Thanatophoric Dysplasia

TD (OMIM 187600, 187610) manifests before or at birth. In the former situation, ultrasonographic examination in midgestation or later reveals a large head and very short limbs; the pregnancy is often accompanied by polyhydramnios and premature delivery. Very short limbs, short neck, long narrow thorax, and large head with midfacial hypoplasia dominate the clinical phenotype at birth (Fig. 687-1). The cloverleaf skull deformity known as kleeblattschädel is sometimes found. Newborns have severe respiratory distress because of their small thorax. Although this distress can be treated by intense respiratory care, the long-term prognosis is poor.

Figure 687-1 Stillborn infant with thanatophoric dysplasia. Limbs are very short, with upper limbs extending only two thirds of the way down the abdomen. The chest is narrow, exaggerating the protuberance of the abdomen. The head is relatively large.

Skeletal radiographs distinguish two slightly different forms called TD I and TD II. In the more common TD I, radiographs show large calvariae with a small cranial base, marked thinning and flattening of vertebral bodies visualized best on lateral view, very short ribs, severe hypoplasia of pelvic bones, and very short and bowed tubular bones with flared metaphyses (Fig. 687-2). The femurs are curved and shaped like a telephone receiver. TD II differs mainly in that there are longer and straighter femurs.

Figure 687-2 A, Neonatal radiograph of a child with thanatophoric dysplasia. Note medial acetabular spurs (arrow), hypoplastic iliac bones, bowed femora with rounded protrusion of proximal femurs, hypoplastic thorax, and wafer-thin vertebral bodies. B, Lateral radiograph of the thoracolumbar spine in thanatophoric dysplasia, showing marked vertebral flattening and short ribs. Ossification defect of the central portion of the vertebral bodies is present.

The TD II clinical phenotype is associated with mutations that map to codon 650 of FGFR3, causing the substitution of a glutamic acid for the lysine. This activates the tyrosine kinase activity of a receptor that transmits signals to intracellular pathways. Mutation of lysine 650 to methionine is associated with a clinical phenotype intermediate between TD and achondroplasia, referred to as severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN). Mutations of the TD I phenotype map mainly to two regions in the extracellular domain of the receptor, where they substitute cysteine residues for other amino acids. Free cysteine residues are thought to form disulfide bonds promoting dimerization of receptor molecules, leading to activation and signal transmission.