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Articles » Skeletal » Achondrogenesis
1992-06-13-19 Achondrogenesis © Knowlton


Sarah Knowlton MD, Cornelia Graves, MD, George E. Tiller, MD, PhD, Philippe Jeanty, MD, PhD

Synonyms: None.

Definition: Lethal osteochondrodysplasia characterized by hypoplasia of bone, resulting in marked limb shortening and associated with severe pulmonary hypoplasia. There may be other anomalies which vary in severity.

Classification: The previously classified Type IA and Type IB of McKusick1-2 are now called Type I and Type II according to the classification of Spranger3. The Type III and Type IV were defined by Gorlin and Whitley4. The last form is the Grebe chondrodysplasia. Types IA, IB, and II demonstrate variable degrees of ossification3,4.

Prevalence: 0.09-0.23:10,0005.

Inheritance: Types IA and IB are autosomal recessive. Type II is autosomal dominant6,7,8.

Pathogenesis: Defective production of cartilage matrix by chondrocytes, resulting in poor ossification6,7.

Associated anomalies: Hydrocephalus, lymphangioma, cystic hygroma, cleft lip and palate, pulmonary hypoplasia, atrial and ventricular septal defects, coarctation of aorta, patent ductus arteriosus, patent foramen ovale, malrotation of GI tract, undescended testes, aplastic testes, anal atresia, inguinal hernia, urinary tract duplication and hydronephrosis, auditory canal atresia, ear deformation, corneal clouding, and blue sclera9.

Differential diagnosis: See table 1.

Prognosis: This is a universally lethal disorder.

Recurrence risk: 25% for Types IA and IB; Type II is sporadic, although germinal mosaicism is possible and may pose a slight risk for recurrence (<5%)7,8,9.

Management: As for disorders with lethal outcomes.

MESH Osteochondrodysplasias-genetics BDE 2870, 0008, 0009, MIM 200600, 200610, 200700, 200710, 200720 POS 3004 ICD9 756.4 CDC 756.436

Address correspondence to Sarah Knowlton, MD, Vanderbilt University, Department of Obstetrics and Gynecology, 21st Avenue and Garland, Nashville, TN 37232-2516. Ph: 615-322- 2114, Fax: 615-343-8881.¶Human Genetics, º Radiology


The prenatal diagnosis of achondrogenesis is possible with ultrasound beginning at 13 weeks gestational age. The major ultrasound findings associated with this lethal osteochondrodysplasia include extreme micromelia, short trunk and neck, poor vertebral ossification, normal to poorly ossified cranium (which appears enlarged relative to the limbs and trunk), and a protuberant abdomen.

Associated findings may include polyhydramnios and a hydropic appearance, both of which may develop as the result of a narrow thorax with subsequent poor swallowing and impaired systemic venous return10. The correct prenatal diagnosis must be made before counseling the parents on appropriate obstetrical management. When pulmonary hypoplasia in addition to evidence of short limbs is seen on ultrasound, this suggests a lethal skeletal dysplasia, however, ­Jeune (“asphyxiating”) thoracic dystrophy is not uniformly lethal.

Case #1

A 22-year-old, G1P0 woman was referred at 21 weeks gestation for a prenatal ultrasound that demonstrated short limbs and hydrocephalus. The patient and her husband were consanguineous (fig. 1).

Fig. 1: Pedigree of case #1.

The husband"s mother also described a stillborn infant that was born “without bones”. There were multiple other siblings that were reported to die in infancy of unknown causes. The patient"s mother also had a sibling with a lethal anomaly presumed to be anencephaly by history. The ultrasound examination revealed a single fetus in cephalic position with normal fluid and a posterior placenta. The decreased mineralization of the bone, most notably the cranial vault, was striking (fig. 2).

Fig. 2: View of the head: note the absent mineralization of the skull.

Severe micromelia was confirmed with a femur length of 13 mm (fig. 3-4).

Fig. 3: This short arm does not reach the anterior midline.


Fig. 4: The femur is short and so poorly mineralized that both sides are visible. 

The chest was hypoplastic and the heart, which appeared to occupy the whole chest, compressed the lungs (fig. 5).


Fig. 5: Four-chamber view: the heart occupies most of the chest, and the ribs are short.

The spine had an apparently normal mineralization (fig. 6).

Fig. 6: The mineralization of the spine appears normal.

Because of the extreme micromelia, the poor mineralization and the absent mineralization of the skull, the diagnosis of Achondrogenesis, Type I was entertained.

Prostin induction was performed, with delivery of an 850g male stillborn, 150 mm in crown-rump length (fig 7-8).


Fig. 7: Case #1: post-mortem X-rays: note the absent mineralization of the spine and skull.


Fig. 8: Case #1: the fetus at 21 weeks.

The autopsy revealed dilation of the lateral ventricles bilaterally with compression of the associated cerebral cortex. The limbs were incised to reveal multiple lobules of cartilage and poorly formed bones. Cytogenetic studies revealed a normal, male 46,XY karyotype.

Case #2

A 19-year-old, G1P0 woman was referred for prenatal ultrasound examination at 21 weeks gestation following the findings of shortened limbs seen by ultrasound during a routine examination. She and her 19-year-old husband had no history of familial birth defects or ossification abnormalities. However, the husband"s mother was noted to be of short stature. The mother was adopted but in contact with her biologic siblings. The parents were not related.

An ultrasound performed at 21 weeks gestation revealed a single fetus in cephalic position with normal amniotic fluid volume, and a posterior placenta. A BPD measured 46 mm, which corresponded to a gestational age of 19 weeks. The femur length and humerus length were both 10 mm, corresponding to an estimated gestational age of 12 weeks. Deficient mineralization of the fetal spine and iliac wings (fig. 10-11) but with normal ossification of the skull (fig. 12), and an abundant amount of soft-tissue (fig. 13) was also seen.


Fig. 10: Sagittal view of the spine: note the poor mineralization.

Fig. 11: Coronal view: poor mineralization of the spine and iliac wings.

Fig. 12: Normal mineralization of the skull.

There was a small thoracic cavity (fig. 13) and the ribs only reached the mid-­axillary line (the level of the right atrium).

Fig. 13: Axial section of the chest: notice the overabundance of soft-tissues (without evidence of hydrops (no pleural or pericardial effusions). Notice that the end of the rib goes no further than the right atrium.

The arms and legs (fig. 14-15) were markedly shortened.

Fig. 14: The arms.

Fig. 15: The legs.

Because of the extreme micromelia, the generally poor mineralization but normal mineralization of the skull, the fetus was felt to have Achondrogenesis, Type II.

After extensive counseling and Prostin induction, a 230g stillborn male fetus measuring 142 mm, was delivered (fig. 9).


Fig. 9: Case #2: the fetus at 19 weeks.

An autopsy revealed a head circumference of 168 mm, a flattened face with wide set eyes and low set ears. Cleft lip or palate were absent. The chest was short with a protuberant abdomen. There was 25 cc of clear peritoneal fluid but no pericardial fluid seen. The lungs were hypoplastic but with normal developing bronchi consistent with the fetal age. Cytogenetic studies revealed a normal, male 46,XY karyotype. Histologic evaluation of a femoral biopsy was consistent with Achondrogenesis Type II. Radiologic evaluation was also performed, which was consistent with the diagnosis.


Prenatal diagnosis by ultrasound is important to distinguish lethal skeletal dysplasias. Specific prenatal diagnosis by ultrasound is also necessary for counseling parents of future recurrent risks.   


Achondrogenesis is a skeletal dysplasia, which is characterized by extremely shortened limbs, normal to poorly ossified skull, poorly ossified spine and pelvis, and severe pulmonary hypoplasia. Type I and II have been distinguished based on clinical, radiologic, and histopathologic features. There is, however, considerable phenotypic heterogeneity seen in this disorder1.

Sub classification

The classification is based on radiographic and histopathologic criteria. The disorganization of the chondrocytes in the growth plate results in absence of matrix formation of cartilage, which may be caused by lack of production of type II collagen11,12.

Type IA (Houston-Harris)

Achondrogenesis type IA is characterized by minimal ossification of the skeleton. This subtype also includes cases that exhibit both, defective ossification of endochondral and intramembranous bone. Therefore, the skull is poorly ossified. There is no ossification of the vertebral bodies, and the iliac bones appear crenate. The ribs have cupped metaphyses and multiple fractures are seen1. Histologically, the cartilage appears hypercellular with chondrocytes clustered in a monochromatic matrix. These chondrocytes contain large round, or oval inclusions and the lacunae are dilated11,12.

The epiphyseal cartilage contains many vascular channels, which are also dilated. The growth plate demonstrates disorganized endochondral ossification with lack of columnization in the proliferative and hypertrophic zones.

The metaphyseal cupping seen on radiographs results from the membranous subperiosteal ossification as it expands along the growth plate11,12.

Type IB (Fraccaro)

Type IB (Fraccaro) is differentiated from subtype IA by cranial vault ossification and the absence of rib fractures. Generally, the long bones are shorter than those seen in type IA1. Histologically, this form is differentiated form type IA by more random dispersement of the chondrocytes in the epiphyseal cartilage. Also, the inclusions are absent, but the cytoplasm appears vacuolated. There is no dilation of the lacunae and the matrix is condensed, forming rings around the chondrocytes11,12.

Type II (Langer-Saldino)

Type II (Langer-Saldino) has a more variable presentation, generally characterized by a small barrel-shaped thorax, no rib fractures and halberd-shaped iliac bones. Borochowitz has suggested that achondrogenesis type II and hypochondrogenesis are phenotypic variations of the same disorder, with hypochondrogenesis representing the milder forms of achondrogenesis type II1. On histology, this severe form contains immature chondrocytes with large, ballooned lacunae, and a diminished intracellular matrix. The growth plate is very disorganized and lacks columnization. There are abundant stellate vascular channels and perivascular fibrosis in the epiphyseal cartilage11,12.

Prototypes I-IV

Whitley and Gorlin4 have also characterized achondrogenesis into prototypes I through IV. Prototype I combine traits of IA and IB, to include rib fractures and the most severe limb shortening. Prototypes II through IV represent cases without rib fractures, those with further development of the long bones, and further ossification of the vertebral bodies. Prototype IV, therefore, represented previous cases classified as hypochondrogenesis. These prototypes are based on radiographic measurement of the Femoral Cylinder index (length of femur/width at mid-shaft), which is a measure of endochondral growth4.


The defective cellular morphology suggests a metabolic defect resulting in reduced synthesis, secretion or deposition of matrix components.

Godfrey and Hollister13 suggested a structural abnormality in the triple helical domain of pro 1(II) collagen based on immunohistologic studies which revealed diminished staining of cartilage matrix for type II collagen in Achondrogenesis, Type II. This implied abnormal production and poor secretion of type II collagen from the chondrocytes. This finding has also been associated with spondyloepiphyseal dysplasia and hypochondrogenesis.

A subsequent study by Vissing, Godfrey, and Hollister6 demonstrated a point mutation in the type II procollagen gene (COL2A1), resulting in a serine for glycine substitution at amino acid 943 of the 1(II) chain.

Recent studies7-8, 14 have documented heterozygosity for mutations in COL2A1 in cases of hypochondrogenesis, and achondrogenesis. These studies suggest that there is a phenotypic continu­um of type II collagen disorders, inherited in an autosomal dominant manner, which range in severity from mild-to-moderate (spondyloepiphyseal dysplasia, Stickler syndrome) to perinatal lethal disorders (hypochondrogenesis, achondrogenesis).

Prenatal diagnosis

The prenatal diagnosis is based on the extreme micromelia, the narrow thorax, and the poor mineralization of the skull and vertebrae. Polyhydramnios and a pseudohydropic appearance are also common. 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 by ultrasound, X-ray will confirm it. However, the absence of demineralization by ultrasound cannot be used to presume a radiological demineralization. Since the recognition of demineralization by ultrasound is fraught with false negatives, there will be a tendency to over report the Type II form.

Differential diagnosis

Achondrogenesis must be differentiated from other skeletal dysplasias (Table 1). Overall, achondrogenesis has 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.

Differential diagnoses of skeletal dysplasias
based on clinical, radiographic and ultrasound findings.








Achondrogenesis Type IA (Houston-Harris)

poorly ossified

short, round chest with multiple rib fractures

very short, broad tibiae & fibulae, wedge-like femora with proximal metaphyseal


unossified vertebral bodies

hypoplastic arch-like iliac bones

with short vertical ischia

Achondrogenesis Type IB (Fraccaro),

poorly ossified

short chest with thin ribs, cupped ends, no fractures

very short

with trapeziod femora, crenated tibiae, unossified fibulae


vertebral bodies

hypoplastic crenated iliae

Achondrogenesis Type II


large calvarium with posterior ossification defect

barrel-shaped, with short ribs

very short with mild-moderate metaphyseal

changes, long fibulae

thoracolumbar ossification

short iliae,

flat acetabular roots, unossified pubic bones, ossified ischia

Kniest dysplasia

frontal flattening, maxillary hypoplasia,

shallow orbits

short ribs

club-like metaphyses, delayed ossification

of femoral heads

diffuse flattening, coronal clefts

small ilia,

increased acetabular angles with irregular edges

Thanatophoric dwarfism

frontal bossing +  clover-leaf


narrow, pear-shaped,

short, bowed, with metaphyseal flaring


normal ossification

small sacrosciatic notches, spiculated acetabulum

Osteogenesis Imperfecta, Type II

soft and membranous


chest at birth


fracture liability




slight rib flaring


with leg bowing, trident hands

thoracolumbar kyphosis, lordosis


short iliac wings





vertebral canal



Spondyloepiphyseal dysplasia


short barrel chest, +  

pectus carinatum

mild rhizomelic shortening with bowing

severe kyphoscoliosis


retarded ossification of pubic bones

Asphyxiating thoracic dysplasia


narrow, long, short

anteriorly cupped ribs      

+   post-axial polydactyly,

variably short


square, short iliae, flat acetabulae


thin and membranous

markedly reduced ossification, short

short with bowing, long bones are frayed

poor ossification

with hypoplastic vertebrae



Achondrogenesis like the other lethal short limb dysplasia, is lethal because of pulmonary hypoplasia. Therefore, the pregnancy can be managed as other pregnancies with fatal outcome.


We would like to thank Dr. Helen Gruber for performing the histologic evaluation on case #2.


1. Van Der Harten HJ, Brons JTJ, Dijkstra DF. et al: Achondrogenesis-hypochondrogenesis: the spectrum of chondrogenesis imperfecta. Pediatric Pathology. 8:571-597, 1988.

2. McKusick VA. Mendelian Inheritance in Man. Catalogs of autosomal dominant, autosomal recessive and X-linked phenotypes. 9th ed. Baltimore, Johns Hopkins Univ Press, 1990.

3. Spranger JW, Langer LO, Wiedemann HR: Bone dysplasias. An atlas of constitutional disorders of skeletal development. Philadelphia: WB Saunders 1974

4. Whitley CB, Gorlin RJ: Achondrogenesis: new nosology with evidence of genetic heterogeneity. Radiology. 148:693-698, 1983.

5. Romero R, Athanassiadis AP, Jeanty P: Fetal skeletal anomalies. Rad Clin N A. 28(1):75-99, 1990.

6. Vissing H, D Alessio M, Lee B. et al: Glycine to serine substitution in the triple helical domain of pro _ 1 (II) collagen results in a lethal perinatal form of short-limbed dwarfism. J Biol Chem. 264, 1989.

7. Tiller GE, Rimoin DL, Murray LW, Cohn DH: Tandem Duplication within a type II collagen gene (col 2A1) exon in an individual with spondyloepiphyseal dysplasia. Proc. Natl. Acad. Sci. USA. 87:3889-93, 1990.

8. Lachman RS, Tiller GE, Graham JM et al.: Collagen, genes and the skeletal dysplasias on the edge of a new era: a review and update. Eur J Radiol 14:1-10, 1992

9. Emez, Rimoin eds:Principles and Practice of Medical Genetics. Vol. II. 1990.

10. Moerman P, Vandenberghe K, Fryns JP. et al: A new lethal chondrodysplasia with spondylocostal dysostosis, multiple internal anomalies and Dandy-Walker cysts. Clinical Genetics. 27:160-164, 1985.

11. Horton WA, Campbell D, Machado MA et al.: Type II collagen screening in the human chondroplasias. Am J Med Genetics. 34:579-583, 1989.

12. Godfrey M, Keene DR, Blank E et al: Type II achondrogenesis—hypochondrogenesis: morphologic and immunohistopathologic studies. Am J Hum Genetics. 43:894-903, 1988.

13. Godfrey M, Hollister DW. Type II achondrogenesis—hypochondrogenesis: identification of abnormal type II collagen. Am J Hum Genetics. 43:904-913, 1988.

14. Lee B, Vissing H, Ramirez F. et al: Identification of the molecular defect in a family with spondyloepiphyseal dysplasia. Science 244:978-980, 1989.

15. Eyre D, Upton MP, Shapiro FD. et al: Nonexpression of cartilage type II collagen in a case of Langer-Saldino achondrogenesis. Am J Hum Genetics. 39:52-67, 1986.

16. Wenstrom KD, Williamson RA, Hoover WW et al.: Achondrogenesis type II (Langer-Saldino) in association with jugular lymphatic obstruction sequence. Prenat Diag 9:527-532, 1989.

17. Pretorius DH, Rumack CM, Manco-Johnson ML. et al: Specific skeletal dysplasias in utero sonographic diagnosis. Radiology. 159:237-242, 1986.

18. Mahony BS, Filly RA, Cooperberg PL: Antenatal sonographic diagnosis of achondrogenesis. J Ultrasound Med. 3:333-335, 1984.

19. Borochowitz Z, Ornoy A, Lachman R, et al.: Achondrogenesis II—hypochondrogenesis: variability versus heterogeneity. Am J Med Genetics. 24:273-288, 1986.

20. Johnson VP, Yiu-Chiu VS, Wierda DR, et al.: Midtrimester prenatal diagnosis of achondrogenesis. J Ultrasound Med. 3:223-226, 1984.

21. Balakuma

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