Mortality in babies with achondroplasia: Revisited

BACKGROUND: Natural history studies performed 30 years ago identifying higher mortality among children born with achondroplasia, a genetic dwarfing condition, resulted in clinical recommendations aimed at improving mortality in childhood. The objective of this study was to determine if mortality rates have changed over the past few decades. METHODS: Children born with achondroplasia during 1996 to 2003 were ascertained from the Texas Birth Defects Registry and matched with death certificate data from the Bureau of Vital Statistics through 2007. Infant and overall mortality rates, both crude and standardized to the 2005 (SMR₂₀₀₅) and 1975 (SMR₁₉₇₅) U.S. populations, were calculated. RESULTS: 106 children born with achondroplasia were identified. Four deaths were reported, with all occurring in the first year of life (mortality rate: 41.4 /1000 live‐births). Infant mortality was higher when standardized to the 2005 U.S. population (SMR₂₀₀₅:6.02, 95% CI:1.64–15.42) than the 1975 population (SMR₁₉₇₅:2.58, 95% CI:0.70–6.61). CONCLUSION: The higher SMR₂₀₀₅ compared with SMR₁₉₇₅, along with the fact that SMR₁₉₇₅ was nearly half that of a previous cohort reported 25 years ago (rate ratio: 0.53, 95% CI: 0.11–2.25), reflect a discrepancy in the changes in mortality in the overall population and in our cohort. Although an overall improvement in mortality, especially after the first year of life, is observed in our cohort, children with achondroplasia are still at a much higher risk of death compared with the general population. A longer follow‐up is needed to elucidate whether evaluation/intervention changes have resulted in significant improvement in long‐term survival among these patients. Birth Defects Research (Part A) 100:247–249, 2014. © 2014 Wiley Periodicals, Inc.     

FGFR3/fibroblast growth factor receptor 3 inhibits autophagy through decreasing the ATG12–ATG5 conjugate,leading to the delay of cartilage development in achondroplasia

FGFR3 (fibroblast growth factor receptor 3) is a negative regulator of endochondral ossification. Gain-of-function mutations in FGFR3 are responsible for achondroplasia, the most common genetic form of dwarfism in humans. Autophagy, an evolutionarily conserved catabolic process, maintains chondrocyte viability in the growth plate under stress conditions, such as hypoxia and nutritional deficiencies. However, the role of autophagy and its underlying molecular mechanisms in achondroplasia remain elusive. In this study, we found activated FGFR3 signaling inhibited autophagic activity in chondrocytes, both in vivo and in vitro. By employing an embryonic bone culture system, we demonstrated that treatment with autophagy inhibitor 3-MA or chloroquine led to cartilage growth retardation, which mimics the effect of activated-FGFR3 signaling on chondrogenesis. Furthermore, we found that FGFR3 interacted with ATG12–ATG5 conjugate by binding to ATG5. More intriguingly, FGFR3 signaling was found to decrease the protein level of ATG12–ATG5 conjugate. Consistently, using in vitro chondrogenic differentiation assay system, we showed that the ATG12–ATG5 conjugate was essential for the viability and differentiation of chondrocytes. Transient transfection of ATG5 partially rescued FGFR3-mediated inhibition on chondrocyte viability and differentiation. Our findings reveal that FGFR3 inhibits the autophagic activity by decreasing the ATG12–ATG5 conjugate level, which may play an essential role in the pathogenesis of achondroplasia.     

Dwarfism in Dexter cattle is not caused by the mutations in FGFR3 responsible for achondroplasia in humans

Dexter cattle carry a genetic defect causing a dwarf phenotype in the heterozygotes (Dx +/–), while homozygotes (Dx +/+) are stillborn with extreme shortening of limbs and gross craniofacial defects and are described as 'bulldog' calves. The heterozygous phenotype has been likened to achondroplastic dwarfism in humans (ACH), which has recently been shown to be the result of mutations in the transmembrane region of the fibroblast growth factor receptor 3 (FGFR3) gene. We have sequenced the transmembrane region of bovine FGFR3 from normal Dexter cattle (Dx -/-) and bulldog calves (Dx +/+). The sequence from both is identical and therefore excludes mutations in the transmembrane region of FGFR3 as the cause of Dexter dwarfism.     

Serum hyaluronidase aberrations in metabolic and morphogenetic disorders

Hyaluronidases are endo-glycosidases that degrade both hyaluronan (hyaluronic acid) (HA) and chondroitin sulfates. Deficiency of hyaluronidase activity has been predicted to result in a phenotype similar to that observed in mucopolysaccharidosis (MPS). In the present study, we surveyed a variety of patients with phenotypes similar to those observed in MPS, but without significant mucopolysacchariduria to determine if some are based on aberrations in serum hyaluronidase (Hyal-1) activity. The study included patients with well-characterized dysmorphic disorders occurring on genetic basis, as well as those of unkown etiology. The purpose of the study was to establish how wide spread were abnormalities in levels of circulating Hyal-1 activity. A simple and sensitive semi-quantitative zymographic procedure was used for the determination of activity. Levels of both beta-N-acetylglucosaminidase and beta-glucuronidase whose activities contribute to the total breakdown of hyaluronan (HA) were also measured, as well as the concentration of circulating HA. Among 48 patients with bone or connective tissue abnormalities, low levels of Hyal-1 activity were found in six patients compared to levels in 100 healthy donors (2.0-3.2 units/microL vs 6(+/- 1 SE) units/microL). These six patients exhibited a wide spectrum of clinical abnormalities, in particular shortened extremities: they included three patients with unknown causes of clinical symptoms, one patient with Sanfilippo disease, one of the seven patients with achondroplasia, and one with hypophosphotemic rickets. Normal levels of serum Hyal-1 activities were found in patients with Morquio disease, GM1 gangliosidosis, I cell-disease, 6 of the 7 patients with achondroplasia, Marfan's-syndrome and Ehlers-Danlos syndrome. No patient totally lacked serum Hyal-1 activity. Serum HA concentration was elevated in patients with Sanfilippo A and I-cell disease. Determination of serum and leukocyte Hyal-1 and serum HA may be useful to evaluate patients with metabolic and morphogenetic disorders.