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PubMed2006

Morphometric determinants of the sagittal dimensions of the cervical spinal canal in achondroplasia: an analysis of the reliability of the Torg ratio.

This study was undertaken to evaluate the accuracy of the Torg ratio for predicting the spinal canal stenosis in achondroplasia, by trying to establish its correlation with the corresponding effective sagittal canal diameter (ESCD) and dural sac ratio (DSR) on the MRI of the cervical spine. Lateral radiographs and the sagittal and axial MRI study of the cervical spine from C3 to C7 level were carried out in 18 asymptomatic achondroplasia subjects. A total of 90 levels were evaluated on the lateral radiographs and on the mid sagittal T2 MR images. On statistic analysis, the highest correlation coefficient for the Torg ratio compared with the ESCD was 0.74 at C6 level and the least was 0.45 at the C5 level. The highest correlation coefficient between the Torg ratio and the DSR was 0.79 at C3 level and the least was 0.42 at the C5 level. The highest coefficient of determination for the ESCD was 54% at C6 which translates into a poor correlation. The highest coefficient of determination for the DSR was 62 at C3 level, indicating a variable correlation. These results clearly show that the Torg ratio is of limited value in the assessment of the true sagittal spinal canal diameter in achondroplasia and its reliability as an indicator of severe cervical canal stenosis is questionable.

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PubMed2004

Constitutive activation of MEK1 in chondrocytes causes Stat1-independent achondroplasia-like dwarfism and rescues the Fgfr3-deficient mouse phenotype.

We generated transgenic mice that express a constitutively active mutant of MEK1 in chondrocytes. These mice showed a dwarf phenotype similar to achondroplasia, the most common human dwarfism, caused by activating mutations in FGFR3. These mice displayed incomplete hypertrophy of chondrocytes in the growth plates and a general delay in endochondral ossification, whereas chondrocyte proliferation was unaffected. Immunohistochemical analysis of the cranial base in transgenic embryos showed reduced staining for collagen type X and persistent expression of Sox9 in chondrocytes. These observations indicate that the MAPK pathway inhibits hypertrophic differentiation of chondrocytes and negatively regulates bone growth without inhibiting chondrocyte proliferation. Expression of a constitutively active mutant of MEK1 in chondrocytes of Fgfr3-deficient mice inhibited skeletal overgrowth, strongly suggesting that regulation of bone growth by FGFR3 is mediated at least in part by the MAPK pathway. Although loss of Stat1 restored the reduced chondrocyte proliferation in mice expressing an achondroplasia mutant of Fgfr3, it did not rescue the reduced hypertrophic zone, the delay in formation of secondary ossification centers, and the achondroplasia-like phenotype. These observations suggest a model in which Fgfr3 signaling inhibits bone growth by inhibiting chondrocyte differentiation through the MAPK pathway and by inhibiting chondrocyte proliferation through Stat1.

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PubMed1977

A new estimate of the achondroplasia mutation rate.

An estimate is derived of the mutation of achondroplasia based upon the accumulated data of recent newborn studies in four cities. In a total of 242,257 births, seven infants had mutant achondroplasia, the diagnosis being confirmed radiologically in all but one. From this, the rate of mutation of the normal to the achondroplasia allele is calculated to be 1.4 x 10(-5) +/- standard error 0.5 x 10(-5). Certain shortcomings of this estimate are discussed.

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PubMed1990

Bes, Aesop and Morgante: reflections of achondroplasia.

The past perception of achondroplasia is reflected in art, beginning about 2000 B.C. Achondroplasia is thought to have provided a model for the representation of a series of figures including the Egyptian god Bes, the Greek teller of fables Aesop, and the Renaissance giant of fiction Morgante. Since these figures were basically viewed as good, the hypothesis is advanced that achondroplasia was perceived as a positive, not a negative, condition during at least part of the past four millenia.

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PubMed1991

Growth-promoting effect of human growth hormone on patients with achondroplasia.

To evaluate the effect of human growth hormone (hGH) on the growth of children with achondroplasia, three patients with achondroplasia and one patient with hypochondroplasia were treated with 0.5 IU/kg/W of pituitary-extracted hGH for 6-12 months. Mean height velocity was significantly increased from 4.0 +/- 0.4 to 7.5 +/- 0.7 cm/year (P less than 0.05) by hGH. The tibial index, defined as the length/width ratio of left tibia, did not change during the treatment, indicating that hGH promotes growth without exaggeration of tubular bone deformity. Case 2, who had atlantoaxial dislocation, developed sleep apnea and neurological deficits during the second hGH treatment, but these were cured by operation. Thus, hGH therapy is effective in promoting growth in patients with achondroplasia, but the complication of atlantoaxial dislocation should be explored and corrected before the treatment.

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PubMed1996

Achondroplasia in Sweden caused by the G1138A mutation in FGFR3.

Achondroplasia, an autosomal dominant inherited disorder, is one of the most common forms of skeletal dysplasia resulting in disproportionate extreme shortness. Recently, two point mutations, both affecting nucleotide 1138 in the fibroblast growth factor receptor type 3 (FGFR3) gene, were found to be the cause of the disorder. We investigated DNA from 16 Swedish patients with achondroplasia for the presence of these mutations. All patients were found to be heterozygous for the G to A transition at nucleotide 1138. Our data thus support previous reports showing a striking genetic homogeneity, in that almost all achondroplasia patients have the FGFR3 G380R mutation at the protein level.

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PubMed1996

Common mutations in the gene encoding fibroblast growth factor receptor 3 account for achondroplasia, hypochondroplasia and thanatophoric dysplasia.

The mapping of the achondroplasia locus to the short arm of chromosome 4 and the subsequent identification of a recurrent missense mutation (Gly380Arg) in the gene encoding fibroblast growth factor receptor 3 (FGFR-3) has been followed by the detection of common FGFR-3 mutations in two clinically related disorders: thanatophoric dysplasia (TD; types I and II) and hypochondroplasia. The relative clinical homogeneity of achondroplasia was substantiated by demonstration of its genetic homogeneity: 100% of patients examined exhibited mutations in the transmembrane domain of FGFR-3. Although most cases of hypochondroplasia were accounted for by a recurrent missense substitution (Asn540Lys) in the first tyrosine kinase domain of FGFR-3, a significant proportion (40%) of the patients in the present study did not possess this Asn540Lys mutation. Furthermore, in three families with hypochondroplasia, the genetic defect was not linked to the FGFR-3 locus, thus supporting the clinical heterogeneity of this disease. In TD, a recurrent mutation located in the second tyrosine kinase domain of FGFR-3 has been detected in all TDII patients. By contrast, seven distinct mutations in three different protein domains were identified in 25 out of 26 TDI patients in this study. This suggests that TD, like achondroplasia, is a genetically homogeneous skeletal disorder.

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PubMed2005

Growth hormone treatment in 35 prepubertal children with achondroplasia: a five-year dose-response trial.

BACKGROUND: Achondroplasia is a skeletal dysplasia with extreme, disproportionate, short stature. AIM: In a 5-y growth hormone (GH) treatment study including 1 y without treatment, we investigated growth and body proportion response in 35 children with achondroplasia. METHODS: Patients were randomized to either 0.1 IU/kg (n = 18) or 0.2 IU/kg (n = 17) per day. GH treatment was interrupted for 12 mo after 2 y of treatment in prepubertal patients to study catch-down growth. Mean height SDS (HSDS) at start was -5.6 and -5.2 for the low- and high-dose groups, respectively, and mean age 7.3 and 6.6 y. RESULTS: Mean growth velocity (baseline 4.5/4.6 cm/y for the groups) increased significantly by 1.9/3.6 cm/y during the first year and by 0.5/1.5 cm/y during the second year. During the third year, a decrease of growth velocity was observed at 1.9/1.3 cm/y below baseline values. HSDS increased significantly by 0.6/0.8 during the first year of treatment and in total by 1.3/1.6 during the 5 y of study. Sitting height SDS improved significantly from -2.1/-1.7 to -0.8/0.2 during the study. Body proportion (sitting height/total height) or arm span did not show any significant change. CONCLUSION: GH treatment of children with achondroplasia improves height during 4 y of therapy without adverse effect on trunk-leg disproportion. The short-term effect is comparable to that reported in Turner and Noonan syndrome and in idiopathic short stature.

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PubMed1979

Achondroplasia and hypochondroplasia. Comments on frequency, mutation rate, and radiological features in skull and spine.

An attempt was made to ascertain all the dwarfs in the State of Victoria. The incidence of achondroplasia proved to be approximately 1 in 26,000 live births in the period 1969 to 1975 when ascertainment was nearly complete. This indicates a mutation rate of 1.93 X 10(-5) per generation in this locus. Paternal age was shown to influence mutation. Ascertainment in earlier years of the study was low despite the very great effort made to find all cases. Patients with hypochondroplasia were particularly difficult to find. However, 25 cases were found for study. Overlap between hypochondroplasia and achondroplasia was found in all features except the facial appearance (which was the basis of definition). Achondroplasia was more severe in all regards, but some individuals with hypochondroplasia were very short and some had extreme degrees of spinal canal stenosis. The classical measurements used to describe the skull changes in acondroplasia failed to distinguish this condition from hypochondroplasia. More efficient indices were devised, but visual assessment of the size of the facial region compared to that of the cranial valult proved more reliable than any index. The clinical distinction based upon facial appearance remains the arbitrary basis of definition.

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PubMed2000

Growth hormone therapy in achondroplasia.

Achondroplasia is one of the most common causes of severe rhizomelic dwarfism. We have previously reported the growth-promoting effect of growth hormone (GH) in this disorder. In this expanded clinical study, dose dependency and the long-term effect of GH were also investigated. Prepubertal children with achondroplasia (82 males and 63 females) were randomly divided into 2 groups. Patients were treated with 0.5 IU/kg per week or 1.0 IU/kg per week subcutaneous recombinant human GH. Of 75 patients, the mutational analysis of fibroblast growth factor receptor-3 revealed that G1138A was detected in 70 and G1138C was found in 2. GH increased growth rate and height z score in a dose-dependent manner. GH also increased serum insulin-like growth factor (IGF)-I, IGF-binding protein-3 and osteocalcin. No adverse effects were observed in either group. We conclude that GH therapy is a useful method for improvement of severe growth retardation of achondroplasia.

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PubMed1996

Short-term recombinant human growth hormone treatment increases growth rate in achondroplasia.

To investigate the effect of recombinant hGH treatment on the growth rate and proportion of individuals with achondroplasia and hypochondroplasia, we studied 15 individuals with these common skeletal dysplasias. The study lasted 24 months and included 6 months of observation, 12 months of hGH therapy (0.04 mg/kg.day), and 6 months of posttreatment growth rate determination. In achondroplasia, the mean growth rate during the hGH treatment (5.3 +/- 1.6 cm) was significantly increased compared with that during the pretreatment (4.0 +/- 1.0 cm.yr, P < 0.01)) and posttreatment periods (3.1 +/- 1.3 cm; P < 0.001). In the 4 children with hypochondroplasia, the growth rate during hGH treatment was 7.0 +/- 2.4 cm/yr and 4.9 +/- 1.5 cm/yr during the pre- and posttreatment periods, respectively. In achondroplasia, there was a significant increase in growth rate of only the lower segment (from 1.1 +/- 1.6 cm/yr to 3 +/- 1.2 cm/yr, P < 0.02). There was no significant acceleration in the growth of the upper segment and of the scanogram measurements of the long bones. No untoward effects were noted. Recombinant hGH increases short-term growth velocity in children with achondroplasia/hypochondroplasia. Unexpectedly, this treatment does not seem to have a lesser effect on limbs than on trunk growth rate and, therefore, during 1 yr of treatment, does not increase body disproportion.

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PubMed1981

Achondroplasia and hypochondroplasia. Clinical variation and spinal stenosis.

Forty-eight patients with achondroplasia and 24 with hypochondroplasia have been reviewed in order to clarify the differences between the two disorders and establish the height, body proportions and other clinical and radiological variations within each group. Some of the "classical" findings in achondroplasia are not always present, and hypochondroplasia at its most severe is indistinguishable from achondroplasia at its least severe. The frequency of spinal stenosis and neurological complications was established in an unselected group of 27 achondroplastic and 12 hypochondroplastic patients aged 10 years and over. Only three of the former were free of symptoms but only three developed serious complications (11 per cent). Measurement of radiographs of the lumbar canal did not in general correlate well with the severity of spinal stenosis symptoms, but it was found that the ratio of interpedicular distances at the first and fourth lumbar vertebrae had some value. Neurological complications were rare in patients with simple narrowing of the spinal canal or with persistence of a thoracolumbar kyphos but when these occurred together there was a high risk of serious neurological involvement.

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PubMed1988

Spirometry and chest wall dimensions in achondroplasia.

Standard values for pulmonary function in short-limbed dwarfism are not available. Therefore, chest diameters and expiratory spirograms were measured in 58 female and 44 male subjects between 7 and 60 years of age with achondroplasia, the most common form of dwarfism. Standing height in adults was 49.6 +/- 3.2 (SD) inches with a sitting/standing height ratio of 0.66 (normal 0.52-0.53). Despite extremely short stature, only AP chest diameters in males were smaller than control subjects of similar age. The following equations were derived for forced vital capacity (FVC): males (under 25 years), FVC(L) = -3.56 + 0.162 X sitting height (in) + 0.067 X age (yrs); males (over 25 years), FVC(L) = -0.73 + 0.162 X sitting height (in) -0.047 X age (yrs); females (under 20 years), FVC(L) = -3.56 + 0.150 X sitting height (in) + 0.067 X age (yrs); females (over 20 years), FVC(L) = -1.92 + 0.150 X sitting height (in) -0.016 X age (years). Similar prediction equations were derived for FEV1 and FEF25-75%: FEV1/FVC % was 84.2 (+/- 6.5) for females and 88.0 (+/- 6.5) for males. We also compared the observed FVC measurements to values calculated using standing heights derived from the subject's sitting height, assuming a normal body proportion. The observed vital capacity in achondroplasia was only 67.6 (+/- 19.2) percent of that predicted for normally proportioned females and 72.4 (+/- 13.6) percent for males, suggesting reduced vital capacity in achondroplasia, due to reduced chest wall compliance or abnormal lung growth.

Achondroplasia↗
PubMed1990

The lungs and airways in achondroplasia. Do little people have little lungs?

Achondroplasia is a unique model of the effects of skeletal dysplasia and dwarfism on the respiratory system. We measured chest dimensions, spirometry, lung volumes, maximal expiratory flow volume curves, nasal and airways resistance, closing volume, maximal inspiratory/expiratory pressures, and tracheal area by acoustic reflection in 12 healthy subjects with achondroplasia. Anterior-posterior thoracic diameter was mildly reduced in men. Vital capacity for all subjects was 108 percent +/- 18.6 percent (SD) of that predicted for achondroplastic subjects, but was reduced when compared with values for people of average stature that were predicted, based on either sitting height or thoracic height. The reduction was relatively greater in male than in female subjects. The RV/TLC and FRC/TLC ratios were normal. Other measurements were similar to those in average-statured adults. We conclude that achondroplasia results in a reduction in vital capacity out of proportion to what would be expected if these subjects had normal limb size. Although the lungs may be small, they are functionally normal, as are the airways.

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PubMed1999

Whole body bone mass and body composition in a girl with achondroplasia, at ages 9 through 12.

A 9-yr-old white female with achondroplasia was one of a group of 773 children who were recruited for a study of the accumulation of whole body skeletal mass during four annual measurements. Measurements of bone, fat, and lean mass were obtained with a Hologic 1000W instrument. The following variables are used to compare the subject with the 130 healthy white girls who participated in the study: bone mineral content (BMC), bone mineral density (BMD), and bone mineral apparent density (BMAD). Ratios of BMC to weight or BMC to height, and BMD to weight or height, were also calculated. We found that the BMC of the subject was lower when compared to the reference group, but the ratios of BMC to weight or BMC to height were similar in both. BMD was also lower in the patient, but, when expressed in relation to height and weight, the ratios were similar or slightly higher in the case. BMAD was higher in the subject with achondroplasia at all ages. The subject had a lower percentage fat and higher percentage lean mass than the reference children. We conclude that the accumulation of bone mass in this subject with achondroplasia is appropriate for her reduced body size.

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PubMed2005

Health supervision for children with achondroplasia.

Achondroplasia is the most common condition associated with disproportionate short stature. Substantial information is available concerning the natural history and anticipatory health supervision needs in children with this dwarfing disorder. Most children with achondroplasia have delayed motor milestones, problems with persistent or recurrent middle-ear dysfunction, and bowing of the lower legs. Less often, infants and children may have serious health consequences related to hydrocephalus, craniocervical junction compression, upper-airway obstruction, or thoracolumbar kyphosis. Anticipatory care should be directed at identifying children who are at high risk and intervening to prevent serious sequelae. This report is designed to help the pediatrician care for children with achondroplasia and their families.

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PubMed2005

Arachnoid cyst resulting in tonsillar herniation and syringomyelia in a patient with achondroplasia. Case report.

Achondroplasia has been associated with varying degrees of cervicomedullary and spinal compression, although usually in the pediatric population. Large arachnoid cysts have also been found to result in tonsillar herniation and syringomyelia. The authors present the case of a patient with achondroplasia who presented with symptoms of foramen magnum compression and syringomyelia, and who was subsequently found to have a large posterior fossa arachnoid cyst. This 38-year-old woman with achondroplasia presented with an 8-month history of headache and numbness of the hands and fingers. Admission magnetic resonance (MR) imaging of the head and spine revealed a large arachnoid cyst in the posterior cranial fossa, a 6-mm tonsillar herniation consistent with an acquired Chiari malformation, and a large cervicothoracic syrinx. The patient was treated using suboccipital craniectomy, C-1 laminectomy, fenestration of the arachnoid cyst, and decompression of the acquired Chiari malformation with duraplasty. Surgical decompression resulted in improvement of the presenting symptoms, adequate decompression of crowding at the foramen magnum, and resolution of the syrinx. Although there was only partial reduction in the retrocerebellar cisternal space on follow-up MR imaging, no residual symptoms were related to this.

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PubMed1989

Foramen magnum decompression in an infant with homozygous achondroplasia. Case report.

Homozygous achondroplasia is a rare yet distinct clinical entity. Most infants succumb to an early death as a result of respiratory compromise due to upper airway obstruction, thoracic cage deformity, and/or cervicomedullary compression. The successful cervicomedullary decompression of a 16-week-old infant with homozygous achondroplasia is described. This report suggests that homozygous achondroplasia is not universally fatal and that these infants are potentially viable if managed by aggressive respiratory and surgical measures.

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