among the 7 cases reported, 2 fitted into the more severe congenital variety and the rest into the milder tarda form, as per the accepted classification of OI at that time. The family tree revealed that the incidence of deep blue sclera and fractures increased with subsequent pregnancies. The outcome of the congenital variety was poor as mortality occurred early, while the tarda type did well later in life.

Historical background and past knowledge: OI is a clinical entity known since 1000 BC, evident through an Egyptian mummy of an infant kept in London’s museum. The medical literature on this disorder can be recognized ever since the seventeenth century, when various alternative terms – like osteomalacia congenita, mollities ossium, fragilitas ossium, and osteopsathyrosis idiopathica – were used to describe it. The term ‘osteogenesis imperfecta’ was first coined by Lobstein in 1835. In 1906, Looser categorized OI into congenital (Vrolik) and tarda (Lobstein) varieties based on clinical severity [2]. The congenital variety was a more severe form that presented with intrauterine fractures, while the tarda variety followed a milder course, often complicated by otosclerosis with advancing age. The tarda variety was subsequently further divided into gravis (fractures occurring in infancy) and levis (fractures in late childhood) type by Seedorff in 1949 [3]. The characteristic triad of blue sclera, hearing loss and brittle bones was established as distinguishing diagnostic feature of OI by this time. The most accepted hypothesis regarding pathogenesis of OI was impaired maturation of collagen and a defect in osteoblastic activity transmitted by autosomal dominance.

Besides the classical triad, other distinguishing features in OI are dentinogenesis imperfecta, ligamentous laxity, bone deformation and short stature. The systemic features associated with morbidity and mortality include basilar invagination leading to potentially lethal neurological outcome, aortic root dilatation, mitral valve prolapse, and restrictive lung disease secondary to scoliosis. There exists wide variation in clinical characteristics of different types of OI, among people with the same type of OI, and even within members of the same family with a particular type of OI.

The most common mode of transmission is autosomal dominant (90%) while a recessive (10%) pattern of inheritance has also been identified in some families. In 2006, Barnes, et al. [7] described the first autosomal recessive OI (type II) due to CRTAP mutations, and several others have been recognized subsequently. The cases of OI without suggestive family history can be explained by de novo mutations or germ cell mosaicism. The various mutations in OI either lead to production of defective collagen which is susceptible to tissue proteolysis, or there is reduced or absent production of normal collagen protein. Besides qualitative and quantitative impairment in the bone matrix, there is inability of the differentiated osteoblasts to mineralize the matrix. This generates mechanically weak bones liable to fractures.

1. Shrivastava DK, Yesikar SS. Familial incidence of Osteogenesis imperfecta: Seven cases in two families. Indian Pediatr. 1965; 2:442-5.

2. King JD, Boblechko WP. Osteogenesis imperfecta: An orthopaedic description and surgical review. J Bone Joint Surg. 1971;53B:72e89.

3. Seedorf KS. Osteogenesis imperfecta. A study of clinical features and heredity based on 55 Danish families comprising 18 affected members. Copenhagen, Denmark: Universitetsforlaget Aarhus.1949.

4. Sillence DO, Senn A, Danks DM. Genetic heterogeneity in osteogenesis imperfecta. J Med Genet. 1979;16:101e16.

5. Van Dijk FS, Pals G, van Rijn RR, Nikkels PG, Cobben JM. Classification of osteogenesis imperfecta revisited. Eur J Med Genet. 2010;53:1-5.

6. Van Dijk FS, Sillence DO. Osteogenesis imperfecta: Clinical diagnosis, nomenclature and severity assessment. Am J Med Genet Part A. 2014;164A:1470-81.

7. Barnes AM, Chang W, Morello R, Cabral WA, Weis M, Eyre DR, et al. Deficiency of cartilage associated protein in recessive lethal osteogenesis imperfecta. N Engl J Med. 2006; 355:2757-64.

8. Korula S, Titmuss AT, Biggin A, Munns CF. A practical approach to children with recurrent fractures. Endocr Dev. 2015;28:210-25.