Search :     
Articles » Skeletal » Thanatophoric dysplasia » Thanatophoric dysplasia, Type I » Thanatophoric dysplasia, 2nd trimester

1994-12-28-07 Thanatophoric dysplasia in monozygotic twins © Norris

Thanatophoric dysplasia in monozygotic twins

Cheryl D. Norris, RDMS, BS, George Tiller, MD, Philippe Jeanty, MD, PhD, Srini Malini, MD

Address correspondence to: Cheryl D. Norris, BS, ( #Women’s Health Alliance Nashville. ¶Women’s Health, Wichita, KS. §Houston, TX.

Synonyms: Thanatophoric dwarfism.

Definition: Thanatophoric dysplasia is a lethal skeletal dysplasia divided into two subtypes. Type I is characterized by extreme rhizomelia, bowed long bones, narrow thorax, a relatively large head, normal trunk length and absent cloverleaf skull. The spine shows platyspondyly, the cranium has a short base, and, frequently, the foramen magnum is decreased in size. The forehead is prominent, and hypertelorism and a saddle nose may be present. Hands and feet are normal, but fingers are short. Type II is characterized by short, straight long bones and cloverleaf skull16.

Etymology: qanath-joroz : death-bringing.

Prevalence: Thanatophoric dysplasia: 0.69:10,000; M:F 2:1; monozygotic twins: 40:10,000; thus thanatophoric dysplasia and monozygotic twins: 0.003: 10,0009.

Recurrence risk: Patients sib: mendelian inheritance, the empiric risk has been computed at 2%15.

Etiology: Unknown.

Pathogenesis: Characteristic generalized disruption of growth plate with persistent mesenchymal-like tissue15.

Associated anomalies: "Clover-leaf skull", horseshoe kidney, hydronephosis, atrial septal defect, defective tricuspid valve, imperforate anus, and radioulnar synostosis.

Differential diagnosis: Chondroectodermal dysplasia, asphyxiating thoracic dysplasia, short rib-polydactyly syndrome and homozygous achondroplasia9.

Prognosis: Uniformly lethal.

Management: Termination of pregnancy.

MESH Thanatophoric dwarfism BDE 0940 POS 3411 MIM 18760 ICD9 756.4 CDC 756.447


Thanatophoric dysplasia is a lethal congenital form of short-limbed chondrodysplasia first described by Maroteaux et al.48. It is the most common form of lethal neonatal dwarfism3, 16, 20, 33. To date, over 100 cases have been described23. The earliest prenatal diagnosis of the disease was made at 19 weeks of gestation30. Approximately 50% of cases with thanatophoric dysplasia present with large for dates measurements secondary to polyhydramnios21. This condition has characteristic sonographic features that suggest the diagnosis prenatally, although distinction from other short-limbed dysplasia syndromes may be difficult33. Fetuses with thanatophoric dysplasia have short limbs and digits, a large head with depressed nasal bridge and a narrow thorax. Occasionally, a cloverleaf skull is present. X-ray shows shortening and bowing of the long bones, with flared metaphyses, short ribs, and a hypoplastic pelvis. Thanatophoric fetuses usually die within the first 48 hours of life from pulmonary hypoplasia caused by a narrow thorax. The longest reported survival time was 167 days33. We report the prenatal diagnosis of thanatophoric dysplasia in monozygotic twins.

Case report

A 25-year-old G1P0 woman was referred at 26 weeks gestation for a prenatal ultrasound that revealed a monochorionic diamniotic twin gestation significant for severe limb shortening in both fetuses. The long bones were short and malformed, the vertebrae flattened, and the thoraces small (fig. 1-6). These findings were considered suspicious for thanatophoric dysplasia.

Figure 1: Sagittal view of the face: minimal frontal bossing.




Figure 2: Several views of the proximal and medial segments demonstrating severe shortening (rhizo- and mesomelia).

Figure 3: view of the hand demonstrating short, stubby fingers.

Figure 4: Platyspondyly.


Figure 5: Discrepancy between the small chest and the larger abdomen.

Figure 6: Absence of cloverleaf shape.

The patient and her husband elected to manage these twins by the premature delivery of stillborns in our outpatient facility. Cervical dilatation was accomplished over several days by repeated insertion of multiple laminaria. The delivery was complicated by fetal "locking" of the twins at the neck. The first twin was breech and was "locked" with the second vertex twin preventing the delivery of the first twin. After surgical "unlocking", the vaginal delivery was essentially routine."


The autopsy and X-ray examinations confirmed the diagnosis of thanatophoric dysplasia and monozygotic twins (fig 7-8). Twin #1 weighed 613g and was significantly smaller than twin #2, which weighed 872g. The significant difference in weight is probably the result of twin-to-twin transfusion syndrome. Both twins had characteristic morphologic and microscopic features of thanatophoric dysplasia including severe micromelia, platyspondyly, narrow thorax and pulmonary hypoplasia. The bowel was incompletely rotated but otherwise normal. No cardiovascular or urinary tract anomalies were found.


Figure 7: X-ray of the twins.

Figure 8: View of the twins.


The ability to diagnoses skeletal dysplasias prenatally by ultrasound is important for perinatal management and prognosis since various dysplasias are associated with different outcomes. Thanatophoric dysplasia is invariably lethal, while hypochondroplasia may be so mild as to go unnoticed in early infancy49.


Thanatophoric dysplasia is a uniformly lethal osteochondrodysplasia characterized by rhizomelia, micromelia, bowing of the femurs, thoracic hypoplasia, and macrocrania13.


Two subtypes of thanatophoric dysplasia are recognized.

  • Type I is the most frequent form, characterized by the typical bowed "telephone receiver" femurs. Although cloverleaf skull is usually absent, a mild form was described in one case16.
  • Type II is characterized by cloverleaf skull and short, straight, long bones.

The differential diagnosis between the two depends on the radiographic findings and histology. There is no agreement regarding the pattern of inheritance of this condition. The first type seems to have an undetermined pattern of inheritance and in most cases is sporadic. The second type seems to be inherited with an autosomal recessive pattern16, 32.


The etiology of thanatophoric dysplasia is unknown. Most cases have been sporadic, with a 2:1 ratio of affected males to females19. Since autosomal recessive inheritance has been implicated in at least one instance of two affected siblings born of consanguineous parents38, the general empiric recurrence risk is about 2%.

Prenatal diagnosis

The sonographic antenatal diagnosis can be made in the presence of short-limbed dwarfism, hypoplastic thorax, cloverleaf skull, frontal bossing and simian crease. Femur bowing, narrow thorax, large head size even without ventriculomegaly, and redundant soft tissues are features that become more pronounced with advancing gestation but may not be present in midtrimester. In 70% of cases, thanatophoric dysplasia is associated with polyhydramnios, which may be massive and lead to premature labor. Fetal movements do not seem to be affected by the disease, but a decrease in motion during the third trimester has been reported. Decreased hand flexure is probably responsible for the presence of simian crease. In the absence of cloverleaf skull, the disease should be suspected when severe rhizomelic dwarfism and a narrow thorax are detected.

Sonographic measurement of fetal femur length, especially when correlated with biparietal diameter, is a reliable method in the identification of certain forms of short-limbed skeletal dysplasias4. Following the detection of shortened extremity bones, Mahoney17 has proposed an evaluation of the following sonographic parameters and questions, which are helpful to achieve a precise diagnosis:

  • What is the degree of bone shortening?
  • The severity of bone shortening varies from extreme (many standard deviations below the mean, with the limbs oriented at approximately right angles to the fetal trunk) to mild-to-moderate (with a more normal orientation of the limbs to the fetal trunk).
  • What is the distribution of involvement?
  • Rhizomelic, mesomelic, or acromelic bone shortening occurs with different dysplasias.
  • Are bone fractures or extremity bowing present?
  • Fractures usually indicate osteogenesis imperfecta.
  • Extremity bowing may indicate the presence of fracture, campomelic dysplasia, or diastrophic dysplasia.
  • Thanatophoric dysplasia may produce a "telephone receiver" appearance of the femurs.
  • What is the degree and distribution of ossification?
  • Diffuse hypomineralization usually indicates osteogenesis imperfecta or hypophosphatasia.
  • Focal hypomineralization of the spine indicates achondrogenesis.
  • What is the calvarial configuration?
  • Cloverleaf skull deformity with micromelia indicates thanatophoric dysplasia.
  • What is the thoracic size?
  • A small thorax indicates a high probability of pulmonary hypoplasia, but the thoracic shape often does not assist in rendering a specific diagnosis.
  • Rib fractures with a bell-shaped thorax usually indicates osteogenesis imperfecta.
  • Is polydactyly present?
  • Polydactyly with skeletal dysplasia usually indicate short-rib polydactyly syndrome, chondrodysplasia punctata, or asphyxiating thoracic dysplasia.

Even in the absence of a positive family history, careful assessment of these criteria allows accurate diagnosis of a specific skeletal dysplasia in over 50% of cases, enabling accurate prognostic assessment in approximately 85% of the cases.

Differential diagnosis

The differential diagnosis should include Ellis-van Creveld syndrome (chondroectodermal dysplasia), asphyxiating thoracic dysplasia, short rib-polydactyly syndrome, and homozygous achondroplasia9. Thanatophoric dysplasia should be included in the differential diagnosis of short-limbed dwarfism that is identifiable by abnormal femur length before 22 weeks gestation2. For a complete list of differential criterias see49.

Associated anomalies

Thanatophoric dysplasia is associated with a form of craniosynostosis, called "cloverleaf skull", in 14% of cases. The cloverleaf skull results from premature closure of the coronal and lambdoid sutures. If hydrocephaly occurs, the rostral expansion of the cortex and of the ventricular system results in an enlarged anterior fontanel and separation and expansion of the temporal bones. The term "cloverleaf" refers to the three leaves formed by the prominent frontal bone in the middle and the two temporal bones on the sides. The mechanism responsible for the skull anomaly is poorly understood. A defect of endochondral ossification resulting in a short skull base and a defect of membranous ossification producing premature synostosis of some cranial sutures has been suggested as the pathogenesis9. Horseshoe kidneys, hydronephrosis, atrial septal defect, defective tricuspid valve, imperforate anus, and radioulnar synostosis have also been described9.

Clinical findings

Birth length ranges from 36 to 46 cm. Limbs are very short and extend away from an essentially normal-sized trunk with thighs abducted and externally rotated. The fingers are very short and conically shaped. The head is relatively large, with a prominent forehead and depressed nasal bridge. Respiratory distress occurs secondary to pulmonary hypoplasia and a small narrow thorax. Hypotonia and numerous skin folds are present. The primitive reflexes are absent15,19. Clinically, a specific diagnosis may be difficult, although the fatal course is highly suggestive of the syndrome. Pathological findings are also nonspecific. Radiographically, however, thanatophoric dysplasia is quite distinct5.

Radiological findings

Radiological findings include platyspondyly (vertebral bodies that have a small vertical diameter), with the narrowest area in the middle of the body in both anteroposterior and lateral projections31. The intervertebral spaces are large, and the posterior vertebral elements are well ossified. Interpedicular distance is narrowed in the mid- or lower lumber spine, and the ilia have a short vertical dimension. The transverse diameter is greater than the vertical. The inferior margin of the ilia is horizontal and the sacrosciatic notches small. The pubic and ischial bones are broad and short, while the thorax is narrow in both anteroposterior and transverse diameters, with short ribs, the ends of which are cupped. The long bones are very short, relatively broad, and bowed with irregular flaring of the metaphyses. Hand and foot bones are very short and broad. Laboratory findings are normal15.


This disease is uniformly fatal shortly after birth9,15. The cause of death is cardiorespiratory failure due to hypoplastic lungs.

Management and treatment

Hydrocephalus, which is often present, may predispose to malpresentation and difficult delivery. In particular, the extended short and rigid neck may impede the passage of the subsequently delivered head through the pelvis during vaginal breech delivery. Cephalocentesis and assisted breech delivery have been performed. Elective cesarean section may be preferred to prevent possible maternal trauma when attempting to deliver the hydrocephalic head. Early prenatal diagnosis, as in this case, may allow elective termination. This can avoid an unfruitful cesarean section or difficult manipulation in vaginal delivery should hydrocephalus give rise to malpresentation in late pregnancy3.


1. Fink IJ, Filly RA, Callen PW, et al. Sonographic diagnosis of thanatophoric dwarfism in utero. J Ultrasound Med 1982;1:337-339.

2. Meizner I, Levy A, Carmi R, et al. Early prenatal ultrasonic diagnosis of thanatophoric dwarfism. Isr J Med Sci 1990;26: 287-289.

3. Loong EPL. The importance of early prenatal diagnosis of thanatophoric dysplasia with respect to obstetric management. Eur J Obstet Gynecol Reprod Biol 1987;25:145-152.

4. Burrows PE, Stannard MW, Pearrow J, et al. Early antenatal sonographic recognition of thanatophoric dysplasia with cloverleaf skull deformity. AJR 1984;143:841-843.

5. Young RS, Pochaczevosky R, Leonidas JC, et al. Thanatophoric dwarfism and cloverleaf skull ("Kleeblattschadel"). Radiology 1973;106:401-405.

6. Iannaccone G, Gerlini G. The so-called "cloverleaf skull syndrome". Pediatr Radiol 1974;2:175-184.

7. Partington MW, Gonzales-Crussi F, Khakee SG, et al. Cloverleaf skull and thanatophoric dwarfism. Arch Dis Child 1971;46:656-664.

8. Brahman S, Jenna R, Wittenauer HJ. Sonographic in utero appearance of kleeblattschadel syndrome. JCU 1979;7:481-484.

9. Romero R, Pilu GL, Jeanty P. Prenatal diagnosis of congenital anomalies. Norwalk, Connecticut, 1988;335-339.

10. Romero R, Pilu GL, Jeanty P. Prenatal diagnosis of congenital anomalies. Norwalk, Connecticut, p. 311-332, 1988.

11. Gould GM, Pyle WL. Anomalies and curiosities of medicine. New York: The Julian Press, 1986; 333-343.

12. Winter, RM, Knowles SAS, Bieber FR, et al. The malformed fetus and stillbirth. New York, Wiley Medical Publications 1988;181-187.

13. Chervenak FA, Isaacson GC, Campbell S. Ultrasound in obstetrics and gynecology. Boston, Little, Brown and Company 1993;2:991-992.

14. Chervenak FA, Isaacson GC, Campbell S. Ultrasound in Obstetrics and Gynecology, Boston, Little, Brown and Company 1993;2:1201-1203.

15. Buyse ML. Birth defects encyclopedia. Cambridge, Blackwell Scientific Medical Publications 1990;1661-1662.

16. Fleischer AC, Romero R, Manning FA, et al. The principles and practice of ultrasonography in obstetrics and gynecology, 4th edition. Connecticut, Appleton and Lange 1991;295-297.

17. Nyberg DA, Mahony S, Pretorius DH. Diagnostic ultrasound of fetal anomalies. Chicago, Year book medical publications 1990;492-507.

18. Warkany J. Congentital malformations. Chicago, Year book medical publications 1981;767-770.

19. Smith DW, Jones KL. Recognizable patterns of human malformation. Philadelphia, W.B. Saunders Company 1982;242-243.

20. Rumack CM, Wilson SR, Charboneau JW. Diagnostic ultrasound. St. Louis, Mosby Year Book 1991;860-863.

21. Callen PW. Ultrasonography in obstetrics and gynecology. Philadelphia, W. B. Saunders Company 1994;259-263.

22. Kalousek DK, Fitch N, Paradice BA. Pathology of the human embryo and previable fetus. New York, Springer-Verlag 1990;96.

23. Hansmann M, Hackeloer BJ, Staudach A. Ultrasound diagnosis in obstetrics and gynecology. Berlin, Springer-Verlag 1985;241-245.

24. Csecsei K, Szeifert G, Nemes Z, et al. Pathomorphological findings of a prenatally diagnosed thanatophoric dwarf. Prog Clin Biol Res 1982;104: 505-518.

25. Stoll C, Dott B Roth MP, et al. Birth prevalence rates of skeletal dysplasia. Clin Genet 1989;35:88-92.

26. Pinto A, Hwang WS, McLeod DR, et al. A new variant of lethal neonatal short-lombed platyspondylic dwarfism. Arch Path Lab Med 1993;117:322-325.

27. Stamm ER, Pretorius DH, Rumach CM, et al. Kleeblattschadel anomaly: in utero sonographic appearance. J Ultrasound Med 1987;6:319-324.

28. Escobar LF, Bixler D, Padilla LM. Quantitation of cranofacial anomalies in utero: fetal alcohol and Crouxon syndromes and thanatophoric dysplasia. Am J Med Genet 1993;45:25-29.

29. Cremin BJ, Shaff MI. Ultrasonic diagnosis of thanatophoric dwarfism in utero. Radiology 1977;124:479-480.

30. Beetham FG, Reeves JS. Early ultrasound diagnosis of thanatophoric dwarfism. JCU 1984;12:43-44.

31. Moore QS, Banik S. Ultrasound scanning in a case of thanatophoric dwarfism with clover-leaf skull. Bri J Radiol 1980;53:241-245.

32. Elejalde BR, de Elejalde MM. Thanatophoric dysplasia: fetal manifestations and prenatal diagnosis. Am J Med Genet 1985;22:669-683.

33. Kassanos D, Botsis D, Katassos T, et al. Prenatal sonographic diagnosis of thanatophoric dwarfism. Int J Gynecol Obstet 1991;34:373-376.

34. Camera G, Dodero D, De Pascale S. Prenatal diagnosis of thanatophoric dysplasia at 24 weeks. Am J Med Genetics 1984;18:39-43.

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

36. Toth Z, Vachter J, Szeifert G, et al. Antenatally diagnosed thanatophoric dysplasia. Acta Paediatr Hung 1982;23:423-430.

37. Burrows PE, Stannard MW, Pearrow J, et al. Early antenatal sonographic recognition of thanatophoric dysplasia with cloverleaf skull deformity. AJR 1984;143:841.

38. Chemke J, Graff G, Lancet M. Familial thanatophoric dwarfism. Lancet 1971;1:1358.

39. Chervenak FA, Blakemore KJ, Isaacson G, et al. Antenatal sonographics findings of thanatophoric dysplasia with cloverleaf skull. Am J Obstet Gynecol 1983;146:984.

40. Filly RA, Golbus MS, Carey JC, et al. Short-limbed dwarfism: ultrasonographic diagnosis by mensuration of fetal femoral length. Radiology 1981;138:653.

41. Graff G, Chemke J, Lancet M. Familial recurring thanatophoric dwarfism. Obstet Gynecol 1971;39: 515.

42. Harris R, Patton JT. Achondroplasia and thanatophoric dwarfism in the newborn. Clin Genet 1971; 2:61.

43. Horton WA, Harris DJ, Collins DL. Discordance for the kleeblattschadel anomaly in monozygotic twins with thanatophoric dysplasia. Am J Med Genet 1983;15:97.

44. Isaacson G, Blakemore KJ, Chervenak FA. Thanatophoric dysplasia with cloverleaf skull. Am J Dis Child 1983;137:896.

45. Mahony BS, Filly RA, Callen PW, et al. Thanatophoric dwarfism with the cloverleaf skull: a specific antenatal sonographic diagnosis. J Ultrasound Med 1985;4:151.

46. Pena SD, Goodman HO. The genetics of thanatophoric dwarfism. Pediatrics 1973;51:104.

47. Thompson BH, Parmely TH. Obstetric features of thanatophoric dwarfism. Am J Obstet Gynecol 1971;109:396.

48. Maroteaux P, Lamy M, Robert JM. Le nanisme thanatophore. Presse Med 1967;75:2219-2524.

49. Allen SH, Jeanty PJ. Hypochondroplasia. The Fetus 1991;7564-1.

Originally published in The Fetus in 1994, posted 6/1999

Help Support :