Col1a1/2 Osteogenesis Imperfecta

Clinical characteristics.

COL1A1/2 osteogenesis imperfecta (COL1A1/2-OI) is characterized by fractures with minimal or absent trauma, variable dentinogenesis imperfecta (DI), and, in adult years, hearing loss. The clinical features of COL1A1/2-OI represent a continuum ranging from perinatal lethality to individuals with severe skeletal deformities, mobility impairments, and very short stature to nearly asymptomatic individuals with a mild predisposition to fractures, normal dentition, normal stature, and normal life span. Fractures can occur in any bone but are most common in the extremities. DI is characterized by gray or brown teeth that may appear translucent, wear down, and break easily. COL1A1/2-OI has been classified into four types based on clinical presentation and radiographic findings. This classification system can be helpful in providing information about prognosis and management for a given individual. The four more common OI types are now referred to as follows:

• Classic non-deforming OI with blue sclerae (previously OI type I)
• Perinatally lethal OI (previously OI type II)
• Progressively deforming OI (previously OI type III)
• Common variable OI with normal sclerae (previously OI type IV)

Diagnosis/testing.

The diagnosis of COL1A1/2-OI is established in a proband by identification of a heterozygous pathogenic or likely pathogenic variant in COL1A1 or COL1A2 by molecular genetic testing.

Management.

Treatment of manifestations: Ideally, management is by a multidisciplinary team including specialists in medical management of OI, clinical genetics, orthopedics, rehabilitation medicine, pediatric dentistry, otology/otolaryngology, and mental health. Parents / other caregivers must practice safe handling techniques. Mainstays of treatment include: bracing of limbs depending on OI severity; orthotics to stabilize lax joints; physical activity; physical and occupational therapy to maximize bone stability, improve mobility, prevent contractures, prevent head and spine deformity, and improve muscle strengthening; mobility devices as needed; and pain management. Fractures are treated with: as short a period of immobility as is practical; small and lightweight casts; physical therapy as soon as casts are removed; and intramedullary rodding when indicated to provide anatomic positioning of limbs. Progressive scoliosis in severe OI may not respond well to conservative or surgical management. Bisphosphonates continue to be used most extensively in severely affected children with OI. Surgical treatment for basilar impression should be done in a center experienced in the necessary procedures. Dental care strives to maintain both primary and permanent dentition, a functional bite or occlusion, optimal gingival health, and overall appearance. Conductive hearing loss may be improved with middle ear surgery; later-onset sensorineural hearing loss is treated in the same manner as when caused by other conditions. Mental health support through psychiatry/psychology and appropriate social worker intervention can improve quality of life.

Prevention of secondary complications: During general anesthesia, proper positioning on the operating room table and use of cushioning such as egg crate foam can help avoid fractures.

Surveillance: Orthopedic evaluation with ancillary therapy services (physical and rehabilitation medicine) as indicated every three months until age one year, every six months from ages one to three years, and then annually or with any new fractures. Physical therapy evaluation in infancy for those with motor delays and as needed to improve mobility and function. CT and/or MRI examination with views across the base of the skull to evaluate for basilar impression if concerning signs or symptoms are present. Cervical spine flexion and extension radiographs in children able to cooperate with the examination or before participating in sporting activities in more mildly affected individuals. Twice-yearly dental visits beginning in early childhood or even infancy for those with (or at risk for) DI. Hearing evaluation at three- to five-year intervals from age five years until hearing loss is identified, then as indicated based on the nature and degree of hearing loss and associated interventions.

Agents/circumstances to be avoided: Contact sports should be avoided.

Genetic counseling.

COL1A1/2-OI is inherited in an autosomal dominant manner. The proportion of affected individuals who represent simplex cases (i.e., a single occurrence of the disorder in a family) varies by the severity of disease. Approximately 60% of probands with mild OI represent simplex cases. Virtually 100% of probands with progressively deforming or perinatally lethal OI represent simplex cases and have a de novo pathogenic variant or a pathogenic variant inherited from a parent with somatic and/or germline mosaicism. Parental somatic and/or germline mosaicism is present in up to 16% of families. Each child of an individual with a dominantly inherited form of COL1A1/2-OI has a 50% chance of inheriting the causative variant and of developing some manifestations of OI. Prenatal testing in at-risk pregnancies can be performed by molecular genetic testing if the COL1A1 or COL1A2 causative variant has been identified in an affected relative. Ultrasound examination performed in a center with experience in diagnosing OI can be valuable in the prenatal diagnosis of the lethal form and most severe forms prior to 20 weeks' gestation; milder forms may be detected later in pregnancy if fractures or deformities occur.

Suggestive Findings

COL1A1/2 osteogenesis imperfecta (OI) should be suspected in individuals with the following clinical, radiographic, and laboratory features.

Clinical features (Table 1)

• Fractures with minimal or no trauma in the absence of other factors, such as non-accidental trauma (NAT) or other known disorders of bone
• Short stature or stature shorter than predicted based on stature of unaffected family members, often with bone deformity
• Blue/gray scleral hue
• Dentinogenesis imperfecta (DI)
• Progressive, postpubertal hearing loss
• Ligamentous laxity and other signs of connective tissue abnormality
• Family history of OI, usually consistent with autosomal dominant inheritance

Radiographic features of OI change with age. The major findings include the following (Table 2):

• Fractures of varying ages and stages of healing, often of the long bones but may also rarely involve ribs and skull. Metaphyseal fractures can be seen in a very small number of children with OI. Rib fractures are much more common in NAT than in OI.
• "Codfish" vertebrae, which are the consequence of spinal compression fractures, seen more commonly in adults
• Wormian bones, defined as "sutural bones which are 6 mm by 4 mm (in diameter) or larger, in excess of ten in number, with a tendency to arrangement in a mosaic pattern" [Cremin et al 1982]. Wormian bones are suggestive of but not pathognomonic for OI.
• Protrusio acetabuli, in which the socket of the hip joint is too deep and the acetabulum bulges into the cavity of the pelvis causing intrapelvic protrusion of the acetabulum
• Low bone mass or osteoporosis detected by dual energy x-ray absorptiometry (DEXA). Bone density can be normal, especially in individuals with OI type I, as DEXA measures mineral content rather than collagen [Deodhar & Woolf 1994, Paterson & Mole 1994, Cepollaro et al 1999, Lund et al 1999].
  Note: (1) A major determinant of bone density may be the individual's ability to ambulate. (2) Bone density standards for children under age two years have been determined after sampling very small populations (often <10 persons); thus, reliability is an issue. (3) Bone density standards for children are based on height; corrections for short stature of severely affected individuals need to be made. (4) Bone density is not typically measured in children before age four years because of their inability to lie still, though this may be accomplished with patience in sleeping infants. (5) The purpose of measuring bone density in individuals known to have OI is to allow for monitoring of the individual's bone density over time, and not for comparison with unaffected individuals.

Laboratory features

• Serum concentrations of vitamin D, calcium, phosphorous, and alkaline phosphatase are typically normal; however, alkaline phosphatase may be elevated acutely in response to fracture and rare instances of abnormally low alkaline phosphatase levels have been noted anecdotally in severe OI.
• Analysis of type 1 collagen synthesized in vitro by culturing dermal fibroblasts obtained from a small skin biopsy reflects the structure and quantity of the collagen. The sensitivity of biochemical testing is approximately 90% in individuals with clinically confirmed OI [Wenstrup et al 1990; PH Byers, personal communication]. Biochemical analysis is essentially no longer used clinically with the advances in molecular diagnostics.

Establishing the Diagnosis

The diagnosis of COL1A1/2-OI is established in a proband by identification of a heterozygous pathogenic or likely pathogenic variant in COL1A1 or COL1A2 by molecular genetic testing (see Table 3). An approach to the molecular diagnosis of OI has been published (see Figure 2) [van Dijk et al 2012], but such approaches are in flux as technology is changing rapidly.

Figure 2.

Preferred diagnostic flow in OI The approach to diagnosis is designed to maximize the likelihood that causative variants will be identified in all affected individuals or assign those without causative variants to research pools. This flow assumes that (more...)

Molecular genetic testing approaches can include a combination of gene-targeted testing (concurrent gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Clinical Description

The severity of COL1A1/2 osteogenesis imperfecta (COL1A1/2-OI) ranges from perinatal lethality to individuals with severe skeletal deformities, mobility impairments, and very short stature to nearly asymptomatic individuals with a mild predisposition to fractures, normal stature, and normal life span.

COL1A1/2-OI is classified into four more common types based on clinical presentation, radiographic features, family history, and natural history [Sillence et al 1979]. An update of the Sillence classification has been proposed and has gained some acceptance [Emery & Rimoin 2012]. Although this classification of COL1A1/2-OI into types is helpful in providing information about prognosis and management of a given individual, the features of different types of COL1A1/2-OI overlap and it is not always easy to categorize the extent of the clinical disorder. It is helpful to remember that the severity of clinical and radiographic features lies on a continuum and that the "types" are defined using characteristics that appear to form clinical "nodes." Interfamilial variability is apparent among individuals with the same OI type and intrafamilial variability is apparent among individuals with the same causative variant. Nonetheless, it is reasonable to continue to think of COL1A1/2-OI in terms of these types in order to provide information about the expected natural history of the disorder.

Classic non-deforming OI with blue sclerae (previously OI type I) is characterized by blue sclerae and normal stature. A small proportion of infants with OI type I have femoral bowing at birth. The first fractures may occur at birth or with diapering. More often, the first fractures occur when the infant begins to walk and, more importantly, to fall. Fractures generally occur at a rate of a few to several per year and then decrease in frequency after puberty. Fracture frequency often increases again in adulthood, especially in postmenopausal women and men beyond the fifth decade [Paterson et al 1984]. Affected individuals may have anywhere from a few fractures to more than 100, but the fractures usually heal normally with no resulting deformity.

Most affected individuals have normal or near normal stature but are often shorter than other members of their families and shorter than predicted based on parental heights.

Joint hypermobility predisposes to a number of minor comorbidities. The primary clinical concern is early-onset degenerative joint disease due to malalignment of articular surfaces.

In their classification of OI, Sillence et al [1979] designated a subset of classic non-deforming OI with dentinogenesis imperfecta (DI) (OI type IB). In individuals with DI, morbidity results not from dental decay but rather from premature wearing down of the teeth. DI can be a significant cosmetic concern. Dental eruption in classic non-deforming OI can sometimes occur early.

Progressive hearing loss occurs in about 50% of adults with classic non-deforming OI, beginning as a conductive hearing loss but often with an additional sensorineural hearing loss component in time.

Perinatally lethal OI (previously OI type II). Abnormalities characteristic of perinatally lethal OI are evident at birth. Weight and length are small for gestational age. The sclerae are dark blue and connective tissue is extremely fragile. The skull is large for the body size and soft to palpation. Callus formation on the ribs may be palpable. Extremities are short and bowed. Hips are usually flexed and abducted in a "frog-leg" position. Although some fetuses with perinatally lethal OI die in utero or are spontaneously aborted, more typically infants die in the immediate perinatal period. More than 60% of affected infants die on the first day; 80% die within the first week; survival beyond one year is exceedingly rare and usually involves intensive support such as continuous assisted ventilation [Byers et al 1988]. Death usually results from pulmonary insufficiency related to the small thorax, rib fractures, or flail chest because of unstable ribs. Those who survive the first few days of life may not be able to ingest sufficient calories because of respiratory distress.

Histologic evaluation of bone from infants with perinatally lethal OI shows marked reduction in collagen in secondary trabeculae and cortical bone [Horton et al 1980]. Cortical bone is hypercellular with large osteocytes. Trabeculae contain woven bone with large immature osteoblasts [Cole et al 1992, Cole & Dalgleish 1995].

Progressively deforming OI (previously OI type III). The diagnosis of progressively deforming OI is readily apparent at birth. Fractures in the newborn period, simply with handling of the infant, are common. In some affected infants, the number and severity of rib fractures lead to death from pulmonary failure in the first few weeks or months of life.

Infants who survive this period generally fare well, although most do not walk without assistance and usually use a wheelchair or other assistance for mobility because of severe bone fragility and marked bone deformity. Affected individuals have as many as 200 fractures and progressive deformity even in the absence of obvious fracture. Progressively deforming OI is often difficult to manage orthopedically, even with intramedullary rod placement.

Growth is extremely delayed and adults with progressively deforming OI are among the shortest individuals known, with some having adult stature of less than one meter.

Intellect is normal unless there have been intracerebral hemorrhages (extremely rare). Faqeih et al [2009] published a report identifying increased risk for intracranial hemorrhage (ICH) in a "small number" of individuals who were identified to have pathogenic variants affecting exon 49 of COL1A2, which codes for the most carboxy-terminal part of the triple-helical domain of the collagen alpha-2(I) chain. They concluded that this pathogenic variant appeared to increase the risk for abnormal limb development and intracranial bleeding. Budsamongkol et al [2019] reported a young boy with marked joint hypermobility, significant DI, brachydactyly, and a COL1A2 pathogenic variant found to be associated with ICH by Faqeih et al [2009]. The boy had not experienced an ICH, but as some of the original affected individuals only presented with ICH in their teenage years, this does not eliminate the risk in this young individual.

Even within progressively deforming OI, considerable heterogeneity is observed at the clinical level. Some individuals have normal-appearing teeth and facies while others have DI, a large head, and enlarged ventricles that reflect the soft calvarium. Relative macrocephaly and barrel chest deformity are observed. Usually sclerae are blue in infancy but lighten with age. Hearing loss generally begins in the teenage years. As molecular testing of this subgroup further differentiates those with COL1A1/2-OI from the autosomal recessive forms, the clinical profile of this heterogeneous group will become more refined.

Basilar impression, an abnormality of the craniovertebral junction caused by descent of the skull on the cervical spine, is common. Basilar impression is characterized by invagination of the margins of the foramen magnum upward into the skull, resulting in protrusion of the odontoid process into the foramen magnum. Basilar impression may progress to brain stem compression, obstructive hydrocephalus, or syringomyelia because of direct mechanical blockage of normal CSF flow [Charnas & Marini 1993, Sillence 1994, Hayes et al 1999]. Symptoms of basilar impression become apparent with neck flexion. Findings include posterior skull pain, C2 sensory deficit, tingling in the fourth and fifth digits, and numbness in the medial forearm. When swimming, affected individuals may perceive that water temperature differs below and above the umbilicus. Lhermitte's sign (tingling on neck flexion) can be demonstrated at any stage. Basilar impression can cause headache with coughing, trigeminal neuralgia, loss of function of the extremities, or paresthesias. At its most severe involvement, sleep apnea and death can occur.

Common variable OI with normal sclerae (previously OI type IV) is characterized by mild short stature, DI, adult-onset hearing loss, and normal-to-gray sclerae. This is the most variable form of OI, ranging in severity from moderately severe to so mild that it may be difficult to make the diagnosis.

Stature is variable and may vary markedly within the family. DI is common but may be mild. Sclerae are typically light blue or gray at birth but quickly lighten to near normal. Hearing loss occurs in some and basilar impression can occur.

Phenotype Correlations by Gene

Most commonly OI results from pathogenic heterozygous variants in either of the genes encoding the alpha helical chains of type 1 collagen that form the collagen triple helical molecule. Quantitative impacts on type 1 collagen tend to result in a milder phenotype when compared to qualitative changes due to a dominant-negative effect. Loss-of-function variants generally are associated with classic non-deforming OI with blue sclerae (previously OI type I).

In general, a clear genotype-phenotype correlation does not exist. General rules for genotype-phenotype correlations in COL1A1/2-OI have been published [Ben Amor et al 2011], but there are exceptions to these rules (e.g., glycine to serine substitutions may lead to a more severe phenotype in COL1A1 than a similar change in COL1A2). The extent of variation and the clinical presentation is represented in Maioli et al [2019] (see Figure 2).

Genotype-Phenotype Correlations

It is important to keep the exceptions in mind when providing genetic counseling, particularly in the prenatal setting. Genotyping can be helpful in distinguishing classic non-deforming OI from all other types of OI.

Classic non-deforming OI almost always results from a pathogenic variant in one COL1A1 or COL1A2 allele that introduces premature termination codons and decreases the stability of mRNA (nonsense-mediated decay of the message resulting in a quantitative reduction of the collagen fibril). These causative variants may occur by codon changes, by frame shifts, and by splicing that results in use of cryptic splice sites and premature termination. The type I collagen molecule contains two pro α1(I) chains and a single α2(I) chain. If the number of available pro α1(I) chains decreases, the amount of the trimer manufactured is diminished because no more than one pro α2(I) chain can be accommodated per molecule.

Perinatally lethal OI, progressively deforming OI, and common variable OI all result from pathogenic variants that alter the structure of either pro α1(I) or pro α2(I) chains. This causes a dominant-negative effect whereby the abnormal protein is integrated into the triple helix and collagen fibril, which in turn undergoes continual remodeling, thus resulting in significantly compromised structural integrity of the bone matrix (a qualitative impact on the protein product).

The most common pathogenic variants result in substitution of another amino acid for glycine in the triple helical domain of either chain; serine, arginine, cysteine, and tryptophan result from substitutions in the first position of the glycine codon and alanine, valine, glutamic acid, and aspartic acid result from substitutions in the second position of the glycine codon. Glycine is the least bulky amino acid, and other substituting amino acids do not fit well into the collagen triple helix.

• Substitutions in the pro α1(I) chain by arginine, valine, glutamic acid, aspartic acid, and tryptophan are almost always lethal if they occur in the carboxyl-terminal 70% of the triple helix and have a non-lethal but still moderately severe phenotype if they occur in the remainder of the chain.
• For the smaller side-chain residues (serine, alanine, and cysteine), the phenotypes are more variable and appear to reflect some characteristics of the stability profile of the triple helix that are not yet fully recognized.
• Much more variability occurs with pathogenic variants that affect glycine residues in the pro α2(I) chain, even with the large side-chain residues; therefore, it is more difficult to determine the genotype-phenotype relationship.

The other common disease-causing variants affect splice sites. Variants that lead to exon skipping in the pro α1(I) chain beyond exon 14 and in the pro α2(I) chain beyond exon 25 are generally lethal. The phenotypes resulting from pathogenic variants in the upstream region are more variable and may lead to significant joint hypermobility.

A relatively small number of pathogenic variants that alter amino acid sequences in the carboxyl-terminal regions of both chains have been identified. These domains are used for chain association and pathogenic variants have the capacity to destroy this property or lead to abnormalities in chain association. The phenotypic effects of pathogenic variants that affect this domain appear to be milder when they result in exclusion rather than inclusion of the chain.

Somatic mosaicism for dominant pathogenic variants has been recognized in perinatally lethal OI, progressively deforming OI, and common variable OI. The phenotype of the individual with somatic mosaicism can range from no identifiable characteristics of OI to one of the mild forms. The current estimate for the incidence of somatic/gonadal mosaicism is up to 16% of families.