Achondrogenesis Differential Diagnoses

  • Author: Harold Chen, MD, MS, FAAP, FACMG; Chief Editor: Bruce Buehler, MD   more...
 
Updated: Aug 11, 2011
 
 

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.[8]

With a considerable phenotypic heterogeneity seen in achondrogenesis,[9] 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).[8]

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 by ultrasonography

Experienced ultrasonographers can recognize various types of achondrogenesis in fetuses as early as 12–14 weeks' gestation. This makes ultrasonography an acceptable option when molecular studies are unavailable or unfeasible.

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 ultrasonic features include polyhydramnios, large head, nuchal edema, reduced rump length, and poor ossification of vertebral bodies and limb tubular bones (leading to difficulties in determining their length).[8, 10]

Characterization of demineralization is important in differentiating between type I and II achondrogenesis.[10] 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, radiological demineralization cannot be presumed. Because the recognition of demineralization by ultrasonography is fraught with false negatives, a tendency to overreport the type II form is noted.[8]

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 type IB and type II may be accomplished by mutation analysis of chorionic villus DNA or amniocyte DNA in the first or second trimester, respectively.

In achondrogenesis type IB, both alleles of DDST should be characterized beforehand, and the source parent of each allele identified. Theoretically, analysis of sulfate incorporation in chorionic villi might be used for prenatal diagnosis, but experience is lacking.

In achondrogenesis type II, the affected fetus usually has a new 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 type 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.[11]

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.[12]

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.[13]

Germline or somatic mosaicism has been documented in other autosomal dominant skeletal dysplasias, such as achondroplasia,[14] pseudoachondroplasia, and osteogenesis imperfecta.[15]

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.[16]

Prenatal diagnosis is possible in the first and second trimester by prenatal ultrasonography and molecular analysis.

Differential Diagnoses

Proceed to Workup
 
 
Contributor Information and Disclosures
Author

Harold Chen, MD, MS, FAAP, FACMG  Professor, Departments of Pediatrics, Obstetrics and Gynecology, and Pathology, Director of Genetic Laboratory Services, Louisiana State University Medical Center

Harold Chen, MD, MS, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics, American Medical Association, and American Society of Human Genetics

Disclosure: Nothing to disclose.

Specialty Editor Board

James Bowman, MD  Senior Scholar of Maclean Center for Clinical Medical Ethics, Professor Emeritus, Department of Pathology, University of Chicago

James Bowman, MD is a member of the following medical societies: Alpha Omega Alpha, American Society for Clinical Pathology, American Society of Human Genetics, Central Society for Clinical Research, and College of American Pathologists

Disclosure: Nothing to disclose.

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Hagop Youssoufian, MD, MSc  Vice President of Clinical Research, ImClone Systems Incorporated

Hagop Youssoufian, MD, MSc is a member of the following medical societies: American Society for Clinical Investigation, American Society of Clinical Oncology, American Society of Hematology, and American Society of Human Genetics

Disclosure: Nothing to disclose.

Paul D Petry, DO, FACOP, FAAP  Consulting Staff, Freeman Pediatric Care, Freeman Health System

Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association

Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD  Professor, Department of Pediatrics and Genetics, Director RSA, University of Nebraska Medical Center

Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association

Disclosure: Nothing to disclose.

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An infant with achondrogenesis type II. Note the disproportionately large head, large and prominent forehead, flat facial plane, flat nasal bridge, small nose with severely anteverted nostrils, micrognathia, extremely short neck, short and flared thorax, protuberant abdomen, and extremely short upper extremities.
This posteroanterior (PA) view radiograph of an infant with achondrogenesis type II shows the relatively large calvaria with normal cranial ossification, short and flared thorax, bell-shaped cage and shorter ribs without fractures, relatively well ossified iliac bone with long crescent-shaped medial and inferior margins, and short tubular bones. The sacrum, pubis, and ischium are not visible.
Lateral view radiograph of an infant with achondrogenesis type II. Note the relatively large head with a normal cranial ossification and enlarged fontanelles, short ribs, absent sternal ossification, ossification only in anterior parts of the vertebral bodies, and short and curved femora.
An infant with achondrogenesis type II. Note the protuberant abdomen and extremely short lower extremities.
Photomicrographs of the costal cartilage of an infant with achondrogenesis type II. This shows prominent hypercellularity, large chondrocytes, deficient matrix, and abnormally large, stellate cartilage canals. The left image is X42, and the right image is X106.
 
 
 
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