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  IN THIS Article
 ::  Abstract
 :: Introduction
 ::  Materials and Me...
 :: Results
 :: Discussion
 :: Conclusions
 ::  References
 ::  Article Tables

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Year : 2018  |  Volume : 64  |  Issue : 2  |  Page : 98-103

A review of skeletal dysplasia research in India

1 Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal, Karnataka, India
2 Department of Orthopedics, Kasturba Medical College, Manipal University, Manipal, Karnataka, India

Date of Submission08-Sep-2017
Date of Acceptance13-Nov-2017
Date of Web Publication23-Apr-2018

Correspondence Address:
Dr. K M Girisha
Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jpgm.JPGM_527_17

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 :: Abstract 

We aimed to review the contributions by Indian researchers to the subspecialty of skeletal dysplasias (SDs). Literature search using specific keywords in PubMed was performed to retrieve all the published literature on SDs as on July 6, 2017. All published literature on SDs wherein at least one author was from an Indian institute was included. Publications were grouped into different categories based on the major emphasis of the research paper. Five hundred and forty publications in English language were retrieved and categorized into five different groups. The publications were categorized as reports based on: (i) phenotypes (n = 437), (ii) mutations (n = 51), (iii) novel genes (n = 9), (iv) therapeutic interventions (n = 31), and (v) reviews (n = 12). Most of the publications were single-patient case reports describing the clinical and radiological features of the patients affected with SDs (n = 352). We enlisted all the significant Indian contributions. We have also highlighted the reports in which Indians have contributed to discovery of new genes and phenotypes. This review highlights the substantial Indian contributions to SD research, which is poised to reach even greater heights given the size and structure of our population, technological advances, and expanding national and international collaborations.

Keywords: India, osteochondrodysplasia, skeletal dysplasia, review

How to cite this article:
Uttarilli A, Shah H, Shukla A, Girisha K M. A review of skeletal dysplasia research in India. J Postgrad Med 2018;64:98-103

How to cite this URL:
Uttarilli A, Shah H, Shukla A, Girisha K M. A review of skeletal dysplasia research in India. J Postgrad Med [serial online] 2018 [cited 2023 Jun 1];64:98-103. Available from:

 :: Introduction Top

Skeletal dysplasias (SDs) are monogenic disorders of the skeletal system categorized as 42 distinct groups and accounting for at least 436 diseases.[1] Dysplasias are the conditions associated with bone and/or cartilage growth or texture.[2] Dysostoses, the conditions secondary to abnormal blastogenesis, are also included in this group since 2006.[2],[3] The birth incidence of individual SDs is very rare, but collectively the incidence is estimated to be 1 in 5000 births worldwide for all the SDs.[4] SDs contribute to significant morbidity in children and even mortality in the perinatal period. Internationally, SD is in the forefront of research in recent years. Discovery of new entities, elucidation of pathogenesis, and the underlying molecular mechanisms have increased drastically over the last few years.[5],[6] Several groups and networks [International Skeletal Dysplasia Registry (ISDR), The International Skeletal Dysplasia Society (ISDS); European Skeletal Dysplasia Network Clinical and Radiographic Management Group (ESDN-CRMG), Short Statured People of Australia Inc. (SSPA), and Little People of America (LPA)] have been working in this field to help clinicians and affected families for diagnosis and management of SDs. India, with its huge population and recent application of high-throughput genomic technologies, has started contributing to the clinical and scientific progress to understand the genetic and molecular basis of SD. At this juncture, we review the Indian contributions to this subspecialty which is poised to reach greater heights.

 :: Materials and Methods Top

A literature search was performed to retrieve all the published literature on SDs with at least one of the contributing author affiliated to an Indian center. PubMed was searched using queries {(“Osteochondrodysplasias”[MeSH]) AND “India”[MeSH], {(“Osteochondrodysplasias”[MeSH]) AND “India”[ad]}, {“Osteochondrodysplasias” AND “India”[ad]}, {“Osteochondrodysplasias” AND “India”}, {“Skeletal dysplasias” AND “India”}, and {“Skeletal dysplasia” AND “India”} as on July 6, 2017. The contribution of experts and publications of historical importance, known to the authors, were added manually. The search identified 642 publications in English language. All the abstracts were read and verified to assert their representation as publications on SDs where at least one of the contributing authors is affiliated to an institution located in India. Publications (n = 102) that did not fit into the inclusion criteria were excluded from the study [publications with (a) unavailability of either the abstracts or the full-text PDF articles (n = 59), (b) not suitable for classification under any of the category (n = 27), and (c) not true representation of SDs (n = 16) were not included]. All the remnant 540 results were categorized as reports based on: (I) phenotypes (description of clinical findings of patients without the molecular diagnosis), (II) mutations (description of the patients with a genetically confirmed skeletal dysplasia, (III) novel genes, (IV) therapeutic interventions, and (V) reviews [Table 1]. All these publications (either abstracts or full texts) were read comprehensively. The major emphasis of the publication was considered in categorizing them [Supplementary Information [Additional file 1]].
Table 1: Categorization of skeletal dysplasia publications, with at least one contributing author from an Indian Institute

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 :: Results Top

Reports on phenotypes

We found 437 publications [case reports and series (n = 431) and novel phenotypes (n = 6)] contributed by Indians on phenotypic description of SD patients. These publications provide an estimate of SD cases in selected centers from India.

Case reports and series

Historically, three reports on phenotypes stand out from an Indian perspective. Verma and colleagues reported a new entity in six fetuses of a consanguineous family showing characteristic features of short-limbed dwarfism with severe thoracic dystrophy, micromelia, postaxial polydactyly, and genital anomalies in the males.[7],[8] This condition is now termed short-rib thoracic dysplasia-3 (SRTD3) with or without polydactyly or Verma-Naumoff syndrome (MIM#613091). The causative gene DYNC2H1 was identified subsequently.[9] In 1994, Agarwal et al. have characterized a peculiar syndrome of late-onset familial spondyloepimetaphyseal dysplasia (SEMD) termed Handigodu disease in the Chanangi and Chaluvadi communities of Karnataka (MIM%613343). This disease is inherited in an autosomal dominant condition with variable presentation.[10] However, the underlying genetic defect is not yet identified even after two decades of its first description. An unusual hand malformation syndrome known as complex camptopolydactyly was first described by Phadke et al. (MIM#607539).[11],[12] Exome sequencing performed after 14 years in the proband had eventually led to the identification of homozygous novel frameshift variation, c.220_221delinsTT in basic helix loop helix A9 (BHLHA9) gene.[13]

In 1995, a hospital-based study was conducted in Karnataka, over a 2-year period which characterized a total of 169 cases of SDs.[14] All these cases were diagnosed using clinical information, pedigree data analysis, screening of the other family members, and detailed radiological evaluation. One hundred cases were osteochondrodysplasias and the remaining were mostly dysostoses. Most of them (88%) were in pediatric age group. The highlight of this study was the report on incidence of SDs in India, which was 19.6 per 10,000 births and 5.2 per 10,000 births for lethal dysplasias. Only 7 cases could be antenatally diagnosed using ultrasound. Though this was a hospital-based study, this represents one of the largest documented series of SD from India, providing a clue to the burden of SD in India.

Nampoothiri et al. have recently published, probably the largest case series of 514 suspected SDs patients from a hospital in Kerala. The diagnostic confirmation was provided for 163 cases: enzyme analysis (54 cases) and mutation analysis (109 cases). It was highlighted that most of their patients were affected with dysostosis multiplex disorders (n = 73) followed by FGFR3 mutations (n = 49) and osteogenesis imperfecta (OI) and decreased bone density group (n = 41).[15] This study illustrates how clinical evaluation and collaborations with international colleagues can help patients and families with SD in an Indian setting.

There are two publications on large series of SDs manifesting in the neonatal period. A hospital-based study was performed over a period of 6 years on 41 North Indian patients with antenatally detected short long bones. Depending on the clinical and radiological assessment, 30 cases were suspected to be lethal.[16] This study emphasized that thanatophoric dysplasia was most common among lethal dysplasias, constituting about 20% of the cases (n = 6), whereas achondroplasia (ACH) (nonlethal dysplasias) constitutes about 27% of the total cases (n = 8). A report on analysis of 273 SD-suspected fetal autopsies from North India had identified 15 autopsied fetuses with short-limbed dwarfism.[17] This report further added that short-rib dysplasia with or without polydactyly group was the commonest dysplasia, constituting to 33% of the cases.

Evaluation of 137 patients with short stature from North India revealed that 32.1% of the total patient cohort was associated with SDs.[18] We also noted a series on clinical and radiological evaluation of 271 adult patients with SEMD tarda Handigodu type, specifically describing the radiological pattern changes in the hips.[19] The publications on clinical reports of smaller groups of patients were not detailed.

Novel phenotypes

Dating back to 1992, Phadke et al.[20] had reported a novel syndrome of metaphyseal dysplasia with multiple joint dislocations. The report of a fetus with ectrodactyly, renal aplasia, limb deformities, and Pierre Robin sequence had helped to delineate a distinct entity of acro-renal-mandibular syndrome.[21] Further characterization of acro-renal-intrauterine-mandibular syndrome was reported by another group.[22] A new phenotype involving the expression of common features of both Ellis-van Creveld and  Curry-Hall syndrome More Detailss with uncharacterized anomalies was reported by Gosh et al.[23] A new entity with massive cranial osteolysis, mosaic hypopigmentation, growth retardation, facial anomalies, and developmental delay was reported for the first time in a 16-month-old girl, which likely represents a Gorham-like syndrome.[24] Girisha et al. had reported a novel syndrome with overlapping clinical features of both the Larsen syndrome and Otopalatodigital syndrome.[25] However, further reports and molecular analysis are necessary for confirmation of these entities.

Reports on mutations

The molecular testing facility in several centers is recently established, as suggested by limited reports on mutations. Fifty one different reports with the clinical and molecular genetic testing of the SD patients were published to-date. It was reported that molecular analysis yields a high detection rates in the range of 41 to 98% of Indian patients affected with various SDs.[26]

Phadke et al.[27] have identified mutations in the PEX gene in 3 patients with rhizomelic chondrodysplasia punctata for the first time in India. Patients 1 and 3 showed homozygosity for 64_65delGC variant in PEX gene. Patient 2 showed homozygosity for another frame shift variant, 540_541insT in the same gene. Haplotype analysis revealed that 64_65delGC variant could be a common mutation in Indian population. The reports on the mutation analysis of the rare genetic conditions, FGFR2 mutation in Apert syndrome, DYM mutation in Dyggve-Melchoir-Clausen syndrome, CA2 mutation in osteopetrosis with renal tubular acidosis[OPTB3], EXT1 and EXT2 mutations in hereditary multiple extoses, COL1A1 mutation in Caffey disease, SOX9 missense mutation in acampomelic form of campomelic dysplasia, novel TCIRG1 mutation in malignant osteopetrosis, and PTH1R mutations with or without overt hypercalcemia in a family affected with Jansen metaphyseal chondrodysplasia were useful in understanding the molecular basis of these rare skeletal disorders.[28],[29],[30],[31],[32],[33],[34],[35] The reports on novel compound heterozygous COL27A1 mutation in Steel syndrome and homozygous LRRK1 mutation in osteosclerotic metaphyseal dysplasia observed in nonconsanguineous families were second reports, validating the cause and effect relationship for two rare SDs.[36],[37]

Nahar et al.[38] have reported the largest mutation series of 130 individuals affected with ACH. This group had suggested that all the patients with ACH were to be initially screened for the presence of two common mutations in FGFR3 gene, c.1138G>A and c.1138G>C. This was in turn proved in 81% of the sporadic ACH cases from Lucknow, India.[39] The report on molecular analysis of 60 Indian patients affected with mucopolysaccharidosis type I (MPS I; n = 30) and mucopolysaccharidosis type II (MPS II; n = 30) disorders was considerable for the presence of recurrent pathogenic variants in both the disorders.[40] Mutations in affected families of Morquio A syndrome (MPS IV A, n = 68 families, GALNS) and GM1 gangliosidosis (n = 50 families, GLB1) disorders were reported by Bidchol et al.[41],[42] They have emphasized that mutation spectrum of Morquio A syndrome patients was distinct to Indian population with high recurrence of pathogenic variants in both Morquio A syndrome and GM1 gangliosidosis (p. Ser287Leu in GALNS and c.75+2InsT in GLB1, respectively). They proposed a cost-effective means of genetic testing in Morquio A syndrome patients as they had found that 45% of the mutant alleles lie in exon 1, 7, and 8 (hotspot regions) of GALNS gene. However, in GM1 gangliosidosis the mutation spectrum was similar to other populations and 51% of the alleles screened showed pathogenic variations in exon 1, 10, and 14. Molecular genetic testing in WISP3 gene had thrown light on the private mutations in largest series of affected families with progressive pseudorheumatoid dysplasia.[43],[44] They also noted founder effect underlies several recurrent mutations. Stephen et al. had reported the largest mutation series in Indian patients affected with OI and emphasized that 71% of the mutations (25 patients) were identified in either COL1A1 or COL1A2 genes. The candidate genes for other seven consanguineous autosomal recessive OI patients were identified by homozygosity mapping using single nucleotide polymorphism (SNP) microarray and exome sequencing by Stephen et al.[45],[46] The reports on IDS mutations in 17 affected families with Hunter syndrome, ARSB mutations in 15 families of Maroteaux–Lamy syndrome, MMP2 mutations in 15 affected families with multicentric osteolysis nodulosis and arthropathy, TCIRG1 and CLCN7 mutations in 8 patients with autosomal recessive osteopetrosis, CHST3 mutations in 7 patients of recessive Larsen syndrome, CTSK mutations in 5 patients with pycnodysostosis, and EIF2AK3 nonsense mutation in five Wolcott-Rallison type of diabetes mellitus were some of the notable publications describing the respective mutation profiles in Indian patients.[47],[48],[49],[50],[51],[52],[53],[54]

Reports on novel genes

Indians researchers have started to contribute to gene discovery recently. We found nine different reports describing the rare variants in novel genes associated with SDs. Whole exome sequencing technologies in combination with or without homozygosity mapping and SNP microarray have helped in identification of various novel genes associated with rare SDs in Indian patients. Whole-genome genotyping analysis in patients with immuno-osseous dysplasia spondyloenchondrodysplasia revealed the presence of biallelic mutations in ACP5 gene.[55] Lohan et al.[56] have identified that microduplications in SHH-ZRS cause Laurin-Sandrow syndrome. The reports on association of CSPP1 mutations in Joubert syndrome with or without Jeune asphyxiating thoracic dystrophy, recurrent BGN mutations in X-linked spondylo-epi-metaphyseal dysplasia (XLR-SEMD), IFT52 variant in a human skeletal ciliopathy, and homozygous nonsense EXOC6B variant in an uncharacterized autosomal recessive SEMD with joint laxity and dislocations were some important Indian contributions.[57],[58],[59],[60] Though EXOC6B is yet to be confirmed as a cause of SD by functional studies and further reports, IFT52 is now validated by functional studies and second index case.[61] Few other reports on novel gene discovery are also noteworthy. Simsek Kiper et al.[62] have showed that a homozygous frameshift variation in sFRP4 gene was found to be associated with the Pyle's disease in humans. A synonymous splice site variant in IFT57 gene was found to be likely associated with an unclassified type of oral-facial-digital syndromes by Thevenon et al.[63] A recent report by Volpi et al.[64] had shown that heparan sulfate levels were significantly altered in patients with severe SD, immunodeficiency, and developmental delay and was caused by biallelic exostosin-like 3 (EXTL3) mutations.

Reports on therapeutic interventions

Thirty-one reports were available on either the surgical interventions or intravenous infusion of certain compounds like bisphosphonates for the treatment of some of the SDs, of which some of the significant reports were detailed in this study. A study on surgical limb lengthening for nine achondroplasia patients by Chilbule et al. showed that all the patients encountered many complications. They further emphasized that limb lengthening of more than 50% of the initial length carries significant risk.[65] A retrospective study on intramedullary rodding of long bones in 16 children with OI showed that the frequency of fractures and the related complications were dramatically reduced after careful and precise implantation of either Sheffield rods or non-elongating rods of appropriate size.[66] An interesting report by Kaur et al.[67] had highlighted the significance of combined medical management (peri- and postoperative pamidronate therapy) and surgical correction (multiple osteotomies and intramedullary fixation) of lower limb deformities in four children with OI. Oral administration of alendronate in a patient with polyostotic fibrous dysplasia was found to significantly increase the bone mineral density and result in reduction of pain and fractures.[68]


Twelve review articles summarizing the clinical, radiological, and molecular findings of different groups of SDs were available. Research progress in hereditary multiple exostoses and OI was detailed in two separate reports by Singh et al.[69],[70] Two contributions to Gene Reviews by Bhavani et al. on progressive pseudorheumatoid dysplasia and multicentric osteolytic nodular arthropathy were the only two such contributions to this widely read ebook.[71],[72]

 :: Discussion Top

We performed a PubMed search-based literature review of Indian contributions to the field of SDs. Most contributions are in the form of case reports describing clinical or radiological features or reports on mutations in small group of patients. However, with national and international collaborations, significant strides have been made for delineation of genotypes for several SDs. Indians have started to contribute to gene discovery as well.

Historically, Indians have contributed to the first descriptions of SRTD3 with or without polydactyly, Handigodu disease, and complex camptopolydactyly.[8],[10],[11] Recently, SRTD16 with or without polydactyly is a new SD, identified by an Indian group.[59]

The mutation series on several SDs are important contributions in understanding the genotypes of these conditions not just in India, but globally as well. Several collaborators across the country have joined hands to publish the largest series of patients with SDs, thus highlighting the strengths of Indian collaborations on monogenic disorders. Noteworthy is the mutation series in the detection of homozygous mutations in large proportion in recessive conditions, despite parents denying consanguineous marriages and presence of founder effect in recurrent mutation.[41],[42],[43],[44],[45] These studies give insights into the population structure and highly prevalent endogamy in Indians.

New gene discovery is now enabled by next generation sequencing facilities established at several centers in the country. However, scientific evidence is enhanced by collaborations to recruit more families and seeking collaborators globally for validation in cellular and animal models. These strategies have resulted in discovery of ACP5, CSPP1, BGN, IFT52, EXOC6, sFRP4, IFT57, and EXTL3 genes.[55],[56],[57],[58],[59],[60],[61],[62],[63],[64]

We might have missed out the publications not indexed using the search terms we used. Some publications not cited in PubMed would also have missed a mention here. Inadvertent omission of some contributions is also likely. However, our intention was to enlist major Indian contributions to the field of SDs that would set stage for Indian researchers to take this to new heights. With available financial, clinical, and technological resources, India is likely to contribute massively to the understanding of pathogenesis and treatment of SDs.

 :: Conclusions Top

Indians have contributed to clinical and molecular description of SDs. This is the first comprehensive review on the subject. Recently, the trend is to define the mutation profiles in Indian patients and collaborate nationally and internationally to discover new disease phenotypes and causative genes. The next generation sequencing facilities being established in different centers across the country had helped in rapid evolvement of clinical and genetics expertise in SD research. All these efforts would eventually lead to diagnosis, care, and informed genetic counseling for affected families in India.

Financial support and sponsorship

The authors acknowledge the support provided by Department of Science and Technology - Science and Engineering Research Board (DST-SERB, India) for the project 'Application of autozygosity mapping and exome sequencing to identify genetic basis of disorders of skeletal development [SB/50/HS/005/2014]', Department of Biotechnology-Federal Ministry of Education and Research (DBT-BMBF, Germany) for 'Development and application of a next generation sequencing based gene panel for disorders with low bone mineral density [BT/IN/Germany-BMBF/05/GK/2015-16]' project, Indian Council of Medical Research (ICMR, New Delhi, India) for the project 'Clinical and molecular evaluation of inherited arthropathies and multiple vertebral segmentation defects [54/2/2013-HUM-BMS]' and all the national and international collaborators. AU has received a research grant from DST-SERB, India, towards the pursuit of National Post-Doctoral Fellowship.

Conflicts of interest

There are no conflicts of interest.

 :: References Top

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Online since 12th February '04
2004 - Journal of Postgraduate Medicine
Official Publication of the Staff Society of the Seth GS Medical College and KEM Hospital, Mumbai, India
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