SUMMARY Review of 10 cases of asphyxiating thoracic dysplasia has shown a wide range of clinical effects and some variability in the radiographic features. Respiratory difficulty was severe in 7 babies and lethal in 6 of these. The seventh child is remarkable for his normal stature and excellent health at 15 years of age. 3 babies had no respiratory difficulty but 2 of them subsequently died of renal failure; one remains alive at 3 years. Microscopical abnormalities in the liver and kidneys were very frequent and appeared to increase progressively with age.

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We report on the largest long-term follow-up study in metatropic dysplasia incorporating data collected over a 37-year period. Case summaries from 11 patients are presented, ranging from 20 weeks of gestation to age 70 years, characterizing the natural history. All patients were seen through the Victorian Clinical Genetics Service and the Southern Cross Bone Dysplasia Centre. Our data lend little support for the current clinical classification of metatropic dysplasia and highlight a spectrum of severity in this rare condition, which we propose has an autosomal dominant inheritance pattern. Complications such as upper respiratory obstruction secondary to laryngo-tracheal dysfunction need to be carefully monitored for in infancy because this is a preventable cause of mortality. The progression of a thoracic kyphoscoliosis in this condition is often relentless and resistant to surgical treatment. Other causes of morbidity include cervical instability, hearing loss, and functional impairments resulting from degenerative joint deformity. Intellectual outcome in all surviving cases has been normal. Final adult heights ranged from 107 to 135 cm.

The evolutionarily conserved hedgehog (Hh) pathway is essential for organogenesis and plays critical roles in postnatal tissue maintenance and renewal. A unique feature of the vertebrate Hh pathway is that signal transduction requires the primary cilium (PC) where major pathway components are dynamically enriched. These factors include smoothened (SMO) and patched, which constitute the core reception system for sonic hedgehog (SHH) as well as GLI transcription factors, the key mediators of the pathway. Here, we report biallelic loss-of-function variations in SMO in seven individuals from five independent families; these variations cause a wide phenotypic spectrum of developmental anomalies affecting the brain (hypothalamic hamartoma and microcephaly), heart (atrioventricular septal defect), skeleton (postaxial polydactyly, narrow chest, and shortening of long bones), and enteric nervous system (aganglionosis). Cells derived from affected individuals showed normal ciliogenesis but severely altered Hh-signal transduction as a result of either altered PC trafficking or abnormal activation of the pathway downstream of SMO. In addition, Hh-independent GLI2 accumulation at the PC tip in cells from the affected individuals suggests a potential function of SMO in regulating basal ciliary trafficking of GLI2 when the pathway is off. Thus, loss of SMO function results in abnormal PC dynamics of key components of the Hh signaling pathway and leads to a large continuum of malformations in humans.