The current case of the week showed two cases of the San Diego type of platyspondylic lethal dysplasia. Description, theory and sonographic findings of the condition are discussed below.

Definition

Skeletal dysplasias (or osteochondrodysplasias - CDD) comprise a heterogeneous group of disorders characterized by generalized abnormalities of skeletal growth and development. Of approximately 125 well described CDD, only about 50 are clinically apparent and identifiable at birth [1-2].

Lethal CDD are heterogeneous groups, with thanatophoric dysplasia (TD) and some variants, such as platyspondylic (PLSD) type San Diego (PLSD-SD), Torrance (PLSD-T) and Luton (PLSD-L). These last three entities show similar roentgenographic features and can be distinguished either by chondro-osseous histologic abnormalities [3-4] or by scapular anomalies.

Thanatophoric dysplasia (TD) is divided in 2 groups (TD1 and TD2), according to clinical, radiologic, and laboratory parameters, in particular, fibroblast growth factor receptor 3 (FGFR3) mutation [5-6].

Variants of the thanatophoric dysplasia differ in radiologic and chondro-osseous criteria.

Lethal platyspondylic dysplasias are severe disorders of bone growth. Affected patients have very short arms and legs, a small chest with short ribs, underdeveloped pelvic bones, and unusually short fingers and toes, called brachydactyly [7]. This disorder is also characterized by flattened spinal bones (platyspondyly), abnormal curvature of the spine, and abnormal scapulae [8].

We describe antenatal discovery of two cases of platyspondylic dysplasia type San Diego. We discuss platyspondylic dysplasias, especially their possible prenatal identification with 3D sonography and spiral CT.

Case report
 
Ms B.O. is a 30-year-old Mahoran patient. The couple is not consanguineous. Two (normal) children were born in 2001 and 2003.

First fetus

In 2005, the patient became pregnant. At 13 weeks of gestation, nuchal translucency was 3.4 mm (normal karyotype - 46, XY). The triple screen test (for AFP, β-hCG, and estriol), and the subsequent ultrasound were skipped.

At 33 weeks of gestation, short upper and lower limbs were discovered on the ultrasound exam. The patient was referred for a second opinion at 38 weeks of gestation. Macrocrania and micromelia were present. The facial profile did not show frontal bossing. Achondroplasia and achondrogenesis were excluded. Spiral CT showed platyspondyly. There was no sign of thanatophoric dysplasia.

At 38 weeks of gestation, caesarian delivery was chosen because of breech presentation. The infant weighed 3000 grams and died 3 hours after birth. Autopsy was refused.
X-rays confirmed platyspondyly with widened intervertebral disc spaces. Limbs were short and rhizomelic, with wide metaphyses. Scapulae were abnormal (with slightly increased pointing of the superior aspect). The thorax was narrow with broad short ribs. Brachydactyly was seen.

The diagnosis of lethal platyspondylic dwarfism, an autosomal-recessive osteochondrodysplasia, was suggested by the neonatologist.

Images 1, 2, 3, and 4: 38 weeks; short fetal bones can be seen.

Images 5, 6, 7, 8, 9, 10, and 11: Spiral CT images of the fetus - platyspondyly,  micromelia and macrocrania were evident. Note the shape of the scapulae on the image 4 - their shape is typical for the San Diego type of the platyspondylic dysplasia.

Image 12: Postnatal X-ray of the newborn showing platyspondyly with widened intervertebral disc spaces.

Images 13: Postnatal appearance of the newborn.

Second fetus

In 2006, the patient became pregnant. Nuchal translucency was 1 mm at 13 weeks of gestation. The triple test and the second ultrasound exam were skipped.

Ultrasound at 33 weeks of gestation showed severe micromelia. The patient was referred to our antenatal unit at 36 weeks of gestation. An abnormal face was seen as well as dysplastic ears. Narrow thorax was noted, with an isolated cardiomegaly. Short limbs were present. 3D sonography of the lower extremities was difficult due to breech presentation. 3D sonography of the spine was performed. Spiral CT scan showed micromelia and either platyspondyly.

We explained to the parents that the fetus probably had the same osteochondrodysplasia as their prior baby. Intrauterine death occurred at 38 weeks.

Clinical and radiologic examination confirmed the diagnosis of platyspondyly. Autopsy was refused by the parents. The final diagnosis was lethal dwarfism platyspondylic type 2, conforming with scapular criteria.

Images 14, 15, 16, 17: 36 weeks; 3D images of the abnormal fetal face (coarse face, flat fetal profile with low nasal bridge, and out-turned lips).

Images 18, 19, 20: 36 weeks; the image 18 showes prenasal edema and short nasal bone of the fetus. The image 19 (2D gray scale image) and 20 (3D image) show abnormal dysplastic ears of the fetus.

Images 21, 22: 36 weeks; the image 21 demonstrates narrow fetal thorax by comparing transverse sections of the fetal abdomen and thorax. Realative cardiomegaly can be seen (Images 21 and 22).

Images 23, 24: 36 weeks; the images show 3D representation of the fetal spine with platyspondyly.

Images 25, 26, 27, 28, 29, and 30: 36 weeks; the images show short fetal bones (micromelia) of the fetus.

Images 31, 32: 36 weeks; 3D images of the short upper fetal extremities.

Images 33, 34, and 35: 36 weeks; Spiral CT images of the fetus - micromelia and macrocrania can be seen.

Image 36: Postnatal X-ray of the newborn showing platyspondyly with widened intervertebral disc spaces. Note the shape of the scapulae typical for the San Diego type of the platyspondylic dysplasia.

Images 37, 38: Postnatal appearance of the stillbirth newborn.

Image 39: Schematic presentation of the characteristic radiographic appearance of the scapula in the different entities. The drawings are from the reported cases and therefore represent different ages. A - Luton type of PLSD; B - San Diego type of PLSD; C - Torrance type of PLSD; D - campomelic dysplasia; E - kyphomelic dysplasia; F - Antley-Bixler syndrome; G - SRP type II (Majewski); H - SRP type III (Verma-Naumoff). Adapted by: Mortier G.R., Rimoin D.L., Lachman R.S. The scapula as a window to the diagnosis of skeletal dysplasias. Pediatr Radiol 1997 ; 27(5) : 447-51.

History
 
Thanatophoric dysplasia is the most frequently occurring skeletal dysplasia, described by Maroteaux in 1967. TD type 1, with curved femora, is rarely combined with cloverleaf skull. TD type 2, with straight femora, is almost always associated with cloverleaf skull [9-10].

Nevertheless, at the end of the 1970s, heterogeneity was recognized in patients with thanatophoric dysplasia.  Three well-defined platyspondylic types of lethal neonatal short limb dwarfism (TD variants) were distinguished. In 1979, Horton et al identified two forms of platyspondylic dysplasia [5]. Because of their geographic discovery, the authors called these forms platyspondylic dysplasia, San Diego type and Torrance type. Winter and Thompson (1982) described another form (Luton type).

Differences between thanatophoric dysplasia and these three types of platyspondylic dysplasia are based on abnormal lesions in the endoplasmic reticulum of the chondrocytes, and on clinical and radiologic examination. Thanatophoric dysplasia and platyspondylic dysplasia San Diego type, however, have similar radiologic features, especially at less than 24 weeks of gestation, including micromelia, short ribs, severe platyspondyly, and similar femoral configurations [8].

In 1986, Koslowski described these unusual radiographic abnormalities: platyspondyly with unique shape of the vertebral bodies; shortening of the long bones without sign of rickets or metaphyseal dysplasia; marked shortening of well ossified short tubular bones; Schneckenbecken-like [German for “snail-like”] pelvis with tri-radiate acetabulum; pseudo-epiphysis of the right ulna, unusual shape of calcaneus; and periarticular calcifications [9].

Brodie, in 1999, suggested that the radiographic and cellular differences between thanatophoric dysplasia and the platyspondylic dysplasia San Diego type may be a consequence of other genetic factors, perhaps in the processing of mutant FGFR3 molecules within the rough endoplasmic reticulum [7].

Nomenclature
 
The origin of the term "platyspondyly" is Greek, platus (wide) and spondulos (vertebrae), meaning “wide vertebrae”.

The heterogeneous group of lethal platyspondylic dysplasias originally included thanatophoric dysplasia type 1 and type 2, as the most common forms of this condition as well as thanatophoric dysplasia"s variants San Diego type and Torrance-Luton type. 

Incidence

Incidence of skeletal dysplasias in the newborn is quite frequent (approximately 3–4.5 per 10.000). The overall frequency of skeletal dysplasias among perinatal deaths is to be about 9 per 1000 [1]. The most common disorders diagnosed are osteogenesis imperfecta, thanatophoric dysplasia, camptomelic dysplasia, and achondrogenesis type II [1].

The frequence of occurrence of thanatophoric dysplasia is approximately 0.6/10.000 births and 4/1000 perinatal deaths. Generally, thanatophoric dysplasia and achondrogenesis account for 60% of lethal skeletal dysplasias. Conversely, lethal platyspondylic dysplasia is very rare. A few affected individuals have been reported worldwide, frequently in newborns or later. Obviously, the prevalence of these lethal platyspondylic dysplasias is indeterminate, because these syndromes are really as yet unknown. 

Etiology
 
The etiology of platyspondylic dysplasia remains to determined. While most reports of platyspondylic dysplasia Torrance type describe sporadic and perinatally lethal cases, the presence of rare cases having longer survival times and dominant inheritance have been suggested recently. Platyspondylic dysplasia Torrance type is probably inherited in an autosomal dominant pattern. In some cases, an affected person inherits the mutation from one affected parent, but other cases may result from new mutations in the gene. These cases occur in people with no history of the disorder in their family.

However, platyspondylic dysplasia San Diego and Luton types seem to be recessive in transmission, as in our case. 

Pathogenesis
 
Platyspondylic dysplasias are a group of heterogeneous disorders including thanatophoric dysplasia and the variants of thanatophoric dysplasia (San Diego, Torrance and Luton type).

Thanatophoric dysplasia is the most common form, based on clinical and radiologic criteria and analysis of mutations in the FGFR3. Kitoh et al (1998) have recently identified FGFR3 mutations in platyspondylic dysplasias San Diego and Torrance types, which are identical to those found in thanatophoric dysplasia type 1, but the known thanatophoric dysplasia FGFR3 mutations were not found in the platyspondylic dysplasia Luton type and not in Schneckenbecken dysplasia. But other authors say that molecular studies in families with Torrance-Luton type did not disclose mutations in the FGFR3 coding region, suggesting that this type of platyspondylic dysplasia is not a variant of thanatophoric dysplasia. Nonetheless, platyspondylic Luton dysplasia is now considered to be a mild phenotypic variant of platyspondylic Torrance dysplasia.

Platyspondylic dysplasia Torrance type is one of a spectrum of chondroectodermal dysplasias caused by mutation in the COL2A111-12. This gene provides instructions for making a protein that forms type II collagen. Mutations in the COL2A1 gene interfere with the assembly of type II collagen molecules, resulting in a reduced amount of this type of collagen in the body. Instead of forming collagen molecules, the abnormal COL2A1 protein builds up in chondrocytes. These changes disrupt the normal development of bones and other connective tissues, leading to the skeletal abnormalities characteristic of platyspondylic dysplasia Torrance type. Its chondro-osseous histology is characterized by hypercellularity with slightly large chondrocytes in the resting cartilage and normal columnization, with incorporation of cartilage into bone at the chondro-osseous junction. 

Sonographic findings

The general radiologic characteristics of platyspondylic dysplasia include wafer-like vertebral bodies, severe hypoplasia of the lower ilia, extremely shortened long bones with ragged metaphyses, and bowing of the radius [13-14].

Platyspondylies share several skeletal changes differing from those of thanatophoric dysplasias types 1 and 2. The spine shows severe platyspondyly and the vertebral bodies are extremely hypoplastic, comparable with those seen in achondrogenesis type I and in the severe form of achondrogenesis type II. The posterior portion of the vertebral bodies is not ossified and is very thin.

The forehead is not prominent.

The rib cage is pear-shaped.

The scapulae differ from the platyspondylic dysplasia type1 [4].

The sacro-sciatic notches of the iliac bones are not narrow.

The femora do not have the "telephone receiver" appearance, which is characteristic in classic thanatophoric dysplasia.

3D sonography can provide better visualization of the spine. We can observe every vertebra and study the posterior elements.

Differential diagnosis
 
• Achondrogenesis: The facial profile is different.

• Achondroplasia: is the most common form of short-limbed dwarfism in humans (occurs 1/20000 live births). More than 90% of cases are sporadic. The facial profile is different as well.

• Thanatophoric dysplasia: is the principal differential diagnosis.

• Asphyxiant thoracic dysplasia: The thorax is very narrowed.

• Lethal Spondylo-epiphysis dysplasia.

• Schneckenbecken dysplasia: is an autosomal recessive illness, associated with poor vertebral mineralization, short limbs with severe angulation of the long bones, and platyspondyly [15]. The thorax is short and narrow. The characteristics are a snail-like configuration of the hypoplastic iliac bones; flat vertebral bodies in the antero-posterior view, but round in the lateral view. Antenatal and perinatal death has occurred in all reported cases [15]. Polyhydramnios is always present.

• Metatropic dysplasia: is a rare dysplasia, described by Maroteaux (1966), characterized by "changing" features during development. The main radiological features at birth are short and "dumb-bell" like metaphyses, irregular epiphyses and marked flattening of the vertebrae [16]. 

Associated anomalies

Hitoh et al write that metaphyseal cupping of the long bones is more severe and chondrocyte columns are better preserved in platyspondylic dysplasia San Diego type than in thanatophoric dysplasia [8].

Mortier showed that scapular sonography is important to identify platyspondylic dysplasia [14]. Some other authors found that the platyspondylic dysplasia Luton type differed radiographically from the San Diego type and Torrance type by the presence of two spikes at the inferior angle of the scapula. It is important to note that hypoplasia of the body of the scapula is characteristic for camptomelic dysplasia, but not for kyphomelic dysplasia, and is also present in Antley-Bixler syndrome, but not in platyspondylic dysplasia.

According to Moeglin, perhaps with spiral CT, and certainly with 3D sonography, we can have better visualization to discover this subtle sign [17]. 

Prognosis and management
 
As a result of serious skeletal problems, many infants with lethal platyspondylic dysplasia are born prematurely and are stillborn (as in our second case) or die shortly after birth from respiratory failure (as our first case).

In contrast to thanatophoric dysplasia type 1 and 2 and platyspondylic dysplasia San Diego type, the Torrance-Luton type with milder symptoms, is compatible with survival to adulthood.

Prenatal discovery of platyspondylic dysplasia is rare and needs precise examination. Parents must be informed about lethal prognosis of these osteochondrodysplasias. As Emerson wrote, "People only see what they are prepared to see", the intrauterine association of shortened long bones, abnormal profile, particular form of scapulae, and platyspondyly, will evoke the platyspondylic dysplasia diagnosis.

Spiral CT and 3D volume rendering allows sequential and systematic visualization of all the different parts of the fetal skeleton, in particular, rachis with coronal scans, and profile (with determination of inter-pedicular distance and measurement of the height of the vertebral bodies), thorax with exploration of the ribs, clavicles, and especially scapulae, pelvis (pubis and iliac bones, ischia) and long bones (epiphysis, metaphysis, diaphysis).

Documentation and classification by radiography and osteochondrohistology is essential, because it is the foundation for the geneticist to counsel the parents about the risk of recurrence. Molecular and biochemical research and classification will be certainly important in the near future. 

Thanks to

We wish especially to thank M. Dr Cormier, Hôpital Necker, Paris, who brought his specialized expertise to diagnose these forms of osteochondrodysplasias.

References

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