Skeletal Dysplasias of the Human Fetus: Postmortem Diagnosis

Abstract

Congenital skeletal disorders comprise a heterogenous group of abnormalities of the bones related to their shape, growth and integrity. They are present at birth or become manifest during gestation causing abnormal development of the fetal skeleton that can be prenatally detected by ultrasonography. They make part of a large group of genetic skeletal disorders, formerly called constitutional disorders of bone. They all refer to abnormal skeletal development on the basis of a defective genetic background. Excluding chromosomal abnormalities affecting the skeleton, the large and heterogeneous family of genetic skeletal disorders comprise (1) disorders with significant skeletal involvement corresponding to the definition of skeletal dysplasias (alternatively called osteochondrodysplasias), (2) metabolic and molecular bone disorders, (3) dysostoses, (4) skeletal malformation and/or reduction syndromes and (5) multiple congenital malformation syndromes with a prominent skeletal involvement. . The genetic skeletal disorders, although individually rare, are not uncommon as a whole group. The latest 2010 Revision of the Nosology and Classification of Genetic Skeletal Disorders (Warman et al., 2011) includes 456 entities. Some 50 of them are perinatally lethal and can be diagnosed at birth (Nikkels, 2009), while some others, non lethal and compatible with short or long term survival, may present with abnormal phenotypic findings at birth or with abnormal ultrasonographic findings in utero and raise a prenatal diagnostic dilemma, as pertains to the possible lethality or morbidity of the affected fetus. With the advent of prenatal ultrasonographic examination, many of the affected fetuses are aborted at an early gestational age. A correct diagnosis and typing of the skeletal disorder is essential for the prognosis and genetic counselling of the family, as well as for the possibility of prenatal diagnosis in subsequent pregnancies. The molecular defects underlying the genetic skeletal disorders are increasingly being identified and have shed some light on the pathogeneses of these conditions. One important example is that of the fibroblast growth factor receptor (FGFR3) defects underlying skeletal dysplasias such as Thanatophoric dysplasia, Achondroplasia etc. Nevertheless, in only a restricted subgroup of fetal skeletal dysplasias is the molecular genetic analysis part of a routine prenatal control able to provide an accurate diagnosis. In most instances, the responsibility of the final diagnosis of a fetal skeletal dysplasia lies on the post-mortem examination and in many institutions it is largely or uniquely the task of the pathologist.