eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Genetics

Achondrogenesis: Differential Diagnoses & Workup

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
Contributor Information and Disclosures

Updated: Apr 23, 2009

Differential Diagnoses

Achondroplasia
Asphyxiating Thoracic Dystrophy (Jeune Syndrome)
Hypophosphatasia
Osteogenesis Imperfecta
Thanatophoric Dysplasia

Other Problems to Be Considered

  • 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

Workup

Laboratory Studies

  • Molecular studies for achondrogenesis are performed on ethylenediaminetetraacetic acid (EDTA)–anticoagulated blood for DNA analysis.
  • Mutation analysis of the DDST gene identifies the following: point mutations, deletions leading to premature stop codons, substitutions or deletions of amino acids within transmembrane domains, substitutions of amino acids in intracellular or extracellular domains, and presumed mutations lying outside the coding region but causing low mRNA levels.
  • Several mutations of the DDST gene have been reported in patients with type IB (the most severe form), patients with atelosteogenesis type II (an intermediate form), and patients with diastrophic dysplasia (the mildest form).
  • Mutation analysis can be used to ascertain carriers, particularly in consanguineous families. However, biochemical analysis of fibroblast cultures has not been able to distinguish heterozygotes from normal homozygotes.
  • Mutation analysis of the COL2A1 gene detects a single base change that has been observed in a patient with achondrogenesis type II in the type II procollagen gene (ie, substitution of serine for glycine in the alpha 1 [II] chain).

Imaging Studies

  • Radiological features may vary, and no single feature is obligatory. Distinction between type IA and type IB on radiographs is not always possible. Degree of ossification is age dependent, and caution is needed when comparing radiographs at different gestational ages.
  • Achondrogenesis type I (Fraccaro-Houston-Harris type)
    • Skull - Varying degree of deficient cranial ossification consisting of small islands of bone in membranous calvaria
    • Thorax and ribs - Short and barrel-shaped thorax; thin ribs with marked expansion at costochondral junction, frequently with multiple fractures
    • Spine and pelvis - Poorly ossified spine, ischium, and pubis; poorly ossified iliac bones with short medial margins
    • Limbs and tubular bones - Extreme micromelia, with limbs much shorter than in type II; flipperlike appendages; prominent spikelike metaphyseal spurs; femur and tibia frequently presenting as bone segments
    • Subtype IA (Houston-Harris type) - Poorly ossified skull, thin ribs with multiple fractures, unossified vertebrae, arched ilium, hypoplastic but ossified ischium, wedged femur with metaphyseal spikes, short tibia and fibula with metaphyseal flare, "rectangular bones"
    • Subtype IB (Fraccaro type) - Adequately ossified skull, absence of rib fractures, ossified posterior vertebral pedicles, crenated ilium, unossified ischium, trapezoid femur, stellate tibia, unossified fibula, arms and legs shorter than in type IA
  • Achondrogenesis type II (Langer-Saldino type)
    • Skull - Normal cranial ossification, relatively large calvaria
    • Thorax and ribs - Short and flared thorax; bell-shaped cage with broader, shorter ribs without fractures
    • Spine and pelvis - Relatively well-ossified iliac bones with long, crescent-shaped medial and inferior margins
    • Limbs and tubular bones - Short, broad bones, usually with some diaphyseal constriction and flared, cupped ends; metaphyseal spurs usually smaller than type I; disproportionately long fibula; mushroom-stem bones

Other Tests

  • Obtain bone and cartilage tissue for histological and biochemical studies.

Procedures

  • Skin and cartilage biopsies for fibroblast and chondrocyte cultures allow study of sulfate incorporation.

Histologic Findings

  • Achondrogenesis type IA has a normal cartilage matrix. No collagen rings are present around the chondrocytes. Vacuolated chondrocytes, intrachondrocytic inclusion bodies (periodic acid-Schiff stain [PAS] positive, diastase resistant), extraskeletal cartilage involvement, enlarged lacunas, and woven bone are all present.
  • Achondrogenesis type IB has a cartilage matrix that shows coarsened collagen fibers that are particularly dense around the chondrocytes, forming collagen rings. Cartilage has reduced staining with cationic dyes, such as toluidine blue or Alcian blue, probably because of a deficiency in sulfated proteoglycans. This distinguishes type IB from type IA, in which the matrix is close to normal and inclusions can be seen in chondrocytes, and from achondrogenesis type II, in which cationic dyes give a normal staining pattern. Thus, the coarsening of fibers and collagen rings are not seen.
  • Achondrogenesis type II has slightly larger than normal and grossly distorted (lobulated and mushroomed) epiphyseal cartilage. Severe disturbance is noted in endochondral ossification and hypercellular reserve cartilage with large, primitive mesenchymal (ballooned) chondrocytes with abundant clear cytoplasm. The cartilaginous matrix is markedly deficient. Overgrowth of membranous bones results in cupping of the epiphyseal cartilages. In addition, a decreased amount and altered structure of proteoglycans, lower relative content of chondroitin 4-sulfate, lower molecular weight and decreased total chondroitin sulfation, absent type II collagen, and increased amounts of type I and type III collagen that are atypical for hyaline cartilage are present.

More on Achondrogenesis

Overview: Achondrogenesis
Differential Diagnoses & Workup: Achondrogenesis
Treatment & Medication: Achondrogenesis
Follow-up: Achondrogenesis
Multimedia: Achondrogenesis
References
Further Reading
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Further Reading

Guidelines have been established for prenatal screening and diagnosis for pediatricians. 16

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Keywords

achondrogenesis type I, Fraccaro-Houston-Harris type achondrogenesis, achondrogenesis type IA, Houston-Harris type achondrogenesis, achondrogenesis type IB, Fraccaro type achondrogenesis, achondrogenesis type II, Langer-Saldino type achondrogenesis, achondrogenesis type III, achondrogenesis type IV, achondrogenesis-hypochondrogenesis type II, chondrodysplasias, hypochondrogenesis, micromelia, CIfemur, atelosteogenesis type II, diastrophic dysplasia, neonatal dwarfism, patent ductus arteriosus, atrial septal defect, ventricular septal defect, rib fractures, osteoarthritis, polyhydramnios, hydrops fetalis, breech presentation, lethal neonatal dwarfism, treatment, diagnosis

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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 Medical Association, American Society of Human Genetics, and Teratology Society
Disclosure: Nothing to disclose.

Medical Editor

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.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

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.

CME Editor

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, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics and Rehabilitation, 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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