Achondrogenesis

Philippe Jeanty, MD, PhD, Sandra Silva, MD

Definition:  This group of lethal neonatal chondrodysplasia with short limb dysplasia contains several entities (see below).

Synonyms: Type IA is the Houston-Harris type, Type IB is the Parenti-Fraccaro type, Type II is the Langer-Saldino type and is also called Chondrogenesis Imperfecta, Achondrogenesis-Hypochondrogenesis, Type II and was the Type IB Achondrogenesis. There are two less common type III and IV. Type II and IV were isolated by Whitley and Gorlin on femoral measurement[1]. The validity of these two last types is questioned with type III probably representing type II and type IV probably representing hypochondrogenesis¹. These essentially radiological categories have been modified several times are being replaced by genetic classification (see below) and thus are mainly of historical interest.

Incidence: Rare with probably less than 100 cases reported.

Etiology: Autosomal recessive (IB) and dominant (II).

Diagnosis:

• Type I achondrogenesis (fig. 4) is a severe chondrodystrophy characterized radiographically by poor ossification of the spine (fig. 1) and pelvis bones which results in stillbirth or early death[2],[3],[4],[5]. The ultrasound manifestation includes very short limbs (fig. 3) and short thin ribs that may have fractures. The short ribs are responsible for the lethal pulmonary hypoplasia and the polyhydramnios from esophageal compression. The abnormal mineralization may or may not be manifested sonographically as bones that are either very ehopenic, or in which both cortical can be imaged (fig. 2). Normally only the proximal cortical side is imaged and the distal side is shadowed by the proximal side.
• Type II also presents with the same findings but the mineralization deficit is less severe and the long bones less short.

Genetic anomalies: Type IA: unknown. Type IB: mutation in the gene for diastrophic dysplasia sulfate transporter gene (DTDST) on the long arm (locus 32-33) of chromosome 5[6],[7],[8]. The diastrophic dysplasia sulfate transporter gene is recessively transmitted and is an allele of the diastrophic dysplasia gene. This is important since the Type II (see below) is an autosomal dominant mutation (and thus involves a new mutation for each case since the disease is lethal) and therefore has a much lower likelihood of recurrence than the 25% risk of the type IB. The diagnosis can be made by CVS in at-risk couples. Type II achondrogenesis is the Langer-Saldino type and is caused by new dominant mutation in the type II collagen gene (COL2A1 gene) on chromosome 12[9]. It is therefore more related to hypochondroplasia, spondyloepiphyseal dysplasia and the Kniest-Stickler syndrome[10]. These may be allelic variants with hypochondrogenesis[11] related to achondrogenesis as hypochondroplasia is related to achondroplasia.

Differential diagnosis: Osteogenesis Imperfecta (type II and occasionally IIIc) and hypophosphatasia also present with demineralization but the limb shortening is not usually as severe.

Prognosis: Lethal

Management: Termination of pregnancy can be offered before viability. Standard prenatal care is not altered when continuation the pregnancy is opted for. Confirmation of diagnosis after birth is important for genetic counseling.

Figures (all figures reprinted with permission from The Fetus 2:3 7564-11, 1992)

Fig 1: Almost absent mineralization of the spine (not the spinal cord)

Fig 2: The appearance of transparent bones in which both cortical can be seen. 

Fig 3: Micromelia with the arms not joining in front of the chest.

Fig 4: The appearance of the fetus at 19 weeks

Reference:

[1] Whitley, C. B.; Gorlin, R. J. : Achondrogenesis: nosology with evidence of genetic heterogeneity. Radiology 148: 693-698, 1983

[2] Parenti, G. C. : La anosteogenesi (una varieta della osteogenesi imperfetta). Pathologica 28: 447-462, 1936

[3] Fraccaro, M. : Contributo allo studio delle malattie del mesenchima osteopoietico: l"acondrogenesi. Folia Hered. Path. 1: 190-208, 1952.

[4] Maroteaux, P.; Lamy, M. : Le diagnostic des nanismes chondro-dystrophiques chez les nouveau-nes. Arch. Franc. Pediat. 25: 241-262, 1968

[5] Langer, L. O., Jr.; Spranger, J. W.; Greinacher, I.; Herdman, R. C. : Thanatophoric dwarfism: a condition confused with achondroplasia in the neonate, with brief comments on achondrogenesis and homozygous achondroplasia. Radiology 92: 285-294, 1969

[6] Superti-Furga, A. : A defect in the metabolic activation of sulfate in a patient with achondrogenesis type IB. Am. J. Hum. Genet. 55: 1137-1145, 1994.

[7] Superti-Furga, A.; Hastbacka, J.; Cohn, D. H.; Wilcox, W.; van der Harten, H. J.; Rimoin, D. L.; Lander, E. S.; Steinmann, B.; Gitzelmann, R. : Defective sulfation of proteoglycans in achondrogenesis type IB is caused by mutations in the DTDST gene: the disorder is allelic to diastrophic dysplasia. (Abstract) Am. J. Hum. Genet. 57: A48, 1995.

[8] Superti-Furga, A.; Hastbacka, J.; Wilcox, W. R.; Cohn, D. H.; van der Harten, H. J.; Rossi, A.; Blau, N.; Rimoin, D. L.; Steinmann, B.; Lander, E. S.; Gitzelmann, R. : Achondrogenesis type IB is caused by mutations in the diastrophic dysplasia sulphate transporter gene. Nature Genet. 12: 100-102, 1996.

[9] Rittler, M.; Orioli, I. M. : Achondrogenesis type II with polydactyly. Am. J. Med. Genet. 59: 157-160, 1995.

[10] Spranger, J. : Pattern recognition in bone dysplasias.In: Papadatos, C. J.; Bartsocas, C. S. : and Spranger, J.: Endocrine Genetics and Genetics of Growth. New York: Alan R. Liss (pub.) 1985. Pp. 315-342

[11] Stanescu, V.; Stanescu, R.; Maroteaux, P. : Etude morphologique et biochimique du cartilage de croissance dans les osteochondrodysplasies. Arch. Franc. Pediat. 34: 1-80, 1977.