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Blomstrand's Lethal Chondrodysplasia: Two Enchondromatosis

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Blomstrand's Lethal Chondrodysplasia: Two Enchondromatosis Blomstrand’s lethal chondrodysplasia Authors: Doctor Caroline Silve1 and Doctor Harald Jüppner2 Creation Date: January 2005 Scientific Editor: Doctor Valérie Cormier-Daire 1INSERM U. 426, Faculté de Médecine Xavier Bichat, 16 rue Henri Huchard, 75018 Paris, France; 2Endocrine Unit, Department of Medicine, and Pediatric Nephrology unit, MassGeneral Hospital for Children, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. [email protected] Abstract Keywords Disease name/Synonyms Definition/Diagnostic methods Clinical features Radiologic and histologic analysis of the skeleton Pathogenesis Molecular genetics Genetics/Prevalence Genetic counseling Antenatal diagnosis Treatment References Abstract Blomstrand’s lethal chondrodysplasia (BLC) (OMIM215045) is a rare recessive human disorder characterized by early lethality, advanced bone maturation and accelerated chondrocyte differentiation. Infants with BLC are typically born prematurely and die shortly after birth. They present a severe dysmorphic syndrome characterized by extremely short limbs. Radiologic studies reveal pronounced hyperdensity of the entire skeleton and markedly advanced ossification. Diagnosis can be made as early as 12-13 gestational weeks by transvaginal ultrasound. BLC is associated with loss-of-function mutation in the gene encoding the PTH/PTHrP receptor (PTHR1). Keywords chondrodysplasia, advanced endochondral bone maturation, lethal, PTHR1 gene Disease name/Synonyms Clinical features Blomstrand’s lethal chondrodysplasia (BLC), The first patient was described by Blomstrand Blomstrand osteochondrodysplasia (BOCD) and colleagues in 1985; descriptions of several other patients followed (3-9). Infants with BLC Definition/Diagnostic methods are typically born prematurely and die shortly Blomstrand’s lethal chondrodysplasia (BLC) after birth. Birth weight, when corrected for (OMIM 215045) is a rare recessive human gestational age, appears to be normal, but may disorder characterized by early lethality, be overestimated because most infants are advanced bone maturation and accelerated hydroptic. The placenta can be immature and chondrocyte differentiation (1, 2). The diagnostic edematous. Nasal, mandibular, and facial bones criteria are based on the clinical and are hypoplastic; the base of the skull is short and radiographic characteristics observed in patients narrow; the ears are low set; the thoracic cage is with this dysmorphic syndrome, early lethality, hypoplastic and narrow with short thick ribs and and, in most cases, parental consanguinity. hypoplastic vertebrae. In contrast, the clavicles are relatively long and often abnormally shaped, Silve C., Jüppner H. Blomstrand’s lethal chondrodysplasia. Orphanet encyclopedia, January 2005. http://www.orpha.net/data/patho/GB/uk-BlomstrLethChondrodysplasia.pdf 1 the limbs are extremely short, and only the Molecular genetics hands and feet are of relatively normal size and Four different defects in the PTHR1 gene were shape. At autopsy, internal organs show no described in genomic DNA from patients apparent structural or histological anomalies, but affected by BLC. The first reported case, a preductal aortic coarctation is observed in some product of non-consanguineous parents, was published cases. The lungs are hypoplastic and shown to have two distinct abnormalities in the the protruding eyes typically show cataracts. PTHR1 gene (16). Through a nucleotide Defects in mammary gland and tooth exchange in exon M5 of the maternal PTHR1 development, previously overlooked, were receptor allele, a novel splice acceptor site was demonstrated in two recently studied fetuses introduced which led to a mutant mRNA with BLC (10). Although these analyses have not encoding an abnormal receptor that lacks a been performed, it is most likely that fetuses with portion of the fifth membrane-spanning domain BLC present severe abnormalities in mineral ion (∆373-383). For yet unknown reasons, the homeostasis. paternal PTHR1 allele from this patient is very poorly expressed, suggesting an unidentified Radiologic and histologic analysis of the mutation in one of the different promoter regions skeleton or in a putative enhancer element. A second Radiological studies of patients with BLC reveal patient with BLC, the product of a pronounced hyperdensity of the entire skeleton consanguineous marriage, was shown to have a and markedly advanced ossification. As nucleotide exchange that leads to a proline to mentioned above, the long bones are extremely leucine mutation at position 132 (P132L) (17, short and poorly modeled, show markedly 18). A homozygous deletion of G at position increased density, and lack metaphyseal growth 1122 (exon EL2) was identified in a third case of plates. Endochondral bone formation is BLC (19). This mutation led to a shift in the open dramatically advanced, and is associated with a reading frame, which resulted in a truncated major reduction in epiphyseal resting cartilage protein that completely diverged from the wild- preventing the development of epiphyseal type receptor sequence after amino acid 364 ossification centers. The zones of chondrocyte (∆365-593). proliferation and of column formation are lacking, All mutant receptors have been demonstrated by and the zone that normally comprises the layer in vitro studies to have greatly reduced agonist- of hypertrophic chondrocytes is poorly defined, stimulated cAMP accumulation, with or without narrow and irregular. Cortical bone is thickened, impaired cell surface expression and/or PTH bone trabeculae are coarse with reduced binding. It is worth noting the P132L mutation diaphyseal marrow spaces. Capillary ingrowth, inactivates the PTHR1 incompletely (17). bone resorption, and bone formation are Abnormalities in skeletal development in the reported by some authors as being unaltered, fetuses carrying that mutation are less severe while others describe these bone remodeling than those observed in most cases, particularly events as deficient. with regard to the bones of the lower limbs. This Based on the severity of the phenotype, two led to the proposal that two forms of BLC can be types named type I (the severe, 'classic' form) distinguished clinically and on the basis of the in and type II (a less severe form) are described vitro characteristics of the mutant PTHR1 (9). (9). The less severe phenotype is associated Of note, mutations in the PTHR1 gene have with a mutation leading to some residual activity been associated to three diseases in addition to of the PTHR1 mutated receptors (see below). BLC, Jansen's metaphyseal chondrodysplasia (JMC) (OMIM 156400) (20), Eiken familial Pathogenesis skeletal dysplasia (21), and enchondromatosis Studies in transgenic mice demonstrated that the (Ollier's disease) (OMIM 16600) (22). PTHrp/PTHR1 signaling pathway is an essential regulator of endochondral bone development Jansen's metaphyseal chondrodysplasia (11) and epithelial-mesenchymal interactions (JMC) during the formation of the mammary glands and JMC is a rare form of short limb dwarfism teeth (12). The findings in patients with BLC associated with laboratory abnormalities that are recapitulate the phenotype observed in the typically observed only in patients with either mouse Pthr1 and Pthrp "knock-out" (13, 14). primary hyperparathyroidism, or the humoral They are the mirror image of those observed in hypercalcemia of malignancy syndrome. Four Jansen chondrodysplasia (OMIM 156400) (15). different heterozygous missense mutations (H223R, I458R, T410P, and T410R) in the PTHR1 gene have been identified in patients with JMC (15, 23). All mutations are associated Silve C., Jüppner H. Blomstrand’s lethal chondrodysplasia. Orphanet encyclopedia, January 2005. http://www.orpha.net/data/patho/GB/uk-BlomstrLethChondrodysplasia.pdf 2 with constitutive activation of the PTHR1 in vitro. Antenatal diagnosis The T410R mutation shows a less pronounced Diagnosis can be made as early as 12-13 constitutive activity than the previously reported gestational weeks by transvaginal ultrasound. T410P substitution, and is associated with a less severe form of JMC. Treatment There is no treatment. Eiken familial skeletal dysplasia Eiken familial skeletal dysplasia has been References described in a unique consanguineous family 1. Maroteaux, P., and Le Merrer, M. (2002) Les (24). It is characterized by multiple epiphyseal maladies osseuses de l'enfant, Médecine- dysplasia, with extremely retarded ossification, Sciences, Flammarion, Paris as well as by abnormal modeling of the bones in 2. Jüppner, H., and Silve, C. (2000) Jansen and hands and feet, and abnormal persistence of Blomstrand, two human chondrodysplasias cartilage in the pelvis and mild growth caused by PTH/PTHrP receptor mutations. In retardation. Serum calcium and phosphate levels The genetics of osteoporosis and metabolic have been found to be normal in all the patients bone disease (Econs. MJ., ed) pp. 357-376, examined, serum PTH level was measured in Humana Press, Totowa, NJ one patient and found to be slightly elevated with 3. Young, I. D., Zuccollo, J. M., and Broderick, N. normal 1,25-(OH)2VitD. A recessive mutation in J. (1993) A lethal skeletal dysplasia with the PTHR1, R485stop, that leads to the generalised sclerosis and advanced skeletal truncation of the last 108 amino-acids of the maturation: Blomstrand chondrodysplasia. J. PTHR1, has been recently identified in a kindred Med. Genet. 30, 155-157 with Eiken syndrome (21). Although the mutant 4. Leroy, J. G., Keersmaeckers,
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