Hemimegalencephaly is a rare central nervous system disorder of neuronal cell lineage, proliferation, maturation, and migration characterized by in utero
Aug. 24, 2021
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In this article, the author provides the pathologic and clinical details of the perinatal lethal and usually dominant form (type II) of osteogenesis imperfecta. New mutations responsible for recessive forms are described. Abnormalities in collagen, which develop from hundreds of different mutations in type I collagen genes, lead to exceptionally brittle bones that become markedly shortened by characteristic, telescoping fractures. The calvaria is thinned, and the brain is enlarged and altered by a host of changes, chiefly neuronal migrational defects. Additional anomalies are recognized and vary among the different types of osteogenesis imperfecta. New forms of treatment are reviewed, and unresolved issues are identified.
• Osteogenesis imperfecta consists of a diverse collection of congenital and heritable (autosomal dominant or, less often, recessive) disorders of connective tissue, which result in fragile and easily fractured bone.
• Osteogenesis imperfecta type II is a perinatal lethal form that involves approximately 4% of all patients with osteogenesis imperfecta.
• In osteogenesis imperfecta type II, cerebral dysgenesis takes several forms but often involves neuronal migration defects or subcortical angiomatosis.
• In patients with nonlethal forms, therapy continues to be refined; in addition to surgery, medical treatment of bone fragility includes the use of bisphosphonate and, in the early stages of development, pre- and postnatal stem cell transplantation.
Osteogenesis imperfecta, a congenital disease characterized by defective bone formation, has been recognized and studied for many decades. One of the earliest cases appeared in Vrolik’s Handbook of Pathological Anatomy, published between 1842 and 1844 (12). In this “brittle bone disease,” bones are abnormally thin or broad and fracture easily, often giving pathognomonic appearances radiographically. Traditionally, cases have been categorized into 4 types with additional subtypes. Some now consider osteogenesis imperfecta to exist in up to 8 forms (136; 103). For purposes of this review, a thorough tabulation of the many details of these types seems unwarranted, and discussion will be oriented toward changes associated with Type II. The group of disorders constituting osteogenesis imperfecta is heritable and presents as autosomal recessive or autosomal dominant conditions. Type II, the perinatal lethal type, can follow either pattern, but the dominant form is considerably more common. Type II is rare within the spectrum of osteogenesis imperfecta patients. In 1 study of 57 patients, only 2 had Type II (138). Type II osteogenesis imperfecta has 3 variants: A, B, and C (158). In Type IIA, long bones are short and broad, with a collapsed or telescoped appearance of multiple fractures; tibiae are angulated; ribs are focally thickened in a manner described as “continuously beaded.” In Type IIB, long bones are similarly altered, but ribs are normal or only partially beaded. In Type IIC, long bones are thin and rectangular with numerous fractures; ribs are thin and beaded. In concert with molecular and other developments, workers continue to suggest modifications to this classification (175).
Patients with osteogenesis imperfecta have short, fragile bones, abnormal (ie, blue) sclerae, variable degrees of deafness, hyperextensible joints, decreased elasticity of skin, and incomplete formation of dentin (158; 75). In affected fetuses or infants, the skull is larger than expected. Craniocerebral fractures or other injuries may occur in the prenatal period, and as with postnatal cases, must be differentiated from injuries sustained as a result of abuse (195). A number of pathologic changes may occur, most likely because of the rather widespread presence of collagen type 1 in the heart (08). The heart and major vessels can be altered by short, fragile chordae; malformed atrioventricular valves; mitral and aortic regurgitation; decreased collagen, elastic fibers, and myxoid change; and disorganized collagen with or without calcification. Valvular heart disease may require valve replacement and even coronary artery bypass grafting if the aortic valve is involved (24). In a large Danish study (N = 575), no association with aortic aneurysm or dissection was identified (54). Lethality in the perinatal period is due to respiratory insufficiency; 1 report of a 25-day survival is available (10).
Changes in the brain may occur as primary dysplasias or secondary to bone alterations. Wormian bones occur with increased frequency in osteogenesis imperfecta and have diagnostic utility but are not associated with particular abnormalities in the CNS (155; 18). Anencephaly has been reported in a fetus with osteogenesis imperfecta, but the finding appears to be coincidental (29). Likewise, a single case of osteogenesis imperfecta with holoprosencephaly has been reported (183). A number of skeletal dysplasias (among which are osteogenesis imperfecta, achondroplasia, spondyloepiphyseal dysplasia, acro-osteolysis, and Hurler syndrome) are associated with a deformation in the cranial base known as basilar impression or secondary basilar invagination (133; 106). Although the change is rare in osteogenesis imperfecta and seems to be restricted to patients with milder forms of the disease, it can have serious consequences. Basilar impression is initiated with softening, or even fracturing, of cranial bones. The squamous portion of the occipital bone folds inward, resulting in abnormal upward curvature of the foramen magnum and elevation of the floor of the posterior fossa. Deformations in contiguous bones result in accentuation of the cranial base angle and craniocervical angle (106). With basilar invagination, the odontoid process extends to the level of or into the foramen magnum; this change and platybasia (flattened cranial base) are present in types III and IV (87). Neurologic symptoms depend on the severity of the invagination; ventricular dilatation can be asymptomatic; elevation of the brain stem and increased traction of the cervical spinal cord may result in dysfunction and myelopathy; cranial nerve palsies may develop secondary to displacement of the brain stem; and cerebellar compression may lead to hydrocephalus, syringohydromyelia, or hindbrain herniation. Abnormalities of the cranial base are found in about one fifth of patients and one half of patients with markedly reduced height (40). Vasculopathic changes (stenoses and prethrombotic occlusion) have been reported in the cerebral arteries of a patient with osteogenesis imperfecta type 4 and are thought to be due to vascular fragility arising from collagen defects (02). It is unclear if this complication affects patients with type II disease.
Hydrocephalus may be of prenatal onset with associated fractures of the occipital bone and narrowing of the foramen magnum (83). One form of perinatally lethal osteogenesis imperfecta has been associated with microcephaly and cataracts in 3 siblings (30). The brains in all were immature for age and showed flattened gyri. Neuronal migrational defects and other forms of CNS dysgenesis are described in the pathogenesis and pathophysiology section.
As stated, individuals with type II osteogenesis imperfecta die during or shortly after the perinatal period, with only the rare exception (04). Some 60% die on the first day of life, whereas 80% die in the first week; survival beyond 1 year is very rare (32). Usually, death comes from respiratory insufficiency, which is due to the combined effects of a dysfunctional thorax (secondary to chest fractures and/or deformities) and pulmonary hypoplasia.
Patients with other forms of osteogenesis imperfecta may also manifest decreased pulmonary function, which appears to be intrinsic to the disease itself or secondary to chest deformities rather than scoliosis (28). Some individuals live a normal life span (especially those with milder conditions) or die of complications related to the disease (respiratory insufficiency or infection; cardiac death, sometimes related to kyphoscoliosis; basilar invagination; intracranial bleeding) (104). Deformities of the spinal column occur most often in the midthoracic region where they affect lung function as well as height (187). Compression fractures may be treated either surgically or medically (92). Mild trauma can have serious consequences in patients with osteogenesis imperfecta, from both orthopedic and cerebral aspects. Muscle strength, range of motion, and gait are affected by the severity of fractures, amount of bone deformity, and success in treatment (26). Subdural hematoma is rare, despite the relative frequency of skull fractures, and has also been reported in the absence of trauma or anticoagulation (151). One study of bleeding tendency in patients uncovered no underlying bleeding disorders or problems with coagulation, instead suggesting that vessel fragility could be a factor (67). Trigeminal neuralgia is a rare complication of basilar invagination. Treatment by percutaneous balloon decompression following cannulation of the foramen ovale is especially difficult when the cranial base is distorted (73; 146). Temporomandibular dysfunction is recognized, and associated malocclusions is more prevalent in patients with moderate to severe osteogenesis imperfecta (Ortega et al 2007; 20).
Type II osteogenesis imperfecta was observed in a male fetus delivered by labor induction at 20 weeks.
No pertinent familial history was obtained. Prenatal ultrasound examination documented skeletal changes consistent with type II osteogenesis imperfecta. Gross autopsy and culture of fetal cells confirmed the diagnosis. A point mutation (substitution of valine for glycine at amino acid 187) was identified within the triple helical region of the a1(I) chain of type I collagen. There was no evidence for a deletion or insertion.
Autopsy findings consisted of growth retardation; shortened, deformed limbs; megalencephaly, with extensive subarachnoid cerebellar hemorrhage; markedly deficient calvarial ossification; multiple telescoping fractures of long bones with marked shortening; multiple rib fractures; and pulmonary hypoplasia (the lung weighed one-half of the expected weight for gestational age). No cardiac or other changes were observed grossly. Microscopically, the fractures showed disorganization typical of various ages and inadequate ossification in calvarial bones.
Cases of type II osteogenesis imperfecta are autosomal dominant or (rarely or at times erroneously thought to be) recessive and result from mutations in 1 of the type I collagen genes (COL1A1 or COL1A2) localized at 7q21-7q22 or 17q21-17q22 (121). Mutations in CRTAP and LEPRE1 have been identified in types VII and VIII and associated with the recessive form (103; 122; 14; 107). Mutations in at least 18 additional genes may also cause the phenotypic changes of osteogenesis imperfecta (168). Several families with recessive osteogenesis imperfecta caused by mutations in WNT1 have been identified (135). Mutations in the gene encoding the RER protein FKBP65 (which is involved in type I procollagen folding) have been found to cause autosomal recessive osteogenesis imperfecta (01). In general, mutations in non-collagenous genes are responsible for less than 10% of cases and result in altered collagen synthesis or bone development; these mutations may be autosomal dominant or recessive or X-linked (153; 143).
Osteogenesis imperfecta I is a genetically determined condition that results from reduced amounts of type I collagen. This, in turn, develops from a nonfunctional allele, the result of mutations in the genes that code for type I collagen. Type I collagen is the principal matrix protein in bone, dentin, sclerae, and ligaments, accounting for the involvement of these tissues in osteogenesis imperfecta. Type II osteogenesis imperfecta is caused by mutations in either COL1A1 or COL1A2. Between these 2 genes, hundreds of mutations have been identified (84; 190). Combined, mutations in the 2 genes are responsible for about 95% of all clinically ascertained patients (177). Many of these are substitutions for glycine, but a variety of single-base deletions, splice junction mutations, and insertions have also been described in the type II form (185). It appears that defects at the C-terminal end of the collagen protein are associated with more severe forms of osteogenesis imperfecta (190). One consequential metabolic change is decreased activity of prolidase, an enzyme necessary for collage synthesis and cell growth; associated with this change are decreases in the expression of beta1 integrin and insulin-like growth factor-I receptors, important in the up regulation of prolidase activity (61). Overglycosylation of collagen may be related to the structural integrity of bone (51).
Most cases represent dominant mutations, and recessive inheritance appears to be rare. Supporting evidence for recessive cases has been controversial. A number of cases resulting from consanguineous matings have been reported, but in some of these, the diagnosis of osteogenesis imperfecta is debated, or the parents are thought to be mosaic. However, newly designated forms appear to be autosomal recessive and due to mutations in the CRTAP and LEPRE1 genes; the phenotypes tend to be severe and overlap with types II and III (110; 14). These 2 genes appear to be responsible for approximately 5% of cases of osteogenesis imperfecta type II (23). Some dominant cases may manifest mild expressivity, thus, complicating diagnosis. All of this suggests that the overall recurrence risk is much lower (ie, 4% to 8%) than the 25% that would be expected from recessive inheritance alone (170). Some of this uncertainty could stem from the possibility that noncollagenous loci are involved in rare and still unclassified forms of osteogenesis imperfecta (177). In fact, the phenotype of patients with noncollagen genes overlaps with both type II and type III osteogenesis imperfecta (60).
Histologic and electron microscopic changes are recognized in dentin (48), and the genetics remain under study (82). The term “dentinogenesis imperfecta” has been applied to those defects observed in cases of osteogenesis imperfecta associated with collagen defects. The reduced level or altered activity of alkaline phosphatase is thought to lead to dysfunction of osteoblasts, whereas structurally abnormal collagen may fail to provide the scaffolding necessary for calcium deposition (149; 148; 48).
A number of dysgenetic changes have been observed in the brains of fetuses with osteogenesis imperfecta type II (178; 52). These include migrational defects such as agyria, abnormal neuronal lamination, nests of neuroblasts in white matter, and hippocampal malrotation. Explanations for these migrational defects are understood incompletely but may relate to the observation that type I collagen promotes neuritic maturation. Vascular microcalcifications have also been observed in the CNS of patients with osteogenesis imperfecta type II and have been associated with proteoglycan and type I and type IV collagen deposits (178). Subcortical angiomatosis has been reported as well (126). Changes such as periventricular leukomalacia and diffuse hemorrhage have been described, but these disorders do not appear to be directly related to osteogenesis imperfecta.
Brtl and OIM mouse models for osteogenesis imperfecta are proving valuable for understanding the genetic mechanisms involved in pathogenesis (89; 88).
Both the incidence and prevalence of osteogenesis imperfecta have been reported, but the numbers vary widely. For example, the incidence has been given as 0.17 per 10,000 live births to 0.5 per 10,000 live births, though others have provided estimates as high as 4.5 per 10,000 births (15). With increased use of molecular diagnosis, the accuracy of this estimate should increase. However, the use of pregnancy termination complicates such efforts and may have particular import in the study of type II osteogenesis imperfecta. In many states, death certificates are required only for fetuses with a gestational age of 20 weeks or more; thus, younger fetuses would not be included in the state's vital statistics.
Workers have begun to examine the evolutionary histories of gene mutations, which appear to vary among different ethnic groups (37). For Latin America (studied from 1978 to 1983), the prevalence of all forms of osteogenesis imperfecta has been given as 0.4 per 10,000 live births (123). In 1 large county in Denmark (studied from 1970 to 1983), the point (birth) prevalence was 2.18 per 10,000 live births, and the population prevalence was 1.06 per 10,000 inhabitants (06). Interestingly, the prevalence of osteogenesis imperfecta among blacks in southern Africa is considerably higher than whites and seems to reflect an increased gene frequency that arose at least 2000 years ago (17; 179). Some 35 mutations in COL1A1 and COL1A2 have been reported in 67 Korean patients (91). Cases have been reported infrequently in China, but reasons for this are unclear (193). Epidemiologic data are lacking for autosomal recessive forms (16).
Maternal age does not appear to have an effect on the appearance of cases. However, paternal age is increased slightly in some, but not all, samples. Mean age (31.15 ± 9.25) was above that of controls in a Latin American, but not Italian, sample (124). In a study of sporadic cases in Scotland, mean age of fathers was 0.87 years greater than expected and relative risk was 1.62 (22). Paternal age was not significantly different among the different subtypes of osteogenesis imperfecta.
Osteogenesis imperfecta cannot be prevented, except by avoidance of pregnancy in women at risk. Therapeutic termination of pregnancy may, of course, prevent the birth of an affected infant and is practiced following diagnosis by prenatal ultrasound and genetic testing.
Osteogenesis imperfecta must be distinguished from hypophosphatasia, the reduction in activity of alkaline phosphatase in tissues (including bone and cartilage) and serum. In this latter condition, the neurocranium fails to ossify, and the skull is soft; the skeleton is mineralized inadequately, and lone bones are shortened and curved to the point of angulation; diaphyseal spurs and fractures are observed. In newborns with hypophosphatasia, bone formation can be exceedingly scant. Ultrasound examination can, therefore, be quite helpful in differentiating the conditions, in addition to molecular methods (194). Both perinatal lethal and infantile forms of hypophosphatasia can occur, and both may occur in the same family (192; 95).
Chondrodysplasia punctata manifests abnormal mineralization of bones during gestation, and, thus, may give the appearance of osteogenesis imperfecta type II by prenatal ultrasound (157).
Patients with infantile copper deficiency may suffer from anemia, vomiting, apnea, hepatomegaly, and "temporary brittle bone disease" and, thus, mimic osteogenesis imperfecta (130).
Hypomineralization of the calvaria in early gestation can give the sonographic appearance of “acrania,” a term erroneously used by some authors to describe acalvaria (186; 108). The sonographic differential in cases of acalvaria or hypocalvaria includes osteogenesis imperfecta, hypophosphatasia, anencephaly, and encephalocele.
Because of the increased incidence of initially unexplained fractures in patients, especially those with mild or incomplete forms of osteogenesis imperfecta, the possibility of nonaccidental trauma (eg, child abuse) must be considered (130; 161; 159). Some workers have used bone mineral content to rule out abuse in mild cases of osteogenesis imperfecta (109). However, baseline information continues to be collected so such findings should be used with extreme care (136; 128). The risk of misdiagnosing child abuse must also be appreciated, perhaps especially in the very young and yet undiagnosed patient with multiple fractures (119).
Osteosarcoma has been reported in an adult with osteogenesis imperfecta, illustrating the need to differentiate (by biopsy) the hyperplastic callus formation that occurs in osteogenesis imperfecta and tumor (166).
The diagnosis of osteogenesis imperfecta has been made traditionally by radiologic means. In 1 large study (N=76), the median number of fractures present at first diagnosis (0 to 114 months) was 3 and involved upper or lower limb and/or the spine (27). Fractures of crumpled or telescoped bones are evident, as are other pathologic bone changes.
Prenatal diagnosis commonly relies on ultrasound examination (65). Increased nuchal translucency (itself a nonspecific finding) and hypoechogenicity of the cranium are reported findings (39). Three-dimensional ultrasound and computed tomography have proven diagnostic as well (164; 195). Increased nuchal translucency in the first trimester has been reported in fetuses with osteogenic imperfecta (181; 80), but this finding is seen in other conditions and is not pathognomonic. Prenatal diagnosis of skeletal dysplasia by imaging is successful in approximately 66% to 89% of cases (191; 152). Three-dimensional sonography, 3-dimensional helical computer tomography (3D-HCT), and fetal MRI can confirm routine ultrasound diagnoses and can reveal additional information (105; 169). In a study, 3-dimensional techniques were more accurate than 2-dimensional ones (145). Using fetal MRI, lung volumes can be ascertained and used as a prognostic indicator (160). Other forms of skeletal dysplasia must be ruled out, of course.
Prenatal genetic workup is most commonly performed utilizing chorionic villous sampling, amniocentesis, or cordocentesis (184). Because genomic screening for the COL1A1 and COL1A2 genes is costly, others have advocated alternative approaches, such as detection of a COL1A1 null-allele (118). To date, this has been used in patients with osteogenesis imperfecta type I. Whole exome sequencing has also been used to detect mutations in COL1A1 (94). Next-generation sequencing with Sanger sequencing has been used to detect mutations in affected patients and 1 fetus (11; 115). The cost of such testing continues to fall. Genetic workup can yield surprising results; 1 Thai boy born to consanguineous parents was found to have a de novo mutation (171).
Optimal management of the patient with osteogenesis imperfecta is multifaceted and includes maximizing function, minimizing deformity and disability, and maintaining comfort, independence, and socialization (84). Much of patient management has centered on orthopedic issues. Surgical techniques continue to be developed and have the potential to bring hope to patients (147). One example is the use of telescoping rods in the long bones of the leg (64). Femoral fractures and the risk of nonunion are especially prevalent in adults (70). In general, treatment modalities are effective in increasing bone density, but do not decrease the risk of fracture (90). However, it is hoped that some treatments currently under evaluation—chiefly sclerostin inhibitory antibodies and TGF beta inhibitors—may be helpful in treating bone fragility (102). Neurologists are likely to see patients with complications that develop secondary to platyspondyly, scoliosis, kyphosis, or basilar impression (53). In the latter condition, decompression and shunting can be lifesaving (56). The percutaneous injection of bone cementing compounds into areas of vertebral fracture (kyphoplasty) has been successful in relieving severe back pain that was unresponsive to other treatment (58). Bone mineral content can be established with dual-energy x-ray absorptiometry or DXA (109; 46). Bone mineral density increases in patients during childhood and appears to exhibit a degree of sexual dimorphism that is not understood (85). Hydrocephalus must be treated, of course. Endoscopic third ventriculostomy in 1 case achieved transient effectiveness, but was complicated by postoperative ischemia with subsequent brain atrophy (72). Cerebral aneurysm has been reported in rare patients with osteogenesis imperfecta (55; 78). Pathogenesis is unclear but may involve a connective tissue abnormality; as noted elsewhere in this review, other intra- and extra-cerebral vascular complications are recognized as well (86; 150).
Because of the presence of multiple fractures, pain is a constant feature of osteogenesis imperfecta. It may be acute or chronic and must be treated accordingly.
Respiratory failure may be life-threatening and may require intubation or long-term tracheotomy. However, newer approaches such as nasal bilevel positive airway pressure (n-BiPAP), may help avoid the use of invasive technologies (176). Nasal deformity may obstruct the airway and require careful surgical intervention (21).
A limited number of pharmaceutical agents have been employed in the treatment of osteoporosis, although new approaches, including gene targeting, are under investigation (31; 172). Bisphosphonates decrease bone resorption and improve bone density, promote remodeling of previous fractures, reduce the incidence of fractures and associated pain, and increase mobility in young patients (66; 71; 09). Cyclic intravenous administration of bisphosphonate has been shown to reduce pain immediately following infusion and to improve physical functioning (63). An oral form appears to be effective in school-aged children (43). However, bisphosphonates have also been reported to cause osteopetrosis in some young patients (101; 189), so this therapy requires continuing care and evaluation. Intravenous cycles of pamidronate, a member of the bisphosphonate family, have shown success in young patients in increasing lumbar bone mineral density with vertebral remodelling, lower frequency of fractures, and better attainment of motor milestones (03). Administration of bisphosphonates is often discontinued when patient growth is complete; one follow-up study suggests that this has no untoward consequences (142).
Unfortunately, the drug has also been associated with acute deterioration of respiratory function to the point of respiratory failure in some patients, and it must be closely monitored (120). A few cases have been treated successfully with bronchodilators, but others have required admission to an intensive care unit (113). Additional adverse effects of therapy include fever, muscle soreness, and gastrointestinal difficulties (139). Because of continuing uncertainties, bisphosphonates should be used in carefully controlled conditions and probably not be used in patients with mild forms of the disease (49; 137; 182).
Because of the potential for bone fracture, patients should avoid excess weight gain. Growth hormone has been used to stimulate collagen production and growth. A group of workers has suggested that growth hormone administration may increase the risk of fractures during puberty (117) by increasing bone turnover, which is already high in patients. Parathyroid hormone is still under investigation and not recommended at present (136).
Early success in pre- and postnatal transplantation of fetal mesenchymal stem cells has been reported (69). Two patients who received both pre- and postnatal infusions have shown engraftment, with no adverse reactions at 6 and 13 years of age (188). Allogeneic bone marrow and mesenchymal stromal cell transplantation have been used to produce chimeric collagen production in bone. This can result in accelerated bone growth post infusion (45; 79). Therapy using adult stem cells continues to be scrutinized (59; 174). In tissue cultures of mesenchymal stem cells derived from affected patients, mutant COL1A1 and COL1A2 genes have been inactivated using viral vectors, resulting in the production of normal type I procollagen and bone (35). Mesenchymal stem cells can be obtained from numerous sources (eg, blood, adipose tissue, bone marrow, amniotic fluid, cord blood) and differentiate into both mesodermal and nonmesodermal tissues, the former including bone; unlike embryonic stem cells, mesenchymal stem cells do not carry the risk of developing into teratomas (77; 96). At this time, workers do not anticipate using stem cell transplantation in cases of perinatal lethal disease (188).
Hearing loss is a problem for more than 50% of patients with osteogenesis imperfecta. This issue is not applicable to perinatal lethal osteogenesis imperfecta, but it is important to less severe forms. Hearing loss increases with age; it is more often conductive in young patients, sensorineural in older ones, and bilateral though not necessarily symmetric (33). Stapedotomy has proven successful in treating patients with conductive hearing loss (180). The basis for hearing loss in osteogenesis imperfecta appears to be multifactorial (76). Otosclerosis in patients involves changes in collagen molecules, notably collagen IV rather than collagen II, for reasons that are not clear (116). The prevalence of otitis media is increased in children and related to craniofacial anomalies (33). Screening for hearing deficits should occur before 5 years of age, with long-term follow-up anticipated (33).
The sclera can be fragile, leading to ocular complications such as uveal prolapse and traumatic scleral rupture (132). In 1 case, thin sclera complicated surgery to repair large and bilateral retinal tears (154). Corneas are thinner in patients than in controls (97). Treatment of basilar invagination is palliative and consists of bracing (using Minerva orthosis), transoral or transmaxillary decompression, and occipitocervical fixation (106; 114). These procedures have been reported to prevent the enlargement of associated syringomyelia (114). There is no treatment for cerebral dysgenesis in osteogenesis imperfecta.
Although intelligence is generally considered normal, the association with autism in a cohort of 7 osteogenesis imperfecta patients is a reminder to clinicians to be mindful of intellectual development (13).
Adequate nutrition is important for general health, but no foods or food supplements will provide a cure. Calcium intake is important for obvious reasons. Type I dentinogenesis imperfecta (discolored, translucent, brittle teeth) occurs in up to 40% of patients with osteogenesis imperfecta and requires special care (99; 162; 98; 173; 34; 140; 163). Other dental changes have been associated with bisphosphonate therapy (average duration at least 6 to 7 years) and include ectopic teeth, tooth impaction, and pulp obliteration (100).
The state of the dentition may dictate how food is prepared (127). Orthodontia or orthognathic surgery may be required, given the increased prevalence of malocclusion, prognathism, and other changes in craniofacial dimensions (38; 167). Pathology of the craniovertebral junction must be considered as part of orthodontic treatment (141). Unfortunately, such pathology (most commonly platybasia) may develop in spite of bisphosphonate therapy, especially when such therapy is initiated at an older age (07). A case of mandibular fracture following simple molar extraction required plate fixation (62).
Given the multi-systemic and chronic nature of the disorder, patients, and also siblings, parents, and other family members, need strong psychosocial support (134; 25). Quality of life is of obvious concern and varies with the severity of disease (47; 74). This is highlighted in a report of adult patients’ experiences with their own disease (165). Occasional families have been falsely accused of child abuse, highlighting the need for thorough workup in patients with unexplained or unexpected fractures (130; 131). A consensus statement for the rehabilitation of patients is available (112).
Osteonecrosis of the jaws has been related to bisphosphonate therapy (44).
Several obstetrical and gynecologic complications have been reported in women with short stature, including those with osteogenesis imperfecta (05). Because of the rarity of patients with osteogenesis imperfecta and the still rarer possibility that these patients will be pregnant, information regarding pregnancy is limited and unsettled. Reported problems include menstrual complications, difficulties with some forms of contraception, reduced fertility, and abortion due to extreme pelvic deformity (19). Women with osteogenesis imperfecta have been reported to experience later menarche than those with other osteochondrodystrophic conditions. Affected women may also experience increased numbers of fractures with the onset of pregnancy. Cesarean delivery is recommended if an affected mother has significant kyphoscoliosis or pelvic fractures or if trauma to an affected fetus (sometimes with cephalopelvic disproportion) is to be minimized (156; 93; 111). In 1 case, Cesarean section was performed at 34 weeks to avoid cardiopulmonary compromise to the mother, a woman of short stature, wheelchair bound, and in whom fetal osteogenesis imperfecta was suspected, based on prenatal ultrasound studies (129). Of course, preterm delivery for reasons of maternal health may result in risks to the neonate (81). Thromboprophylaxis is indicated in mothers with reduced mobility (129). Affected women may experience postpartum hemorrhage secondary to uterine atony; therefore, close observation and infusion of oxytocin have been recommended (156). Because of the risk of hyperthermia during anesthesia, spinal or epidural modes of administration may be preferred. Congenital malformations, including skeletal abnormalities, have not been identified in the offspring of women treated with bisphosphonates before or during pregnancy (50). Because of the complex nature of this disorder, treating affected women during pregnancy calls for a multidisciplinary team (36).
The risk of transmission to offspring is approximately 4% to 8% in cases arising from a sporadic, de novo dominant mutation and 25% if recessive.
Patients with osteogenesis imperfecta can be expected to require a significant number of procedures that require anesthesia. Individuals are especially prone to malignant hyperthermia (hyperpyrexia) during surgery. Although the origin of this reaction is unknown, it has compelled anesthesiologists to reconsider the appropriateness of certain anesthetic agents (57; 68).
The skeletal abnormalities in osteogenesis imperfecta complicate the administration of anesthesia by oronasal routes and have been the subject of several reports. Intubation and other procedures are complicated by limited opportunity for hyperextension of the neck as well as dental abnormalities, restrictive lung disease secondary to deformities of the chest, scoliosis, and the presence of basilar impression (73; 41).
In 1 review of 205 anesthetic procedures, challenges included significant blood loss (17%), difficult intravenous catheter placement (4%), difficult airway placement (1.5 %), and perioperative fracture (1%) (144). Ideally, anesthesiologists will have adequate time to prepare for the unique demands posed by this disease (42).
Joseph R Siebert PhD
Dr. Siebert of the University of Washington has no relevant financial relationships to disclose.See Profile
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