Rib Cage Deformities Alter Respiratory Muscle Action and Chest Wall Function in Patients with Severe Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) is an inherited connective tissue disorder characterized by bone fragility, multiple fractures and significant chest wall deformities. Cardiopulmonary insufficiency is the leading cause of death in these patients.Seven patients with severe OI type III, 15 with moderate OI type IV and 26 healthy subjects were studied. In addition to standard spirometry, rib cage geometry, breathing pattern and regional chest wall volume changes at rest in seated and supine position were assessed by opto-electronic plethysmography to investigate if structural modifications of the rib cage in OI have consequences on ventilatory pattern. One-way or two-way analysis of variance was performed to compare the results between the three groups and the two postures. compared to predicted values, on condition that updated reference equations are considered. In both positions, ventilation was lower in OI patients than control because of lower tidal volume (p<0.01). In contrast to OI type IV patients, whose chest wall geometry and function was normal, OI type III patients were characterized by reduced (p<0.01) angle at the sternum (pectus carinatum), paradoxical inspiratory inward motion of the pulmonary rib cage, significant thoraco-abdominal asynchronies and rib cage distortions in supine position (p<0.001).In conclusion, the restrictive respiratory pattern of Osteogenesis Imperfecta is closely related to the severity of the disease and to the sternal deformities. Pectus carinatum characterizes OI type III patients and alters respiratory muscles coordination, leading to chest wall and rib cage distortions and an inefficient ventilator pattern. OI type IV is characterized by lower alterations in the respiratory function. These findings suggest that functional assessment and treatment of OI should be differentiated in these two forms of the disease

Generalized Connective Tissue Disease in Crtap-/- Mouse

Mutations in CRTAP (coding for cartilage-associated protein), LEPRE1 (coding for prolyl 3-hydroxylase 1 [P3H1]) or PPIB (coding for Cyclophilin B [CYPB]) cause recessive forms of osteogenesis imperfecta and loss or decrease of type I collagen prolyl 3-hydroxylation. A comprehensive analysis of the phenotype of the Crtap-/- mice revealed multiple abnormalities of connective tissue, including in the lungs, kidneys, and skin, consistent with systemic dysregulation of collagen homeostasis within the extracellular matrix. Both Crtap-/- lung and kidney glomeruli showed increased cellular proliferation. Histologically, the lungs showed increased alveolar spacing, while the kidneys showed evidence of segmental glomerulosclerosis, with abnormal collagen deposition. The Crtap-/- skin had decreased mechanical integrity. In addition to the expected loss of proline 986 3-hydroxylation in α1(I) and α1(II) chains, there was also loss of 3Hyp at proline 986 in α2(V) chains. In contrast, at two of the known 3Hyp sites in α1(IV) chains from Crtap-/- kidneys there were normal levels of 3-hydroxylation. On a cellular level, loss of CRTAP in human OI fibroblasts led to a secondary loss of P3H1, and vice versa. These data suggest that both CRTAP and P3H1 are required to maintain a stable complex that 3-hydroxylates canonical proline sites within clade A (types I, II, and V) collagen chains. Loss of this activity leads to a multi-systemic connective tissue disease that affects bone, cartilage, lung, kidney, and skin

Superior odontoid migration in the Klippel–Feil patient

Klippel–Feil syndrome (KFS) is an uncommon condition noted primarily as congenital fusion of two or more cervical vertebrae. Superior odontoid migration (SOM) has been noted in various skeletal deformities and entails an upward/vertical migration of the odontoid process into the foramen magnum with depression of the cranium. Excessive SOM could potentially threaten neurologic integrity. Risk factors associated with the amount of SOM in the KFS patient are based on conjecture and have not been addressed in the literature. Therefore, this study evaluated the presence and extent of SOM and the various risk factors and clinical manifestations associated therein in patients with KFS. Twenty-seven KFS patients with no prior history of surgical intervention of the cervical spine were included for a prospective radiographic and retrospective clinical review. Radiographically, McGregor’s line was utilized to evaluate the degree of SOM. Anterior and posterior atlantodens intervals (AADI/PADI), number of fused segments (C1–T1), presence of occipitalization, classification-type, and lateral and coronal cervical alignments were also evaluated. Clinically, patient demographics and presence of cervical symptoms were assessed. Radiographic and clinical evaluations were conducted by two independent blinded observers. There were 8 males and 19 females with a mean age of 13.5 years at the time of radiographic and clinical assessment. An overall mean SOM of 5.0 mm (range = −1.0 to 19.0 mm) was noted. C2–C3 (74.1%) was the most commonly fused segment. A statistically significant difference was not found between the amount of SOM to age, sex-type, classification-type, AADI, PADI, and lateral cervical alignment (P > 0.05). A statistically significant greater amount of SOM was found as the number of fused segments increased (r = 0.589; P = 0.001) and if such levels included occipitalization (r = 0.616; P = 0.001). A statistically significant greater amount of SOM was also found with an increase in coronal cervical alignment (r = 0.413; P = 0.036). Linear regression modeling further supported these findings as the strongest predictive variables contributing to an increase in SOM. A 7.20 crude relative risk (RR) ratio [95% confidence interval (CI) = 1.05–49.18; risk differences (RD) = 0.52] was noted in contributing to a SOM greater than 4.5 mm if four or more segments were fused. Adjusting for coronal cervical alignment greater than 10°, five or more fused segments were found to significantly increase the RR of a SOM greater than 4.5 mm (RR = 4.54; 95% CI = 1.07–19.50; RD = 0.48). The RR of a SOM greater than 4.5 mm was more pronounced in females (RR = 1.68; 95% CI = 0.45–6.25; RD = 0.17) than in males. Eight patients (29.6%) were symptomatic, of which symptoms in two of these patients stemmed from a traumatic event. However, a statistically significant difference was not found between the presence of symptoms to the amount of SOM and other exploratory variables (P > 0.05). A mean SOM of 5.0 mm was found in our series of KFS patients. In such patients, increases in the number of congenitally fused segments and in the degree of coronal cervical alignment were strongly associated risk factors contributing to an increase in SOM. Patients with four or greater congenitally fused segments had an approximately sevenfold increase in the RR in developing SOM greater than 4.5 mm. A higher RR of SOM more than 4.5 mm may be associated with sex-type. However, 4.5 mm or greater SOM is not synonymous with symptoms in this series. Furthermore, the presence of symptoms was not statistically correlated with the amount of SOM. The treating physician should be cognizant of such potential risk factors, which could also help to indicate the need for further advanced imaging studies in such patients. This study suggests that as motion segments diminish and coronal cervical alignment is altered, the odontoid orientation is located more superiorly, which may increase the risk of neurologic sequelae