Achondrogenesis 

Updated: Jan 25, 2019
Author: Santina A Zanelli, MD; Chief Editor: Maria Descartes, MD 

Overview

Practice Essentials

Achondrogenesis is characterized by severe micromelia, macrocrania, and short trunk. Although rare, it is the second most common lethal skeletal dysplasia after thanatophoric dysplasia

Achondrogenesis is classified as type I (ACGIA, ACGIB) and type II forms (ACGII). Achondrogenesis type II, hypochondrogenesis, and neonatal spondyloepiphyseal dysplasia congenita are now known to be phenotypic variants of the same disorder.

Achondrogenesis results from mutations in the TRIP11 (ACGIA), SLC26A2 (ACGIB), and COL2A1 (ACGII) genes, with achondrogenesis types IA and IB being autosomal recessive conditions and achondrogenesis type II most often being sporadic. Prenatally, polyhydramnios and hydrops leading to fetal demise can be observed. Skeletal anomalies include severe micromelia, a short and narrow thorax with pulmonary hypoplasia, and absent or very abnormal ossification of the skull and vertebral bodies.

Background

Marco Fraccaro first described achondrogenesis in 1952.[1] He used the term to describe a stillborn female with severe micromelia and marked histologic 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 radiologic and histologic criteria.

See the image below.

An infant with achondrogenesis type II. Note the d 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.

In 1983, a new radiologic 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 (1-2.8). 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. This radiologic 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).

See the images below.

This posteroanterior (PA) view radiograph of an in 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 achondro 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.

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. Achondrogenesis type I was subdivided further in 1988 on the basis of convincing histologic criteria. 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.

Currently, three 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 is caused by recessive mutations in the TRIP11 gene, type IB results from recessive mutations of the SLC26A2 gene, and type II is caused by autosomal dominant mutations of the COL2A1 gene.

Achondrogenesis II results from heterozygosity for a new dominant mutation in the COL2A1 gene[3] at the chromosomal locus 12q8.11–q13.2. Intramolecular heterogeneity has been recognized, and genotype–phenotype correlations have been demonstrated.[4]

Several heritable osteochondrodysplasias have now been recognized as members of the family of type II collagen disorders, all of which result from dominant mutations in the COL2A1 gene.[5, 6, 4] Phenotypes within this group range from severe lethal dwarfism at birth to relatively mild conditions with precocious osteoarthrosis and little or no skeletal growth abnormality. Achondrogenesis II-hypochondrogenesis and lethal spondyloepiphyseal dysplasia congenita (SEDC) represent the more severe end of the spectrum.[7] These entities are characterized by severe disproportionate short stature of prenatal onset. The distinction between these phenotypes is mainly based on clinical, radiographic, and morphological features but considerable phenotypic overlap often hampers proper classification.

Mutations within the COL2A1 gene also cause hypochondrogenesis (OMIM 200610), spondyloepiphyseal dysplasia (SED) congenita (OMIM 183900), SED Namaqualand type (OMIM 142670), mild SED with precocious osteoarthritis, spondyloepimetaphyseal dysplasia Strudwick type (OMIM 184250), Kniest dysplasia (OMIM 156550), multiple epiphyseal dysplasia with myopia and conductive deafness, spondyloperipheral dysplasia (OMIM 271700), and Stickler dysplasia type I (OMIM 108300).[8, 9]

Pathophysiology

Achondrogenesis type IA (ACGIA; OMIM 200600):

Mutation of the TRIP11 gene, located on chromosome 14q32, has been identified in ACGIA. Mutational change leads to abnormal secretion of Golgi microtubule-associated protein 210 (GMAP-210), a protein associated with skeletal development. 

Achondrogenesis type IB (ACGIB; OMIM 600972):

A series of mutations in the SLC26A2 gene, on chromosome 5q32, have been identified in patients with ACGIB. Homozygosity or compound heterozygosity for these mutations leads to premature stop codons or structural mutations in transmembrane domains and abnormal synthesis of sulfated proteoglycans in cartilage.

Achondrogenesis type II (ACGII; OMIN 256050):

Heterozygous mutations in the COL2A1 gene, located on chromosome 12q13, have been identified in ACGII, as well as in 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 directly related 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.

Epidemiology

Frequency

United States

Lethal achondrogenesis types I and II are both rare, with prevalence ranging from 0.09-0.23 in 10,000 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, radiologic, histologic, and molecular findings.

 

Presentation

History

Prenatal diagnosis should be suspected in the presence of micromelia, macrocrania with absent or abnormal ossification, and abnormal vertebral ossification. Prenatal history in patients with achondrogenesis may include the following:

  • Polyhydramnios

  • Hydrops

  • Breech presentation

Physical

Achondrogenesis type I

See the list below:

  • 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[10]

  • Heart -Patent ductus arteriosus, atrial septal defect, ventricular septal defect

  • Abdomen - Protuberant

  • Limbs - Extremely short (micromelia), much shorter than type II; flipper-like appendages

Achondrogenesis type II

See the list below:

  • 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)

Common and unique characteristics of the three types of achondrogenesis are summarized in Table 1, below.[11, 12, 13, 14]

Table 1: Achondrogenesis characteristics (Open Table in a new window)

  IA IB II
Skull Absent or severely reduced ossification Normal or reduced ossification for age Normal ossification
Long bones

Short and bowed

Stellate, longitudinally oriented

Metaphyseal spurring

Very short, square or stellate

Metaphyseal spurring

Poor ossification of phalanges

Short and bowed

Metaphyseal flaring and cupping

Thorax

Short, barrel-shaped

Ribs: Short and horizontally oriented, with splayed anterior ends

Multiple fractures (beaded appearance)

Ribs: Short and thin, typically no fractures

Short, barrel- or bell-shaped

Short ribs, no fractures

Spine

Vertebral bodies: Absent or rudimentary ossification

Vertebral bodies: Absent or rudimentary central ossification

Vertebral lateral pedicles: Usually ossified

Variable

Vertebral bodies and pedicles: Ossified or unossified

Pelvis

Sacrum: Absent or rudimentary ossification

Iliac bone: Abnormal ossification giving a crescent-shaped appearance

Ischium: Not ossified.

Halberd-like iliac bone

Ischial and pubic bones: Unossified

 

 

DDx

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

 

Workup

Laboratory Studies

Mutation analysis of the TRIP11, SLC26A2, and COL2A1 genes can be used to make the diagnosis of achondrogenesis and/or ascertain carriers, particularly in consanguineous families.

Multiple mutations have been described:

  • TRIP11 gene - Homozygous or compound heterozygous mutations, including nonsense, frameshift, and splice mutations

  • SLC26A2 gene - Homozygous or compound heterozygous mutations, including 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

  • COL2A1 gene - Heterozygous mutation; a single base change has been described in a patient with ACGII (ie, substitution of serine for glycine in the alpha 1 [II] chain)

Imaging Studies

Radiologic 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)

See the list below:

  • 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[24]

  • Limbs and tubular bones - Extreme micromelia, with limbs much shorter than in type II; flipper-like appendages; prominent spike-like 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)

See the list below:

  • 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

See the list below:

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

Procedures

See the list below:

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

Histologic Findings

See the list below:

  • 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.

 

Treatment

Medical Care

Medical care

Medical care is supportive in achondrogenesis. 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. It is important to consider the possibility of germline mosaicism in de novo dominant conditions such as achondrogenesis II. Couples having delivered a pregnancy considered to have a de novo dominant disorder should be counseled that the recurrence risk is greater than the background risk, although the exact recurrence risk is uncertain. If 2 or more siblings are affected, the recurrence risk increases further.[18]

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

  • Obstetricians

  • Neonatologists

  • Ultrasonographers

 

Follow-up

Prognosis

See the list below:

  • Achondrogenesis 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:

Little People of America (LPA), Inc

PO Box 745

Lubbock, TX 79408

Phone: 1-888-LPA-2001

email: LPADataBase@juno.com

Parents of Dwarfed Children

11524 Colt Terrace

Silver Spring, MD 20902

Phone: 301-649-3275

International Skeletal Dysplasia Registry

Cedars-Sinai Medical Center

444 S San Vicente Boulevard

Suite 1001

Los Angeles, CA 90048

Phone: 310-855-7488

email: mpriore@mailgate.csmc.edu

International Center for Skeletal Dysplasia

St. Joseph Hospital

7620 York Road

Towson, MD 21204

Phone: 410-337-1250