Achondrogenesis

Achondrogenesis describes a rare group of lethal skeletal dysplasias. Currently, 3 variants have been defined: type 1A (Houston-Harris), type 1B (Parenti-Fraccaro), and type 2 (Langer-Saldino).

  • Processes: congenital
  • Incidence: 0 / 100.000

Overview

Achondrogensis is a collection of a number of disorders which are the severest forms of congenital chondrodysplasia. The major characteristics of the conditions are skeletal deformities usually depicted by shortened limbs and a generally small body. Infants born with achondrogenesis have severe health problems thus they are born prematurely or as stillbirth. Of the number that survives past the birth stage, majority die of respiratory problems. Some of the infants however, have gone on to live longer with the aid of intensive medical care [1].

According to research, there are three forms of achondrogenesis. They are: achondrogeneis type 1A, achondrogenesis type 1B and achondrogenesis type 2. The various types are differentiated by the signs and symptoms, pattern of inheritance and genetic cause. There is possibility of the existence of other types of achondrogenesis but these have not been characterized as their cause has not been documented.

Type 1A of achondrogenesis is caused when there is a defect in the microtubules of the Golgi apparatus. A nonsense mutation in the thyroid hormone receptor interactor 11 gene (Trip11), which encodes the Golgi microtubule-associated protein 210 (GMAP-210), showed defects that are similar to this disease in mice [3].

Human patients with achondrogenesis type 1A also had a loss of function mutations in GMAP-210 when their DNA was sequenced. GMAP-210 is responsible for the movement of proteins from the endoplasmic reticulum to the Golgi apparatus but with this defect, it is unable to do so and therefore the proteins remain in endoplasmic reticulum causing it to become swollen. With the loss of the Golgi apparatus, the functions of certain cells are affected but the cells affecting the formation of bones and cartilages are the most affected.

A similar mutation in SLC26A2 (responsible for the encoding of a sulfate transporter) is what causes achondrogenesis type 1B.

Etiology

The disorder is an inherited one which means it is passed down through families. Some of them are recessive meaning that both parents carry the defective gene and in such a situation, the chance of the subsequent child to be affected by the condition is about 25% [4].

To differentiate them, type 1a is autosomal recessive disorder with a chromosomal locus that is unknown. Type 1b is an autosomal recessive disorder which arises from mutations of the diastrophic dysplasia sulfate transporter gene found at 5q32-q33. Type 2 achondrogenesis on the other hand, is an autosomal dominant type 2 collagenopathy which arises from mutations in the COL2A1 gene. It is located at 12q13.1-q13.3.

Epidemiology

Types 1 and 2 lethal achondrogenesis are both rare. The respective frequencies are not known but the overall frequency has been placed at 1 per 40,000 births [2].

With achondrogenesis type 1, the number of still births is higher than achondrogenesis type II. For babies who have achondrogenesis type 1 the gestation period is shorter and they survive for a shorter period than those who have type II. Their limbs are also much shorter and this buttresses the point that type 1 achondrogenesis is the more severe form.

There is no racial predilection with achondrogenesis and males and females are affected equally. All cases of achondrogenesis are detected at birth and so there is no age difference.

Pathophysiology

In patients with achondrogenesis type 1B, a series of mutations in the DDST gene has been identified. Achondrogenesis type 1B is associated with the homozygosity and heterozygosity for these mutations. The mutation leads to structural mutations in the transmembrane domains and premature stop codons.
Diastrophic dysplasia with less severe phenotypes or type II atelosteogenesis arises when regulatory mutation is caused by extracellular loops, low messenger RNA (mRNA levels) or cytoplasmic tail mutations. The skin fibroblasts and chondrocytes from patients with the type 1B are not able to incorporate exogenous sulfate when cultured [5].

Type 2 achondrogenesis and other collagenopathies like spondyloepiphyseal dysplasias and hypochondrogensis are caused by different mutations in the gene which encodes type II collagen (COL2A1). Type 2 has a single base change serine is replaced by glycine within the procollagen gene of the alpha 1(II) chain. This brings about a disruption in the triple helix formation thereby leading to a paucity of type II collagen in the matrix of the cartilage. Apart from skeletal abnormalities, severe pulmonary hypoplasia which is believed to be related directly to the underlying pathology in the expression of collagen, is linked with achondrogenesis [6].

The Whitely and Gorlin prototype 4 (type II achondrogenesis/hypochondrogenesis show immmunohistolgic findings which show an evident abnormal intracellular accumulation of type II collagen within vacuolar structures of chondrocytes. This suggests the presence of poorly secreted and abnormal collagen. The observed phenotype is as a result of the molecular defects of type II collagen and new dominant mutations.

Prognosis

The outcome is often very negative. Majority of infants diagnosed with achondrogenesis are either stillborn or die shortly after birth due to the breathing problems that come with an abnormally small chest [7].

Presentation

In patients with achondrogenesis, prenatal history may include any of the following: Breech presentation, hydrops and polyhydraminos [8].

Presentation for achondrogenesis type I

  • There is lethal neonatal dwarfism with a mean birth weight of 1200 g.
  • Head is disproportionately large, the skull is soft, the forehead is sloping, the facial plane is convex, there is a flat nasal bridge and a host of other craniofacial defects.
  • The neck is extremely short.
  • There is lung hypoplasia and short and barrel-shaped thorax.
  • There is ventricular septal defect, patent ductus arteriosus and atrial septal defect.
  • The abdomen is protuberant.
  • Micromelia (extremely short limbs is noted) and it is shorter than what is seen in type II achondrogenesis. The appendages are flipper like as well.

Presentation for achondrogenesis type II

  • There is lethal neonathal dwarfism but the mean birth weight is 2100 g.
  • Craniofacial features include a large a head, very large forehead, flat facial plane, flat nasal bridge, small nose with a severely anteverted nostrils, there is normal philtrium in most cases as well as micrognathia. 
  • The neck is extremely short.
  • There is lung hypoplasia, bell shaped cage and a short and flared thorax.
  • Limbs are short.

Workup

The molecular studies for achondrogenesis are performed on EDTA-anticoaagulated blood for DNA analysis [9].

With mutation analysis of the DDST gene, the following is identified: point mutations, deletions leading to premature stop codons, substitutions and deletions of amino acids within transmembrane domains, presumed mutations lying outside the coding region but causing low mRNA levels and substitutions of amino acids in intracellular or extracellular domains.

Radiological features often vary and no single feature is obligatory. It is not always possible to differentiate between type 1A and type 1B on radiographs. The degree is ossification is dependent of age and caution is needed radiograph comparisons at different stages of gestation.

Bone and cartilage tissues should be obtained for use in histological and biochemical studies.

Treatment

There is presently no treatment for the underlying disorder and so medical care is supportive [10].

Prevention

This condition can only be prevented with the help of accurate genetic counseling. For the genetic counseling to be effective however, the types of achondrogenesis in both parents must be properly established [11].

Patient Information

This condition is often diagnosed at birth even when the child is stillbirth. This is where medical care comes in. As a parent of such a child however, you need to bear in mind that the chances of the child surviving beyond early infancy is very low. Therefore, effort must be put into ensuring that you are ready for whatever happens next by enrolling into a support group. Most importantly, your focus should be on ensuring that there is no repetition by going for genetic counseling and constant medical checks before and immediately after conception is confirmed.

References

  1. Sharma PP, Salihu HM, Oyelese Y, et al. Is race a determinant of stillbirth recurrence? Obstet Gynecol 2006; 107:391.
  2. Borochowitz Z, Lachman R, Adomian GE, Spear G, Jones K, Rimoin DL. Achondrogenesis type I: delineation of further heterogeneity and identification of two distinct subgroups. J Pediatr. Jan 1988;112(1):23-31.
  3. Lethal skeletal dysplasia in mice and humans lacking the GolginGMAP-210, Patrick Smits, N Engl J Med, 362:206, Jan. 21, 2010
  4. Fraccardo M. Contributo allo studio delle malattie del mesenchima osteopoietico: l achondrogenesi. Folia Hered Path. 1952;1:190-208.
  5. Whitley CB, Gorlin RJ. Achondrogenesis: new nosology with evidence of genetic heterogeneity. Radiology. Sep 1983;148(3):693-8.
  6. Mortier GR, Weis M, Nuytinck L, et al. Report of five novel and one recurrent COL2A1 mutations with analysis of genotype-phenotype correlation in patients with a lethal type II collagen disorder. J Med Genet. Apr 2000;37(4):263-71.
  7. Spranger J, Winterpacht A, Zabel B. The type II collagenopathies: a spectrum of chondrodysplasias. Eur J Pediatr. Feb 1994;153(2):56-65.
  8. Freisinger P, Bonaventure J, Stoess H, Pontz BF, Emmrich P, Nerlich A. Type II collagenopathies: are there additional family members?. Am J Med Genet. May 3 1996;63(1):137-43
  9. Stillbirth Collaborative Research Network Writing Group. Association between stillbirth and risk factors known at pregnancy confirmation. JAMA 2011; 306:2469.
  10. Wigglesworth JS. Monitoring perinatal mortality. A pathophysiological approach. Lancet 1980; 2:684.
  11. Hall JG. Review and hypotheses: somatic mosaicism: observations related to clinical genetics. Am J Hum Genet. Oct 1988;43(4):355-63

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