1993-12-01-04 Atelosteogenesis, type I © den Hollander www.thefetus.net/
Atelosteogenesis, type I
Nicolette S. den Hollander, MD, Patricia A. Stewart, PhD, Helen Brandenburg, MD, PhD, Hans J. van der Harten, MD, PhD ,Hans L. Gaillard, MD, PhD
Address correspondence to: Nicolette S. den Hollander, MD, Department of Obstetrics and Gynecology, Academic Hospital Dijkzigt, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands, Ph: 31‑10‑463‑9222, Fax: 31‑10‑408‑7213 §Pathology Department, Free University Hospital, Amsterdam, The Netherlands ¶Pathology Department, Academic Hospital Dijkzigt, Rotterdam, The Netherlands
Synonyms: Osteochondrodysplasia, giant cell chondrodysplasia, spondylohumerofemoral hypoplasia15,16.
Definition: Lethal neonatal micromelic osteochondrodysplasia with diagnostic X‑ray and characteristic clinical and histopathological features.
Etymology: From ateleV: incomplete, osteon: bone and ‑genhV production
Prevalence: Less than 10 cases of atelosteogenesis, type I, have been documented1‑8.
Etiology: Unknown. No familial cases or parental consanguinity have been reported in atelosteogenesis type I. Both sexes are affected.
Pathogenesis: Pathologic examination of cartilage shows that resting cartilage is relatively intact but shows hypocellular areas interspersed with areas of normal cellularity. Multinucleated giant cells may be found in the areas of hypocellularity. These giant chondrocytes are not specific to any single lethal skeletal dysplasia4.
Associated anomalies: Depressed nasal bridge, micrognathia, eyelid edema, cleft soft palate. Polyhydramnios is often diagnosed.
Differential diagnosis: Disorders manifested by osteochondrodysplasias with micromelia such as thanatophoric dysplasia, achondrogenesis, diastrophic dysplasia, fibrochondrogenesis.
Prognosis: Stillborn or neonatal death due to respiratory distress in all cases.
Recurrence risk: Low: all observed cases have been sporadic. Thus far, no familial cases have been reported.
Management: Early ultrasound diagnosis allows pregnancy termination if opted by the parents, but a precise prenatal diagnosis of this lethal condition may be difficult.
MESH Bone abnormalities ICD9 7564.4 MIM 108720 POS 3552 CDC 756.440
Atelosteogenesis is a rare neonatally lethal osteochondrodysplasia characterized by severe limb shortening, bowed extremities, hypoplastic or absent fibulae, joint dislocations, clubfeet, narrow chest, depressed nasal bridge, micrognathia and eye lid edema.
In the 1980"s several authors reported cases of atelosteogenesis1‑9. In 1987, Sillence and Kozlowski8 reported 4 cases of neonatal osteochondrodysplasia resembling atelosteogenesis but with some distinctive radiographic and characteristic histopathological features. These cases were separated from diastrophic dysplasia, and atelosteogenesis type II was proposed for this entity. Contrary to type I atelosteogenesis, type II has proved to be autosomal recessive.
In 1990, Stern et al. proposed the name atelosteogenesis type III for a skeletal dysplasia whose manifestations overlap those of atelosteogenesis and oto‑palato‑digital syndrome type II. In contrast with atelosteogenesis type I and type II, “type Ill” is not a lethal condition. Three out of five patients with this syndrome, described by Stern, have survived infancy.
We present a case of prenatally diagnosed short‑limbed osteochondrodysplasia that turned out to be atelosteogenesis type 1.
A healthy 29‑year‑old G1P0 and her 41‑year‑old blind (due to a congenital rubella infection) husband were referred to our division of prenatal diagnosis for a detailed ultrasound examination.
The husband had a son with cleft lip and palate from a previous marriage. At the time of referral the gestational age was 13 and a half weeks. The ultrasound examination revealed a normal singleton fetus with a 28 mm BPD.
An ultrasound scan at 22 and a half weeks revealed appropriate biometry of head and abdomen but severe shortness of all extremities. All measured limbs were below the fifth percentile for gestational age. There was abundant amniotic fluid. Anatomic study of the fetus demonstrated micrognathia (fig. 1), small thorax, small broad hands with short fingers and echo‑dense fingertips, bowed lower legs with broad feet in severe equinovarus position (fig. 2). The face appeared edematous, although this probably represented an over abundance of soft tissue. On ultrasound, the density of the bones visualized, with the exception of the echodense fingertips, was essentially normal.
Figure 1: Profile of the fetus at 22 and a half weeks. Note the micrognathia.
Figure 2: One of the lower limbs of the fetus demonstrating the equinovarus position of the foot.
The differential diagnosis of a skeletal dysplasia such as diastrophic dysplasia and achondrogenesis was proposed.
Amniocentesis revealed a normal, female karyotype and slightly raised alpha‑fetoprotein.
The pregnancy was terminated at 23 weeks of gestation and a 510g female stillborn with a crown rump length of 195 mm, a head circumference of 210 mm and a foot length of 32 mm was delivered (fig. 3, 5, 6).
Figure 3: The 23-week fetus after delivery. Note the micrognathia, short limbs, hands and equinovarus position of the feet.
Figure 5: Short limbs and equinovarus position of the feet.
Figure 6: The hand: note the short stubby digits, overabundant soft-tissue (Michelin-man appearance) and the simian crease.
Radiographs (fig. 4) showed incomplete ossification of the thoracic and cervical vertebral bodies with marked hypoplasia of the lower thoracic and lumbar vertebral bodies. In these bodies, the anterior and posterior ossification centers were separated by coronal clefts (translucent bar).
Figure 4: X-ray of the fetus.
The thorax appeared relatively small and bell‑shaped. Most striking were the short and distally tapered humori and femora. There was bowing of the ulnae, the radii, the tibias and absence of the fibulae. The distal phalanges of the fingers were ossified, but there was no mineralization of the ossification centers of the middle and proximal phalanges. The distal and proximal phalanges of the toes were partly mineralized. The feet were in severe equinovarus position. The pelvis showed rounded iliac bones, flat acetabulae and unossified pubic bones.
No definite abnormalities of the skull were noted. Histologic study of the cartilage showed an intact reserve zone with hypocellular areas interspersed with areas of normal cellularity with a few giant cells.
The growth plate showed a narrow hypertrophic zone and irregular column formation.
Based on radiologic and histologic findings, the diagnosis of atelosteogenesis type I was made.
In table I, some radiographic and histopathologic differences between atelosteogenesis type I and type II are presented based on the data of Sillence and Kozlowski8.
Atelosteogenesis type II can be distinguished from type I by radiographic and histopathologic criteria. The dysplastic ossification pattern in type I and type II is similar.
Due to insufficient radiologic and histopathologic documentation, not all earlier presented cases1‑7 of atelosteogenesis can be reclassified as type I or type II.
An ultrasonographic and clinical marker for atelosteogenesis type II is the unusually wide space between first and second digit of both hands and feet (hitchhiker thumb or toe). In the fetus described above we saw small broad hands and broad feet with normal position of fingers and toes. Remarkable were the echodense fingertips. These echodense structures were the only bones, terminal phalanges, in the hands with mineralized ossification centers. Ossification of the terminal phalanges (hands) starts between 11 and 12 weeks of gestation and can be observed by ultrasound between 12 and 13 weeks. Within the next two weeks the mid‑ and proximal phalanges are mineralized14 . The process of mineralization in the present fetus probably went wrong around 12 weeks of gestation.
Table 1: Radiographic and histopathologic differences between atelosteogenesis type I and type II8
Less shortening than type II,
humerus: absent distal parts,
femur: distally tapered
Marked shortening with widening of the metaphyses
humerus: V or U shaped distal end
femur: distal end rounded
fibula: present in all cases
All tubular bones hypoplastic and dysplastic with delayed mineralization
Tubular bones severe hypoplastic and dysplastic; second and third
metacarpals and metatarsals larger than remaining bones
Iliac bones almost round, irregular outline of iliac
Incomplete ossification of vertebral bodies with coronal clefting
Cervical kyphosis with hypoplastic and dysplastic changes; lumbosacral
Resting cartilage intact but hypocellular areas in which giant cells
may be found. The proliferative and hypertrophic zone is shortened
and distorted by prolongation of relatively acellular areas between
the cell columns.
Resting cartilage extremely abnormal; matrix attenuated
with many cystic areas containing only radiating threads of matrix.
In contrast to atelosteogenesis type I, autosomal recessive inheritance of type II is suggested by parental consanguinity11 and by recurrence of this disorder in a subsequent pregnancy6,8,12 . All cases of atelosteogenesis type I have been sporadic in otherwise normal families without consanguinity.
According to Hunter and Carpenter13 atelosteogenesis type I, II and III have different radiologic and histopathologic appearances Still, more cases must be studied before it can be stated with certainty6 that they are distinct conditions.
The inutero diagnosis of atelosteogenesis is unusual. The diagnosis is based primarily on the radiographic appearance of the spine, long bones and hands and histopathologic study of the growth cartilage.
Recently, Nores et al.12 described a case of atelosteogenesis type II prenatally diagnosed at 15 weeks of gestation. A previous pregnancy of the same patient was terminated at 22 weeks of gestation because of severe micromelia, spinal abnormalities, talipes equinovarus and abducted thumbs and toes. At post‑mortem examination, atelosteogenesis type II was diagnosed.
The ultrasound diagnosis of atelosteogenesis type II is probably easier than that of type I because of the suggested autosomal recessive inheritance.
1. Kozlowski K, Tsuruta T, et al. New forms of neonatal dwarfism. Report of 3 cases. Pediatr Radiol 10: 155‑160, 1981.
2. Maroteaux P, Spranger J, Stanescu V, et al. Atelosteogenesis. Am J Med Genet 13: 15‑25, 1982.
3. Sillence DO, Lachman RS, et al. Spondylohumerofemoral hypoplasia (Giant cell chondrodysplasia): a neonatally lethal short‑limb skeletal dysplasia. Am J Med Genet 13: 7‑14, 1982.
4.Yang SS, Roskamp J, et al. Two lethal chondrodysplasias with giant chondrocytes. Am J Med Genet 15: 615‑625, 1983.
5. Kozlowski K, Bateson EM. Atelosteogenesis. ROEFO 140: 224‑225, 1984.
6.McAlister WH, Crane JP, et al. A new neonatal short limbed dwarfism. Skeletal Radiol 13:271‑275, 1985.
7. Chervenak FA, Isaacson G, et al. Antenatal diagnosis of frontal cephalocele in a fetus with atelosteogenesis. J Ultrasound Med 5: 111‑113, 1986.
8. Sillence DO, Kozlowski K, et al. Atelosteogenesis: evidence for heterogeneity. Pediatr Radiol 17: 112‑118, 1987.
9. Herzberg AJ, Effmann EL, Bradford WD. Variant of atelosteogenesis? Report of a 20‑week fetus. Am J Med Genet 29: 883‑890, 1988.
10. Stern HJ, Graham JM, Lachman RS, et al. Atelosteogenesis type Ill: a distinctive skeletal dysplasia with features overlapping atelosteogenesis and oto‑palato‑digital syndrome type 11. Am J Med Genet 36: 183‑195, 1990.
11. Temple K, Hall CA, et al. A case of atelosteogenesis. J Med Genet 27: 194‑197, 1990.
12. Nores JA, Rotmensch S, Romero R, et al. Atelosteogenesis type 11: sonographic and radiological correlation. Prenat Diagn 12:741‑753, 1992.
13. Hunter AGW, Carpenter BF. Atelosteogenesis I and boomerang dysplasia: a question of nosology. Clin Genet 39: 471‑480, 1991.
14. Brons JTJ,van der Harten HJ. Skeletal dysplasias ‑ Pre‑ and postnatal identification. An ultrasonographic, radiologic and pathologic study, Academic Thesis “All in” BV, Amsterdam, 1988.
15. Romero R, Pilu G, Jeanty P, et al. Prenatal diagnosis of congenital anomalies. Appleton & Lange, p. 340‑341, 1988.
16. Buyse ML, MD. Birth Defects Encyclopedia, Blackwell Scientific Publications, p. 207‑208, 1990.