What is New
Emeritus Professor David Sillence, AM MB BS MD (Melb) FRACP, FAFRM, FAFPHM, FRCPA, FFSci (RCPA)
Specialities of Genomic Medicine and Paediatrics and Adolescent Health, Sydney University Clinical School
Children’s Hospital Westmead 2145 Australia
E: david.sillence@sydney.edu.au
M: +61 415 760 572
Summary
- Introduction to Bone Fragility syndromes
- A new Dyadic Naming System for OI and Bone Fragility syndromes
- Bone fragility is shared with many other rare disorders
- Digenic Inheritance of OI and Bone Fragility in some families
- Recognising Sex-Linked inheritance and its consequence for families
- Multidisciplinary Care Clinics have revolutionized care of people with OI.
1. Introduction to Bone Fragility Disorders
Reports of individuals and families with bone fragility in the medical literature have been made for over 200 years. Accidental fractures are not uncommon in children. Population studies in European societies show that, on average, normal children may have up to 2 long bone fractures by 10 years, and 3 long bone fractures by 19 years of age. Vertebral fractures however are highly suggestive of underlying bone fragility.
Fractures in multiple family members raise our curiosity and concern. In 1788, Dr Olaus Ekman described a Swedish family with 3 generations of individuals with bone fragility. Although many names have been given to heritable bone fragility, the Latin description Osteogenesis Imperfecta, i.e. imperfect development of bone, has prevailed.
An organization offering peer support, Osteogenesis Imperfecta (Foundation (OIF) USA was constituted in 1970 and similar organizations formed in many countries including Australia, The OI Foundation (Victoria) was founded in 1976,the OI Society of NSW in 1977 and the OI Federation of Europe (OIFE) in 1994. These organizations aimed to provide support for families, education about bone fragility and research and engagement with health professionals. In 1975 Professor David Danks in Victoria encouraged several young graduate students including Dr David Sillence and Ms Alison Senn to research the population of people with various types of bone fragility. The study took 3 years and reviewed all the records including X-rays and pathology records and included family histories of all the infants and children who had died in the previous 25 years with a recorded history of OI. They studied patterns in 190 families from which they concluded that OI was not a single entity but could be grouped into at least 4 groups. These were published as 4 types and given Roman numerals. OI types I-IV. Later a further subgroup, OI type V was added. There is an international committee tasked since 1970 with naming genetic disorders of the skeleton. As the years have progressed, more and more disorders have been added such that each OI group was found to have more than one cause. In 2012 the expert committee recommended that the five clinical types were numbered with Arabic numerals, OI types 1-5.
Until 2000, many pamphlets and books suggested that there were only 2 or 3 genes in which variations produced these 5 syndromes. However, discoveries since the successful Human Genome Project have established that there are many more genes involved. The online database of genes, known as Online Mendelian Inheritance in Man (OMIM) has retained Roman numerals alongside the name of many further genes discovered since the 2000s. There are at least 24 genes which are correlated with OMIM OI types, I to type XXIV. These 24 genes are integrated into the 5 broad clinical types OI type 1 to OI type 5. Researchers have discovered at least 16 other genes in which bone fragility occurs as part of a multisystem syndrome e.g. OI with jaw cysts; or OI with joint contractures (Bruck syndromes); Doughnut radiographic shapes in the skull.
2. A Dyadic Naming of OI and Bone Fragility Syndromes
In 2023 the International Nosology group for the International Skeletal Dysplasia society (responsible for naming genetic bone disorders) recommended a new Dyadic (dual) naming system.
The Dyadic Nosology combines a clinical description with a genomic identification. The international committee recommended the universally – used, expanded Sillence nosology for the Osteogenesis Imperfecta syndromes/accepted phenotypic or named syndromes, as the clinical description. The genes named follow the international nomenclature (in Italics). I have listed some examples but for the full nosology, please refer to the paper.
Non-Deforming OI with Distinctly blue sclerae also known as: Osteogenesis Imperfecta type 1
This has several subtypes and these types have Autosomal Dominant Inheritance
(see below).
OI type 1, COL1A1-related
OI type 1, COL1A2-related
OI type 1, increased bone density types
OI type 1, PHLBD1 – related
Common Variable OI with Normal Sclerae also known as: Osteogenesis Imperfecta type 4
This has a number of subtypes including
OI type 4, COL1A1-related
OI type 4, COL1A2-related
OI type 4, MBTPS2- related
OI type 4, FKBP10-related
OI type 4, KIF5B-related
All three patterns of inheritance are observed, Autosomal dominant and recessive and Sex-Linked Inheritance.
Potentially Deforming types of OI, known as: Osteogenesis Imperfecta type 3
Has over 20 subtypes. All three patterns of inheritance are observed
Severe Perinatal OI – Osteogenesis Imperfecta type 2
Has at least 5 subtypes and may result from autosomal dominant or recessive inheritance. Frequently babies die with numerous fractures in infancy.
Osteogenesis Imperfecta type 5
The syndrome known as OI type 5 with abnormal bone formation between forearm bones results from a specific genomic variant in the gene IFITM5. Thus, the
designation OI type 5, IFITM5-related is used.
However, there are other variants in this gene which result in a bone fragility syndrome similar to OI types 3 and 4.
3. Bone Fragility is shared with many types of Bone Disorders
Special Syndromes include
Bruck syndrome type 1, FKBP10 -related (with joint contractures)
Bruck syndrome type 2, PLOD2 -related (with joint contractures)
Familial Osteoporosis with Calvarial Doughnut lesions, SGMS2-related
There are more than 18 disorders in this group. At various stages of growth and development these may be clinically indistinguishable from the numbered OI syndromes.
4. Digenic inheritance.
There are now multiple instances where people have inherited two pathogenic genomic variants simultaneously. Sometimes these are inherited simultaneously from one parent and in some cases each parent contributes a single copy of the two genes which have a complementary effect in producing bone fragility. There are frequently separate health consequences.
5. Sex-Linked Inheritance
There are at least 3 genes in which genomic variants can result in a type of bone fragility. These are PLS3, MBTPS2, SMS. X-Linked inheritance is significant in that all the daughters of affected males are affected to a varying extent .and we know that women carriers may be affected and present with various osteoporosis syndromes at various times of life. These include young adult-onset osteoporosis, osteoporosis which may result in fractures during pregnancy or after delivery and premenopausal osteoporosis in young women.
6 Multidisciplinary Care Clinics
Advanced care resulted in setting up interdisciplinary teams (MDTs) offering multidisciplinary care integrating physiotherapy, occupational therapy, advances in orthotics with medical therapies and orthopaedic surgery. These were first pioneered in the chronic disability sectors and then developed in hospitals and academic departments.
A number of specialists were interested in medical therapies for bone diseases. Dr Eva Aström and Dr Stefan Söderhall from the Karolinksa Institute in Sweden, presented their studies at the 1995 International OI meeting in Oxford England and galvanized multiple research groups to investigate the parameters for treatment of osteoporosis in OI with intermittent injections of a bisphosphonate, Cyclic Intravenous Pamidronate. We undertook extensive clinical trials and adopted regimens of Cyclic Intravenous Pamidronate in children and young adults in Australia. In small children the results were almost miraculous. In the 2020s there are now many programs, newer bisphosphonate medicines both oral and intravenous and various treatment regimens for treating OI and bone fragility. Precision diagnosis is becoming even more important as the differences in response to treatment of the various types of OI has become apparent.
INFORMATION ABOUT:
Family history and genetic counselling: There are several patterns of genetic inheritance which are important for families to know about when it comes to disorders of bone fragility. Often there has been a family history in a parent or relatives that was overlooked in previous generations. The Centre for Genetics Education (CGE) www.genetics.edu.au contains resources for families from Australia and New Zealand and regional clinics where English is used. The CGE website can also be accessed via the QR code below
Dominantly inherited disorders show remarkable variability. Autosomal Recessive inheritance of certain types of OI type 3 may be revealed only by genomic testing. X-Linked disorders may become apparent not only in male relatives but in female carriers at various times of life. See Centre for Genetic Education.
URL: https://www.genetics.edu.au/Sitepages/Inheritance.aspx.
for explanations about the patterns of heritability. This same information can also be accessed via the QR code below
Genomic and Genetic Testing: Genetic testing for heritable bone fragility disorders is now done by genomic testing. See the Centre for Genetics Education
URL: https://www.genetics.edu.au/SitePages/Genetic-and-genomic-testing-DNA.aspx This same information can also be accessed via this QR code below Centre for Genetics Education Website Inheritance information Information on genetic and genomic testing of DNA
This involves sequencing the DNA (known as the genome) using a rapid diagnostic technique. For convenience, most services will sequence a common panel of genes in which variants have been known to cause bone fragility. In 2024 there are 24 separate genes in which variants result in OI but there are a similar number of additional genes in which variants result in bone fragility. This is likely to change as further discoveries are made. The report of testing is likely to be phrased in the two-fold format (known as the Dyadic format), for example Osteogenesis Imperfecta type 1, COL1A1 related; or Osteogenesis Imperfecta type 5, IFITM5-related etc.
REFERENCES
1. Sillence D. A dyadic nosology for osteogenesis imperfecta and bone fragility syndromes. 2024. Calcified Tissue International. 2024 June 28. Doi: 10.1007/s00223-024-01248-7. Online ahead of print. PMID: 38942908.
2. van Dijk F, Sillence DO. Osteogenesis Imperfecta: Clinical Diagnosis, Nomenclature and Severity Assessment. American Journal of Medical Genetics 164A (6):1470-1481, 2014.
3. Sillence DO, Senn AS, Danks DM. Genetic heterogeneity in Osteogenesis Imperfecta. J Med Genet 16:101-106, 1979.
This paper was prepared for the proceedings of the 2024 National Conference of OI Australia. It presents the new International agreed naming of the many genetic disorders known as Osteogenesis Imperfecta and Bone Fragility syndromes. It is provided to educate and assist members and caring professionals in communication about the disorders which affect them. Although there are only 3 references, the 2024 paper is the result of several years of committee deliberations of the International Skeletal Dysplasia Society expert committee. The author is indebted to Ms Thulasee Sri Ganeshan, Centre for Genetic Education to provide the document with QR code links to information vital to understanding family inheritance patterns and modern genomic investigations.
