Thanatophoric Dysplasia

Derived from the word thanatophorus (meaning "death-bearing"), thanatophoric dysplasia is a lethal genetic disease [1] [2] [3]. Appearing in approximately 1 per 20,000 births, it arises as a result of mutations in the fibroblast growth factor receptor 3 (FGFR3) gene, located on the short arm of chromosome 4 [2] [4]. The prognosis is quite poor, as the majority of neonates die during the first few hours of life, the most common cause being hypoplasia of the lungs and subsequent respiratory distress [1] [4] [5]. Rare reports have documented patients who managed to survive through infancy and reach adulthood [4]. The clinical presentation is distinguished by the appearance of skeletal and central nervous system malformations, and two subtypes have been described in the literature [1] [3]. Disproportionately short extremities that are bowed in type 1, but often straight in type 2, as well as a narrow thoracic cage (and consequent underdevelopment of the lungs) with very short ribs, platyspondyly (flat and immature vertebrae, more severely encountered in type 1 patients), and a very large head are main skeletal features [1] [2] [3] [4]. The pelvic girdle is particularly smaller, whereas a depressed nasal bridge and a prominent forehead are also reported [1] [2]. On the other hand, premature fusion of sutures in the brain (termed cloverleaf skull deformity) is one of the main central nervous system (CNS) manifestations of thanatophoric dysplasia, principally affecting the temporal lobes [2] [3] [6]. In addition, dysplasia of hippocampus, megalencephaly, ventriculomegaly, and abnormal enlargement of the temporal lobes are common [3] [6].

Despite the disorder being life threatening, early recognition is vital. A detailed patient history, a comprehensive physical examination, and the use of imaging studies are the necessary steps in identifying this skeletal disorder. However, the role of prenatal ultrasonography, is perhaps pivotal, due to its ability to identify skeletal and CNS manifestations prenatally. One of the signs associated with an increased risk of developing thanotophoric dysplasia by several authors is the presence of polyhydramnios [1] [3]. The detection of a cloverleaf-shaped deformity of the skull, hypoplasia of the rib cage, limb length abnormalities, as well as flattening of the vertebrae and other associated skeletal or CNS changes can be visualized on standard ultrasonography during the second trimester [2] [5]. Postnatal assessment, if possible, mandates the use of plain X-rays, that will show very short (bowed or straight, depending on the subtype) long bones and shrunken vertebrae with wide intervertebral spaces [3]. As the exact type of dysplasia cannot be determined solely on clinical and imaging criteria, genetic studies should be implemented in order to make a definite diagnosis.

1. Dighe M, Fligner C, Cheng E, Warren B, Dubinsky T. Fetal skeletal dysplasia: an approach to diagnosis with illustrative cases. Radiographics. 2008;28(4):1061-1077.
2. Sahinoglu Z, Uludogan M, Gurbuz A, Karateke A. Prenatal diagnosis of thanatophoric dysplasia in the second trimester: ultrasonography and other diagnostic modalities. Arch Gynecol Obstet. 2003;269:57–61.
3. Miller E, Blaser S, Shannon P, Widjaja E. Brain and bone abnormalities of thanatophoric dwarfism. AJR Am J Roentgenol. 2009;192(1):48-51.
4. Nikkel SM, Major N, King WJ. Growth and development in thanatophoric dysplasia – an update 25 years later. Clin Case Rep. 2013;1(2):75-78.
5. Machado LE, Bonilla-Musoles F, Osborne NG. Thanatophoric dysplasia. Ultrasound Obstet Gynecol. 2001;18:85-86.
6. Hevner RF. The cerebral cortex malformation in thanatophoric dysplasia: neuropathology and pathogenesis. Acta Neuropathol. 2005; 110:208-221.