Final Diagnosis -- Osteogenesis imperfecta Type II


Osteogenesis imperfecta Type II (OI II).


The skeletal dysplasias represent a large group of disorders with a broad range in severity. The most severe forms are the lethal skeletal dysplasias, which present in the fetus and can be diagnosed in utero. The lethality of these disorders typically derives from the very small chest cavity that develops in these fetuses. The resulting constriction in lung volume leads to severe pulmonary hypoplasia and nearly uniform perinatal mortality. The most common lethal skeletal dysplasias include thanatophoric dysplasia (most common), achondrogenesis, osteogenesis imperfect type II, hypophosphatasia congenita, campomelic dysplasia, short-rib polydactyly syndromes, fibrochondrogenesis, atelosteogenesis, and chondrodysplasia punctata. Thanatophoric dysplasia and osteogenesis imperfecta type II together account for 30% of lethal skeletal dysplasia cases.

Prenatal diagnosis of lethal skeletal dysplasias involves a comprehensive evaluation which usually starts with the anatomy scan in the second trimester. If concern for a skeletal dysplasia is raised, the follow-up diagnostic process includes a thorough ultrasonographic evaluation of the bones; absence or presence, length, fractures, shapes and growth over time. Currently, prenatal diagnosis using ultrasound has very high sensitivity and specificity for the diagnosis of lethal skeletal dysplasias. Cases of suspected lethal skeletal dysplasia are typically referred for a Genetics consultation, and ancillary testing, such as amniocentesis with karyotype and possibly molecular testing, may be recommended. After delivery, clinical, radiologic, molecular, and pathologic examination are employed to confirm the diagnosis.

Pathologically, this is a typical osteogenesis imperfecta Type II case. This disorder presents with multiple (sometimes almost innumerable) fractures in the ribs and long bones, with consequent malformation of the bones. Macroscopic and radiologic examinations show deformed upper and lower extremities with shortened long bones with multiple fractures. The ribs will often have a beaded appearance, due to the multiple adjacent fractures. Radiologically, the bones have a "crumpled" appearance. All bones are extremely delicate and easily fractured. Histology of the long bones shows thinned cortices with small, thin, hypercellular trabeculae and often extensive metaplastic cartilage.

Most cases of OI II are autosomal dominant. The disorder arises from mutation in one of the two type I collagen genes, COL1A1 and COL1A2. Nearly all are new mutations, with the parents being unaffected. A smaller number of cases show autosomal recessive inheritance. The first of these to be identified was the gene for cartilage associated protein, CRTAP. This protein appears to be required for prolyl 3-hydroxylation of type I and type II collagens. More recently, mutation in other genes has also been associated with autosomal recessive OI II. These include LEPRE1 and PPIB. The autosomal recessive forms of OI II may have a milder phenotype than the autosomal dominant form. The autosomal recessive forms were originally designated as OI IIB (with the autosomal dominant form as OI IIA). More recently, however, several new categories of OI have been developed, and the autosomal recessive forms of OI IIB have been reclassified as OI VII.


Warman ML, Cormier-Daire V, Hall C, Krakow D, Lachman R, LeMerrerM, Mortier G, Mundlos S, Nishimura G, Rimoin DL, Robertson S, Savarirayan R, Sillence D, Spranger J, Unger S, Zabel B, Superti-Furga A. 2011. Nosology and classification of genetic skeletal disorders: 2010 revision. Am J Med Genet Part A 155:943-968.

Schramm T, Gloning KP, Minderer S, Daumer-Haas C, Hörtnagel K, Nerlich A, Tutschek B. Prenatal sonographic diagnosis of skeletal dysplasias. Ultrasound Obstet Gynecol. 2009;34(2):160.

Contributed by Lananh Nguyen, MD and Tony Parks, MD

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