Address correspondence to Catherine J. Babcook, MD, Department of Radiology, Ultrasound, UCSF Medical Center, 505 Parnassus, Room L374, San Francisco, CA, 94143-0628, Ph: 415-476-5219, Fax: 415-476-9803

Synonyms: Diastrophic dwarfism¹, le nanisme diastrophique (tortuous dwarfism) ². Early cases may have been misdiagnosed as achondroplasia with clubfoot deformities which were difficult to correct surgically¹.

Definition: A rare osteochondrodysplasia that results in micromelic limb shortening. With notable exceptions, it is associated with normal intelligence.

Prevalence: Unknown, but rare in the general population. It is distinctly more prevalent among Finns (0.3:10,000), constituting the most common skeletal dysplasia in Finland.

Etiology: Autosomal recessive inheritance. The gene has been mapped to the distal long arm of chromosome 5³.

Pathogenesis: Unknown. Larger than normal collagen fibrils have been extracted from the cartilage matrix in these patients.

Associated anomalies: Bilateral clubfoot deformity, "hitchhiker" thumbs and/or great toes, ulnar deviation of the hands, generalized joint deformities, kyphoscoliosis, micrognathia, cleft palate, deformed ears, congenital heart defect (occasionally).

Differential diagnosis: Other micromelic skeletal dysplasias and pseudodiastrophic dysplasia.

Prognosis: Usually non-lethal and associated with normal intelligence, although a lethal variant has been described and mental retardation has been reported⁴. Increased perinatal mortality due to respiratory problems and high incidence of neurological complications secondary to spine anomalies. Severe physical handicap is typical with attendant problems in psychosocial adaptation.

Recurrence risk: 25% chance of recurrence.

Management: Early prenatal diagnosis offers the option of pregnancy termination. Perinatal management involves close monitoring for respiratory complications. Orthopedic intervention is often required for correction or stabilization of skeletal deformities.

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

See also pages 7564-7-12

Introduction

We report the findings in a case of diastrophic dysplasia.

Case report

A 30-year-old pregnant woman had a low maternal serum alpha-fetoprotein level discovered during routine screening and was referred for a Level I sonogram to confirm her dates. Biometry at this time showed a short femur. She was then referred to our institution for a Level II sonogram at 20 weeks" gestation as determined by her last menstrual period. There was no family history of dwarfism. Sonography revealed a single, live, intrauterine fetus with a biparietal diameter, head circumference and abdominal circumference consistent with a gestational age of 20 weeks. However the femur length measured 21 mm and was therefore less than the 5^th percentile for the gestational age (fig. 1).

Figure 1: The femur measured 21 mm, which is less than the 5 ^th percentile for the gestational age of 20 weeks 4 days. This femur length would be consistent with a 15 or 16 week old fetus.

This femur length would be consistent with a gestational age of 15 or 16 weeks. The remaining long bones were also short, but none of the long bones were bowed or fractured, and mineralization appeared sonographically normal (figs. 2 and 3).

Figure 2: The humerus measured less than the 5 ^th percentile for gestational age.

Figure 3: Short tibia. The tibia measured less than the 5^th percentile for the gestational age of the fetus.

There was a severe bilateral club foot deformity, and the great toes on both feet were displaced proximally and abducted ("hitchhiker" toes) (fig. 4).

Figure 4: Hitchhiker toe and clubfoot. The first digit on both feet was proximally displaced and abducted; this can be a finding of either the great toes or the thumbs. The characteristic bilateral clubfoot deformity was present.

The spine demonstrated a thoracic kyphoscoliosis, but platyspondyly was not present (fig. 5). No other organ abnormalities were noted. This constellation of findings made diastrophic dysplasia the leading diagnostic possibility.

Figure 5: A mild thoracic kyphoscoliosis was present.

Following genetic counseling, the parents decided to continue the pregnancy. At 40 weeks" gestation, a 2495g female infant was delivered. The infant showed short stature, contractures of the hands, bilateral clubfoot deformities, bilateral medial deviation of the great toes, thoracic scoliosis and was deaf. No features suggestive of pseudodiastrophic dysplasia were present on postnatal skeletal radiographs, and the radiographic findings confirmed the diagnosis of diastrophic dysplasia. The child"s perinatal course was unremarkable. The child is well at 16 months" follow-up with corrective surgery planned for her foot deformities. Figure 6 shows a different child with diastrophic dysplasia and the characteristic "hitchhiker" appearance of the first digits (affecting the toes in this case, as in our case). Figure 7 illustrates the radiographic appearance of the "hitchhiker" thumb in another affected child. The characteristic bilateral clubfoot deformity and "hitchhiker" toes are illustrated in the radiograph in figure 8.

Figure 6: Different child demonstrating the same "hitchhiker" appearance of the great toes as in our case. (Reprinted with permission from¹⁶).

Figure 7: Bilateral clubfoot deformity and "hitchhiker" toes. Radiographic appearance of the characteristic findings of the foot in a patient with diastrophic dysplasia. (Reprinted with permission from¹⁶.

Figure 8: "Hitchhiker thumb". Radiographic appearance of the abnormally abducted thumb in a child with diastrophic dysplasia. (Reprinted with permission from¹⁶.)

Discussion

Prevalence

Diastrophic dysplasia is a rare osteochondrodysplasia. It has been observed in most white populations but is remarkably more prevalent in Finns. In 1990 there were 160 patients known to be affected in Finland, while it is estimated that less than 300 patients have been described in the rest of the world^3.

Etiology and pathogenesis

The genetic locus for diastrophic dysplasia has been mapped to the distal part of the long arm of chromosome 5, distal to the gene for adenomatous polyposis coli³. Evidence suggests that diastrophic dysplasia is genetically homogeneous, at least in Finland.

Although the genetic locus has been mapped, the underlying biochemical defect in cartilage has been more difficult to identify. There are broad collagen fibrils surrounding degenerating chondrocytes in the cartilage of patients with diastrophic dysplasia. Stanescu et al suggested that this might be due to a structural defect in type II collagen⁵. This hypothesis is based on their report of an abnormal segment long spacing (SLS) crystallite pattern in type II collagen from diastrophic dysplasia patients. However, Murray et al⁶ found normal type II collagen in their patients with diastrophic dysplasia and believe the previously reported spacing crystallite pattern was due to an artifact of alignment of the crystallites. In addition, they reported that the broad collagen fibrils thought to be characteristic of diastrophic dysplasia cartilage can be seen in normal subjects when the cartilage structure is disrupted by extraction with guanidine and, thus, may be artifactual. The biochemical defect therefore remains obscure.

Diagnosis

Prenatal sonographic diagnosis is initiated by the identification of a significantly shortened femur. Measurements of all fetal long bones should then be made. The majority of reported cases diagnosed on prenatal sonography have shown micromelic shortening with most bones less than or equal to the 5th percentile for gestational age^7-12. However, one postnatal study describes clinical heterogeneity in their cases, with some patients being more mildly affected and showing less severe micromelic limb shortening or rhizomelic shortening¹³. This appears to be less common.

To date, the majority of prenatal diagnoses have been made in fetuses suspected of having diastrophic dysplasia because of an affected sibling. In this setting, the finding of micromelic bone shortening is virtually diagnostic even without identifying associated abnormalities.

Associated anomalies

In de novo diagnoses, this bone dysplasia must be differentiated from other micromelic dysplasias. This may be accomplished by identifying one or more of the associated abnormalities (Table 1).

Table 1: Associated anomalies.

Bilateral clubfoot deformity is virtually always present and should be sought. An additional characteristic finding is proximally inserted and abducted thumbs or great toes ("hitchhiker" thumbs or toes), although this is not seen universally. Ulnar deviation of the fingers can also occur, and these findings of the digits are often due to the presence of longitudinal bracketed epiphyses.

Kyphoscoliosis may be seen in utero but may not manifest until the postnatal period or later. A study of 101 patients with diastrophic dysplasia in Finland, aged newborn to 79 years, found a prevalence of scoliosis of 37%¹³. Only two patients underwent surgery because of their scoliosis.

Other associated anomalies which may be identified on prenatal sonography include micrognathia, cleft lip and congenital heart defect. The ear deformities have not been appreciated until the postnatal period.

Differential diagnosis

The differential diagnosis is that of other mild micromelic dysplasias, namely asphyxiating thoracic dystrophy (Jeune syndrome) and chondroectodermal dysplasia (Ellis van Creveld syndrome). These two entities cannot be distinguished from each other in utero but can be differentiated from diastrophic dysplasia. Both asphyxiating thoracic dystrophy and chondroectodermal dysplasia are characterized by small thoraces and increased cardiothoracic ratios, not found in diastrophic dysplasia. Polydactyly may be seen in both but is not a feature of diastrophic dysplasia. Associated renal disease may occur with asphyxiating thoracic dystrophy. Congenital heart defects (usually atrial septal defects) are frequently associated with chondroectodermal dysplasia and occasionally may occur in diastrophic dysplasia (particularly the rare, lethal form). The absence of bilateral clubfoot deformity in asphyxiating thoracic dystrophy and chondroectodermal dysplasia should also help in the correct diagnosis of diastrophic dysplasia.

In the less common situation of diastrophic dysplasia with rhizomelic limb shortening, achondroplasia must be differentiated, and, again, the bilateral clubfoot deformity, as well as the "hitchhiker" thumbs and toes should be helpful.

A chondrodysplasia mimicking diastrophic dysplasia is now considered a distinct skeletal dysplasia and is termed pseudodiastrophic dysplasia^14,15. An even rarer entity than diastrophic dysplasia (about 7 cases of pseudodiastrophic dysplasia are reported in the world literature), this dysplasia has not been diagnosed prenatally. It appears that pseudodiastrophic dysplasia can be distinguished at birth by the presence of an enlarged head with midface hypoplasia, long clavicles, platyspondyly, horizontal acetabular roofs and medial and lateral acetabular spikes, rhizomelic limb shortening and characteristic interphalangeal joint dislocations of the hands. The majority of these features are unlikely to be appreciated on prenatal sonography, and differentiation of these two entities may not be possible until the postnatal period. Clubfoot deformity is present in both dysplasias, but the "hitchhiker" thumbs and toes appear to be lacking in pseudodiastrophic dysplasia, which may be helpful. The overall deformity and disability appear somewhat similar in the two dysplasias, and the mode of inheritance is the same, perhaps making prenatal distinction less critical.

Prognosis

Delivery of a live newborn at term is the norm. In general, mortality is increased in infancy due to respiratory difficulties, but life expectancy thereafter is not obviously shortened.

However, Gustavson et al⁴ reviewed 14 Swedish postnatal cases of diastrophic dysplasia, of whom 6 died in the perinatal period of respiratory and circulatory insufficiency. They considered these patients to represent a lethal form of the dysplasia. They found that most (4/6) infants in the lethal group had associated congenital heart defects (atrial and ventricular septal defect, patent ductus arteriosus, patent foramen ovale, myocardial hypertrophy), compared with none in the non-
lethal group. Cleft palate was much more common in the non-lethal group (5/8) compared to the lethal group (1/6).

Significant morbidity is common secondary to the skeletal deformities and the associated psychosocial difficulties. Parents with a previously affected child frequently undergo prenatal sonography with the intention of terminating a subsequently affected pregnancy⁹.

References

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2. Lamy M, Maroteaux P: Le nanisme diastrophique. Presse Med 68:1977-1980, 1960.

3. Hastbacka J, Kaitila I, et al: Diastrophic dysplasia gene maps to the distal long arm of chromosome 5. Proc Natl Acad Sci USA 87:8059, 1990.

4. Gustavson KH, Holmgren G, et al: Lethal and non-lethal diastrophic dysplasia: a study of 14 Swedish cases. Clin Genet 28:321-334, 1985.

5. Stanescu R, Stanescu V, Maroteaux P: Abnormal pattern of segment long spacing (SLS) cartilage collagen in diastrophic dysplasia. Collagen Rel Res 2:111-116, 1982.

6. Murray LW, Hollister DW, Rimoin DL: Diastrophic dysplasia: evidence against a defect of type II collagen. Matrix 9:459-67, 1989.

7. O"Brien GD, Rodeck C, Queenan JT: Early prenatal diagnosis of diastrophic dwarfism by ultrasound. Br Med 280:1300, 1980.

8. Mantagos S, Weiss RR, Mahoney M, Hobbins JC: Prenatal diagnosis of diastrophic dwarfism. Am J Obstet Gynec 139:111-113, 1981.

9. Kaitila I, Ammala P, et al: Early prenatal detection of diastrophic dysplasia. Prenat Diagn 3:237-244, 1983.

10. Gollop TR, Eigie A: Brief clinical report: prenatal ultrasound diagnosis of diastrophic dysplasia at 16 weeks. Am J Med Genet 27:321-324, 1987.

11. Gembruch U, Niesen M, et al: Diastrophic dysplasia: a specific prenatal diagnosis by ultrasound. Prenat Diagn 8:539-545, 1988.

12. Gonçalves LF, Jeanty P. Diastrophic dysplasia. The Fetus 2:7564-7-12, 1992.

13. Poussa M, Merikanto J, et al: The spine in diastrophic dysplasia. Spine 16:881-887, 1991.

14. Bertrand JG, Tyi A, et al: Pseudo-diastrophic dysplasia. Annales de Pediatrie 38:19-22, 1991 (Abstr).

15. Eteson DJ, Giampiero B, et al: Pseudodiastrophic dysplasia: a distinct newborn skeletal dysplasia. J Pediatr 109:635-641.

16.Spranger, Langer and Wiedemenn, eds. Bone dysplasias: an atlas of constitutional disorders of skeletal development. Stuttgart: Gustav, Fischer and Verlag, 1974; 103.