Thanatophoric Dysplasia

THANATOPHORIC DYSPLASIA

Kliegman: Nelson Textbook of Pediatrics, 18th ed.

ACHONDROPLASIA GROUP

THE achondroplasia group represents a substantial percentage of patients with chondrodysplasias and contains thanatophoric dysplasia (TD), the most common lethal chondrodysplasia with an incidence of 1/35,000 births; achondroplasia, the most common nonlethal chondrodysplasia with an incidence of 1/15,000 to 1/40,000 births; and hypochondroplasia. All three have mutations in a small number of locations in the FGFR3 gene. There is a strong correlation between the mutation site and the clinical phenotype.

TD presents 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 . The cloverleaf skull deformity known as kleeblattschödel 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 694-1 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 . The femurs are curved and shaped like a telephone receiver. TD II differs mainly in that there are longer and straighter femurs.

Figure 694-2 A, Neonatal radiograph of a child with thanatophoric dysplasia. Note medial acetabular spus (black 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 FGFR 3, 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 or 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.

TD I and TD II represent new mutations to normal parents. The recurrence risk is low. Because the mutated codons in TD are mutable for unknown reasons and because of the theoretical risk of germ cell mosaicism, parents are offered prenatal diagnosis for subsequent pregnancies.

Gabbe: Obstetrics: Normal and Problem Pregnancies, 5th ed.

Thanatophoric dysplasia is the most common lethal skeletal dysplasia. In this condition, there is extreme shortening of the long bones. The femur is often bowed, resembling a telephone receiver . The fetus has a small, narrow chest that results in lethal pulmonary hypoplasia . The abdomen and head appear relatively enlarged. In about one of six cases, the head has a cloverleaf shape. Hydrocephalus and polyhydramnios are common.

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