Achondrogenesis Differential Diagnoses

Diagnostic Considerations

Achondrogenesis may be differentiated from other skeletal dysplasias by having the most severe degree of limb shortening. The demineralization is only a differential diagnosis in osteogenesis imperfecta and hypophosphatasia, which do not present with the same degree of limb shortening. ^[15]

With a considerable phenotypic heterogeneity seen in achondrogenesis, ^[16] types I and II are distinguished based on clinical, radiologic, and histopathologic features. Achondrogenesis type I (Parenti-Fraccaro) is inherited autosomal recessive and is the more severe form, characterized by inadequate ossification of the skull, spine, and pelvis, extensive shortening of tubular bones, and multiple rib fractures. Achondrogenesis type II (Langer-Saldino) is characterized by various degrees of calcification of the pelvis, skull, and spine without rib fractures, and most type II cases are sporadic (new autosomal dominant mutations). ^[15]

Other differentials to consider include the following:

• Atelosteogenesis type II

• Fibrochondrogenesis

• Grebe dysplasia

• Homozygous achondroplasia

• Hypochondrogenesis

• Lethal osteogenesis imperfecta

• Roberts syndrome

• Schneckenbecken dysplasia

• Short rib-polydactyly syndromes

• Spondyloepiphyseal dysplasia congenita, lethal form

Prenatal diagnosis of achondrogenesis is possible as early as the first and second trimesters by prenatal ultrasonography and molecular analysis.

Prenatal diagnosis by ultrasonography

Achondrogenesis, a lethal form of congenital chondrodystrophy, is characterized by extreme micromelia. The prenatal diagnosis of achondrogenesis is based on extreme micromelia, narrow thorax, and poor mineralization of the skull and vertebrae. Other ultrasonographic features include polyhydramnios, macrocrania with variable ossification anomalies, nuchal edema, reduced rump length, and poor ossification of vertebral bodies and limb tubular bones (leading to difficulties in determining their length). ^{[15, 17]}

Characterization of demineralization is important in differentiating between type I and II achondrogenesis. ^[17] When the demineralization affects the skull and iliac wings, the presumptive diagnosis is type I; when the skull appears normally mineralized the presumptive diagnosis is type II. When demineralization is present on ultrasonography, radiographic findings may confirm it. However, in the absence of demineralization on ultrasonography, radiologic demineralization cannot be presumed. Because the recognition of demineralization by ultrasonography is fraught with false negatives, a tendency to over-report the type II form is noted. ^[15]

Achondrogenesis type I should be strongly suspected when ultrasonography reveals an extremely echo-poor appearance of the skeleton and a poorly mineralized skull, as well as short limbs and rib fractures.

Prenatal diagnosis by molecular studies

Prenatal diagnosis of achondrogenesis may be accomplished by mutation analysis of chorionic villus DNA or amniocyte DNA in the first or second trimester, respectively.

In achondrogenesis types IA and IB, both alleles should be characterized beforehand and the source parent of each allele identified.

In ACGII, the affected fetus usually has a de novo dominant mutation of the COL2A1 gene. Asymptomatic carriers may be present in families of an affected patient. Prenatal diagnosis may be possible if the mutation has been characterized in the affected family.

Genetic counseling

Recurrence risk is 25% for achondrogenesis types IA and type IB.

Achondrogenesis type II is usually caused by a new dominant mutation; however, asymptomatic carriers may be present in the family.

Recurrence of achondrogenesis type II within the same family is evidence for germline mosaicism. A family with recurrent achondrogenesis type II in 3 fetuses documented a mosaic father with an intermediate phenotype. A case report noted recurrent achondrogenesis type II in 2 fetuses from unaffected parents, and a report of 2 siblings with achondrogenesis type II has been made. ^[18]

Germline mosaicism for a dominant mutation in one parent can mimic autosomal recessive inheritance when two or more children are born to apparently normal parents.

In the case of germline mosaicism, phenotypically normal individuals may transmit several gametes that are clonal descendants of a single progenitor cell, in which a de novo mutation occurred during early embryonic development. ^[19]

In the case of somatic mosaicism, the manifestation of such a mutation in a mosaic parent may range from none or minimal to a severe generalized effect. It could also result in a milder but different phenotype, such as the observations of severe Kniest dysplasia in two unrelated children with COL2A1 mutations and mild Stickler syndrome or spondyloepiphyseal dysplasia in their mosaic parents. ^[20]

Germline or somatic mosaicism has been documented in other autosomal dominant skeletal dysplasias, such as achondroplasia, ^[21] pseudoachondroplasia, and osteogenesis imperfecta. ^[22]

The possibility of germline mosaicism should always be considered in case of an apparently de novo dominant mutation, and the family should not be counseled that the recurrence risk is zero.

Estimating the exact recurrence risk for healthy parents with only one child affected, although this risk is quite low considering that achondrogenesis type II/hypochondrogenesis is not that infrequent and no other written reports of recurrence are noted. ^[23]

Differential Diagnoses

• Asphyxiating Thoracic Dystrophy (Jeune Syndrome)

• Genetics of Achondroplasia

• Genetics of Osteogenesis Imperfecta

• Hypophosphatasia (HPP)

• Thanatophoric Dysplasia