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AUTHOR AND EDITOR INFORMATION
Section 1 of 10  
Author: Harold Chen, MD, MS, FAAP, FACMG, Professor, Departments of Pediatrics, Obstetrics and Gynecology, Pathology, Director of Perinatal Genetics and Genetic Laboratory Services, Louisiana State University Medical Center; Laboratory Director, Hema-Con Cancer Cytogenetics Laboratory, Gainesville, Florida
Harold Chen is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, American Society of Human Genetics, and Teratology Society
Editors: James Bowman, MD, Senior Scholar of Maclean Center for Clinical Medical Ethics, Professor Emeritus, Department of Pathology, University of Chicago; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Hagop Youssoufian, MD, MSc, Vice President of Clinical Research, ImClone Systems Incorporated; Paul D Petry, DO, FACOP, FAAP, Clinical Assistant Professor of Pediatrics, University of North Dakota, School of Medicine and Health Sciences; Consulting Staff, Altru Health System; Bruce Buehler, MD, Professor, Department of Pathology and Microbiology, Director, Hattie B Munroe Center for Human Genetics, Chairman, Department of Pediatrics, University of Nebraska Medical Center
Author and Editor Disclosure
Synonyms and related 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
Background
Marco Fraccaro first described achondrogenesis in 1952.1 He used the term to describe a stillborn female with severe micromelia and marked histological cartilage changes. The term was later used to characterize the most severe forms of chondrodysplasia in humans, which were invariably lethal before or shortly after birth. By the 1970s, researchers concluded that achondrogenesis was a heterogeneous group of chondrodysplasias lethal to neonates; achondrogenesis type I (Fraccaro-Houston-Harris type) and type II (Langer-Saldino type) were distinguished on the basis of radiological and histological criteria. In 1983, a new radiological classification of achondrogenesis (types I-IV) by Whitley and Gorlin was adopted in the McKusick catalog.2 According to this classification, type I and type II have the same femoral cylinder index (CIfemur; calculated as length of femur divided by width of femur) range (1.0-2.8). Both types have crenated ilia and stellate long bones. Multiple rib fractures are characteristic of type I but not type II. Type III has nonfractured ribs, halberd ilia, mushroom-stem long bones, and a CIfemur of 2.8-4.9. Type IV has nonfractured ribs, sculpted ilia, well-developed long bones, and a CIfemur of 4.9-8.0. This radiological classification based on the CIfemur was later abandoned. Researchers suggested that achondrogenesis type III probably corresponds to type II and that type IV probably corresponds to mild type II (hypochondrogenesis). In the late 1980s, structural mutations in collagen II were shown to cause achondrogenesis type II, which thus constitutes the severe end of the spectrum of collagen II chondrodysplasias.3 Achondrogenesis type I was subdivided further in 1988 on the basis of convincing histological criteria.4 It was subdivided into type IA, which has apparently normal cartilage matrix but inclusions in chondrocytes, and type IB, which has an abnormal cartilage matrix. Classification of type IB as a separate group has been confirmed by the discovery of its association with mutations in the diastrophic dysplasia sulfate transporter (DDST) gene, making it allelic with diastrophic dysplasia.5
Currently, 3 variants of achondrogenesis have been defined based on radiologic and histopathologic features: type IA (Houston-Harris), type IB (Parenti-Fraccaro), and type II (Langer-Saldino). Achondrogenesis IA appears to be autosomal recessive, but the mutant gene is still unknown. Type IB is caused by recessive mutations of the diastrophic dysplasia sulfate transporter gene (SLC26A2), and type II is caused by autosomal dominant mutations of the type II collagen gene (COL2A1).
Pathophysiology
A series of mutations in the DDST gene has been identified in patients with achondrogenesis type IB.5, 6 Homozygosity or compound heterozygosity for these mutations, which leads to premature stop codons or structural mutations in transmembrane domains, is associated with achondrogenesis type IB. Extracellular loops or cytoplasmic tail mutations or low messenger RNA (mRNA) levels, which cause regulatory mutation, usually result in atelosteogenesis type II or diastrophic dysplasia with less severe phenotypes. Chondrocytes and skin fibroblasts cultured from type IB patients are unable to incorporate exogenous sulfate. Different mutations in the gene that encodes type II collagen (COL2A1) cause achondrogenesis type II as well as other type II collagenopathies (eg, spondyloepiphyseal dysplasias, hypochondrogenesis). Type II has a single base change, substituting serine for glycine in the type II procollagen gene of the alpha 1(II) chain. This disrupts the triple helix formation, leading to a paucity of type II collagen in the cartilage matrix. Epiphyseal cartilage lacks type II collagen. It is replaced by type I and type III collagens, which are not normally produced by chondrocytes. Differentiated chondrocytes do not express type II collagen. In addition to skeletal abnormalities, severe pulmonary hypoplasia, thought to be related directly to the underlying pathology in collagen expression, is associated with achondrogenesis. Type II achondrogenesis/hypochondrogenesis (Whitley and Gorlin prototype IV) has immunohistologic findings that demonstrate apparent abnormal intracellular accumulation of type II collagen within vacuolar structures of chondrocytes. This suggests the presence of abnormal, poorly secreted type II collagen. Molecular defects of type II collagen and new dominant mutations account for the observed phenotype.
Frequency
United States
Lethal achondrogenesis types I and II are both rare. Their respective frequencies are unknown; however, the overall frequency has been estimated at 1 in 40,000 births.
Mortality/Morbidity
- Achondrogenesis type I results in stillbirth more frequently than type II.
- Babies with achondrogenesis type I who are not stillborn typically have a shorter gestation and survive for a shorter time than those with type II. They are also smaller with much shorter limbs, which supports the general view that type I is the more severe form.
Race
- Achondrogenesis has no racial predilection.
Sex
- Males and females are equally affected.
Age
- Achondrogenesis is detected prenatally or at birth because of typical clinical, radiological, histological, and molecular findings.
History
Physical
- Achondrogenesis type I
- Growth - Lethal neonatal dwarfism, mean birth weight of 1200 g
- Craniofacial - Disproportionately large head; soft skull; sloping forehead; convex facial plane; flat nasal bridge, occasionally associated with a deep horizontal groove; small nose, often with anteverted nostrils; long philtrum; retrognathia; increased distance between lower lip and lower edge of chin; double chin appearance (often)
- Neck - Extremely short
- Thorax - Short and barrel-shaped thorax, lung hypoplasia
- Heart - Patent ductus arteriosus, atrial septal defect, ventricular septal defect
- Abdomen - Protuberant
- Limbs - Extremely short (micromelia), much shorter than type II; flipperlike appendages
- Achondrogenesis type II
- Growth - Lethal neonatal dwarfism, mean birth weight of 2100 g
- Craniofacial - Disproportionately large head, large and prominent forehead, flat facial plane, flat nasal bridge, small nose with severely anteverted nostrils, normal philtrum (often), micrognathia
- Neck - Extremely short
- Thorax - Short and flared thorax, bell-shaped cage, lung hypoplasia
- Abdomen - Protuberant
- Limbs - Extremely short (micromelia)
Causes
- Type IA is an autosomal recessive disorder with an unknown chromosomal locus. In the current International Nomenclature of Constitutional Disorders of Bone, type IA is classified under spondylodysplastic and other perinatally lethal groups of osteochondrodysplasias.
- Type IB is an autosomal recessive disorder resulting from mutations of the diastrophic dysplasia sulfate transporter (DDST) gene (SLC26A2), which is located at 5q32-q33.
- Type II is an autosomal dominant type II collagenopathy resulting from mutations in the COL2A1 gene, which is located at 12q13.1-q13.3.
Achondroplasia
Asphyxiating Thoracic Dystrophy (Jeune Syndrome)
Hypophosphatasia
Osteogenesis Imperfecta
Thanatophoric Dysplasia
Other Problems to be Considered
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
Lab Studies
Molecular studies 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. There is severe disturbance 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.
Medical Care
- Medical care: Medical care is supportive. No treatment is available for the underlying disorder.
- Genetic counseling
- Achondrogenesis type IA and type IB are inherited as autosomal recessive disorders. For a couple who has an affected child, the recurrence risk is 1 in 4 (25%). This risk is markedly higher than the recurrence risk for achondrogenesis type II, which is usually caused by a new dominant mutation. In type II, asymptomatic carriers may be present in the families of affected patients.
- Genetic counseling must rely on accurate differentiation between achondrogenesis type I and type II.
Consultations
Consultations should be made with the following specialists:
- Clinical geneticists
- Radiologists
- Anatomical pathologists
- Perinatologists
- Ultrasonographers
Prognosis
- The condition is universally lethal.
Patient Education
- Current information about the syndrome should be made available to the families.
- Families may be referred to the following groups for helpful information and support:
Medical/Legal Pitfalls
- Failure to refer to clinical geneticists and physicians who are experienced in lethal skeletal dysplasias for diagnosis
- Failure to give genetic counseling after confirmation of diagnosis
Special Concerns
- 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.
- Prenatal ultrasound findings include polyhydramnios, fetal hydrops, a disproportionately large head, nuchal edema, a narrow thorax, reduced rump length, short limbs, and poor ossification of vertebral bodies and limb tubular bones (leading to difficulties in determining their length).
- 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: evidence for germline mosaicism.
- Prenatal diagnosis is possible in the first and second trimester by prenatal ultrasonography and molecular analysis.
| Media file 1:
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. |
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Media type: Photo
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| Media file 2:
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. |
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Media type: Radiograph
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| Media file 3:
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. |
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Media type: Radiograph
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| Media file 4:
An infant with achondrogenesis type II. Note the protuberant abdomen and extremely short lower extremities. |
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Media type: Photo
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| Media file 5:
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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Media type: Photo
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Achondrogenesis excerpt Article Last Updated: Nov 8, 2007
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