Lethal and life-limiting skeletal dysplasias: Selected prenatal issues

Abstract

Skeletal dysplasias are a heterogeneous group of congenital bone and cartilage disorders with a genetic etiology. The current classification of skeletal dysplasias distinguishes 461 diseases in 42 groups. The incidence of all skeletal dysplasias is more than 1 in every 5000 newborns. The type of dysplasia and associated abnormalities affect the lethality, survival and long-term prognosis of skeletal dysplasias. It is crucial to distinguish skeletal dysplasias and correctly diagnose the disease to establish the prognosis and achieve better management. It is possible to use prenatal ultrasonography to observe predictors of lethality, such as a bell-shaped thorax, short ribs, severe femoral shortening, and decreased lung volume. Individual lethal or life-limiting dysplasias may have more or less specific features on prenatal ultrasound. The prenatal features of the most common skeletal dysplasias, such as thanatophoric dysplasia, osteogenesis imperfecta type II, achondrogenesis, and campomelic dysplasia, are discussed in this article. Less frequent dysplasias, such as asphyxiating thoracic dystrophy, fibrochondrogenesis, atelosteogenesis, and homozygous achondroplasia, are also discussed.

Molecular diagnosis and novel genes and phenotypes in a pediatric thoracic insufficiency cohort

“…We assembled and phenotyped a diverse cohort of children with thoracic insufficiency and identified clear patterns of comorbidities including eye, kidney, brain, cardiac and endocrine disease. Exome sequencing of this cohort identified a molecular etiology in 57% of the participants (24/42), with 18/24 probands having a positive diagnosis identified and 6/24 probands having strong candidate genes identified, consistent with previous cohort studies [10][11][12][13][14][15][16][17][18] . Identified genes commonly encoded structural and functional components of the primary cilium, bone, and extracellular matrix.…”

“…Thoracic insufficiency syndromes (TIS) have a broad phenotypic and genetic spectrum, and despite advances in next-generation sequencing the diagnostic success rate ranges from 30 to 75% in most studies [10][11][12][13][14][15][16][17][18] , with particularly low success rates in individuals with isolated scoliosis [23][24][25] and particularly high success rates in skeletal dysplasias 26 . We assembled and phenotyped a diverse cohort of children with thoracic insufficiency and identified clear patterns of comorbidities including eye, kidney, brain, cardiac and endocrine disease.…”

“…Advances in next-generation sequencing have improved the molecular diagnosis rate for skeletal malformation syndromes. Molecular etiology is identified in 50-90% of individuals with skeletal dysplasia; however, molecular diagnosis is rarer in individuals with scoliosis without skeletal dysplasia or in individuals with non-syndromic scoliosis due to our incomplete understanding of the genetics of skeletal malformations [10][11][12][13][14][15][16][17][18] . Additionally, despite molecular diagnosis, there remains uncertainty about disease course due to the rarity of these conditions and lack of long-term natural history studies delineating the full phenotypic spectrum.…”

Spontaneous Rupture of Unscarred Uterus in a Term Primagravida with Lethal Skeletal Dysplasia Fetus (Thanatophoric dysplasia). A Case Report and Review of the Literature

“…Thanatophoric dysplasia is the most lethal form of skeletal dysplasias caused by an autosomal dominant mutation in the FGFR 3 gene. 31,32 Regarding our case report, it is worth noting that the lack of antenatal care during pregnancy was an important factor that contributed to this patient's rupture of the uterus. Antenatal care is an effective method of improving pregnancy outcomes.…”

“…Thanatophoric dysplasia is the most lethal form of skeletal dysplasias caused by an autosomal dominant mutation in the FGFR 3 gene. 31 , 32 …”