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PubMed2000

The neurological complications of achondroplasia.

The genetics of achondroplasia are discussed, and then the clinical features. The respiratory complications are only considered when related to the neurological ones which are the concern of this paper; and their effects on morbidity and mortality. Cervicomedullary compression can cause pain, ataxia, incontinence, apnea, and respiratory arrest. One of the signs can be progressive quadriparesis which can be a presenting symptom; and may be caused by a vascular lesion as well as by cord compression. Also nerve root compression in the neural foramina can cause symptoms and signs in the limbs. Enlargement of the head is a feature of achondroplasia. This may be due to subdural haematoma related to the wide subarachnoid spaces, and to trauma. Hydrocephalus is common, and may be non-communicating and due to aqueduct stenosis, but is much more often communicating and the result of raised intracranial venous pressure. Shunting may be necessary, but surgery directed towards relieving the venous pressure may be more logical. Otitis media often affects these children, and can cause deafness and subsequently delayed language development. Sleep disturbances can be the result of both neurological and respiratory complications. Apart from the treatment for hydrocephalus the most important decision is often the question of operating on the cervical medullary compression. Risk factors such as brisk reflexes, small foramen magnum, and central hypopnea, can be an indication for surgery; but timing can be difficult as the cord compression can resolve spontaneously. The intelligence levels of these children are usually normal, and studies have shown a surprisingly high level of satisfaction with the services provided.

Achondroplasia↗
PubMed2006

The achondroplasia mutation does not alter the dimerization energetics of the fibroblast growth factor receptor 3 transmembrane domain.

The Gly380 --> Arg mutation in the TM domain of fibroblast growth factor receptor 3 (FGFR3) of the RTK family is linked to achondroplasia, the most common form of human dwarfism. The molecular mechanism of pathology induction is under debate, and two different mechanisms have been proposed to contribute to pathogenesis: (1) Arg380-mediated FGFR3 dimer stabilization and (2) slow downregulation of the activated mutant receptors. Here we show that the Gly380 --> Arg mutation does not alter the dimerization energetics of the FGFR3 transmembrane domain in detergent micelles or in lipid bilayers. This result indicates that pathogenesis in achondroplasia cannot be explained simply by a higher dimerization propensity of the mutant FGFR3 TM domain, thus highlighting the importance of the observed slow downregulation in phenotype induction.

Achondroplasia↗
PubMed1994

The gene for achondroplasia maps to the telomeric region of chromosome 4p.

Achondroplasia is the most common type of genetic dwarfism. It is characterized by disproportionate short stature and other skeletal anomalies resulting from a defect in the maturation of the chondrocytes in the growth plate of the cartilage. We have now mapped the achondroplasia gene near the telomere of the short arm of chromosome 4 (4p16.3), by family linkage studies using 14 pedigrees. A positive lod score of z = 3.35 with no recombinants was obtained with an intragenic marker for IDUA. This localization will facilitate the positional cloning of the disease gene.

Achondroplasia↗
PubMed1996

Graded activation of fibroblast growth factor receptor 3 by mutations causing achondroplasia and thanatophoric dysplasia.

The longitudinal growth of the skeleton arises from the continuous process of endochondral ossification occurring at the ends of growing long bones. Dwarfism results when this process is disrupted, as in the autosomal dominant human skeletal diseases hypochondroplasia (HCH), achondroplasia (ACH) and thanatophoric dysplasia (TD). Interestingly, these disorders display a graded spectrum of phenotypic severity and are the result of distinct missense mutations in the fibroblast growth factor receptor 3 gene (FGFR3). TD, characterized by neonatal lethality and profound dwarfism, is the result of FGFR3 mutations, including an R248C substitution in the extracellular domain or a K650E substitution in the tyrosine kinase (TK) domain. ACH, which is non-lethal and presents less severe dwarfism, results almost exclusively from a G380R substitution in the transmembrane domain. Homozygous achondroplasia resembles the phenotype of TD. In this report the effect of the ACH and TD mutations on the activity and regulation of FGFR3 are analysed. We showed that each of the mutations constitutively activate the receptor, as evidenced by ligand-independent receptor tyrosine phosphorylation and cell proliferation. Moreover, the mutations that are responsible for TD were more strongly activating than the mutation causing ACH, providing a biochemical explanation for the observation that the phenotype of TD is more severe than that of ACH.

3T3 Cells↗
PubMed2003

Anaesthetic management of a patient with achondroplasia.

A 12-year-old girl diagnosed with achondroplasia was admitted for bilateral ear surgery and adenotonsillectomy. She had classical symptoms and signs of upper airway obstruction, which is often seen in patients with achondroplasia. We describe the anaesthetic management of this patient, emphasizing the airway difficulties encountered and their anaesthetic implications.

Achondroplasia↗
PubMed2005

First trimester increased nuchal translucency associated with fetal achondroplasia.

A 30-year-old woman, gravida 2, para 1, was referred for nuchal translucency, free beta-human chorionic gonadotropin (beta-hCG), and pregnancy-associated plasma protein A (PAPP-A) screening at 12 weeks gestation. The nuchal translucency was increased to 3.8 mm, resulting in a post-test result of 1:15 risk for Down syndrome by a combination of maternal age plus nuchal translucency, and 1:5 by a combination of maternal age plus nuchal translucency plus free beta-hCG plus PAPP-A. The patient underwent uncomplicated chorionic villus sampling that demonstrated a normal 46,XY fetus. The patient was then followed-up weekly by ultrasound. At 18 weeks gestation, generalized features of rhizomelic micromelia together with macrocrania and narrow thorax were seen. All fetal long bones were less than 2 standard deviations from the mean value. At that time, DNA analysis was performed on stored villi and a G380R mutation in the locus gene encoding for the fibroblast growth factor receptor 3 on chromosome 4p16.3 was found, leading to a prenatal diagnosis of achondroplasia. The couple opted for termination of pregnancy after counseling. Postmortem X-ray was done and confirmed the ultrasound diagnosis of achondroplasia. This is the second known case of increased nuchal translucency in the first trimester associated with prenatal confirmed diagnosis of fetal osteochondrodysplasia.

Abortion, Induced↗
PubMed1985

[Prenatal ultrasonic diagnosis of achondroplasia].

The pregnancy of a woman with achondroplasia was monitored by ultrasound from the 29th to the 38th week of gestation. Starting with the 29th week of gestation, there was a suspicion of the foetus having the same skeletal dysplasia. The following measurements were in the pathological range: the length of the upper arm, the humerus, the lower arm, the thigh, the femur, the leg, the tibia, as well as the maximal thigh diameter, the ratios of thigh diameter to crown-rump length and maximal thigh diameter to the biparietal diameter. Unsuspected head-rump measures associated with measurements, displayed an achondroplasia which had been discovered in the newborn.

Achondroplasia↗
PubMed1981

Ventricular size and intelligence in achondroplasia.

Of 10 children with macrocephaly in association with achondroplasia only two children had progressive hydrocephalus. They were treated with a shunt procedure. One of these is intellectually and neurologically normal, and one is wheelchair bound and mentally retarded, with a spastic quadraplegia. Three children showed mild dilatation of the ventricles and one of these died from severe constriction at the foramen magnum. The other two are neurologically normal; one is intellectually normal but below average (WISC 88) and the other is slow normal at 18 months of age. Four children with demonstrated megalencephaly and a fifth with probable megalencephaly are all intellectually and neurologically normal. Intelligence in achondroplasia appears to be mainly in the normal range.

Achondroplasia↗
PubMed2002

The observed human sperm mutation frequency cannot explain the achondroplasia paternal age effect.

The lifelong spermatogonial stem cell divisions unique to male germ cell production are thought to contribute to a higher mutation frequency in males. The fact that certain de novo human genetic conditions (e.g., achondroplasia) increase in incidence with the age of the father is consistent with this idea. Although it is assumed that the paternal age effect is the result of an increasing frequency of mutant sperm as a man grows older, no direct molecular measurement of the germ-line mutation frequency has been made to confirm this hypothesis. Using sperm DNA from donors of different ages, we determined the frequency of the nucleotide substitution in the fibroblast growth factor receptor 3 (FGFR3) gene that causes achondroplasia. Surprisingly, the magnitude of the increase in mutation frequency with age appears insufficient to explain why older fathers have a greater chance of having a child with this condition. A number of alternatives may explain this discrepancy, including selection for sperm that carry the mutation or an age-dependent increase in premutagenic lesions that remain unrepaired in sperm and are inefficiently detected by the PCR assay.

Achondroplasia↗
PubMed1998

Japanese sisters with Pfeiffer syndrome and achondroplasia: a mutation analysis.

The authors report the rare existence of a family that includes an older sister with Pfeiffer syndrome and a younger sister with achondroplasia. Gene analysis of these patients showed a T341P mutation in the FGFR2 gene in the patient with Pfeiffer syndrome, and a G380R mutation in the FGFR3 gene in the patient with achondroplasia. Both mutations have been reported previously. Their parents had no mutation in either locus. This result suggests the possibility that there may be predisposing factors for different FGFR mutations.

Achondroplasia↗
PubMed2000

Reoperation for spinal restenosis in achondroplasia.

The characteristics of spinal restenosis in achondroplasia and its treatment are evaluated in this study. Radiologic and surgical findings were correlated to establish the causes of achondroplastic spinal restenosis and the benefits of its therapy. Eight patients (five men, three women) with spinal restenotic complications of achondroplasia were studied. The most common neurological sign of recurrent stenosis was impaired motor function. The mean interval between the most recent surgeries was 8.2 years (9.5 years for surgeries at the same levels). The most common causes of recurrent stenosis were facet hypertrophy and disk disease. The complications were a dural tear and cerebellar hemorrhage in one patient and transient neurological deterioration in another. One patient died after operation. Restenosis can occur many years after original decompression in the achondroplastic spine, and repeated operation can successfully lessen pain and neurological symptoms in most patients.

Achondroplasia↗
PubMedDate not supplied

Spinal fusion for kyphosis in achondroplasia.

Persistent thoracolumbar kyphosis in patients with achondroplasia is typically prevented with sitting modifications and bracing. When the kyphosis persists and progresses despite bracing, spinal fusion is indicated to prevent further progression and neurologic complications. Previous reports have suggested that instrumentation in such patients carries a high risk of neurologic injury. The purpose of this study was to evaluate the safety and efficacy of a two-stage procedure to control progressive kyphosis in the patient with achondroplasia. The authors treated four such patients (4-8 years old) surgically. The first stage involved an anterior spinal fusion with instrumentation and a posterior spinal fusion, and the second stage involved an additional posterior fusion. There were no neurologic complications. Correction ranged from 23.0% to 31.25%. All patients achieved a solid fusion. These results suggest that when nonoperative treatments fail, this procedure for thoracolumbar kyphosis in the achondroplastic patient can be done safely and effectively.

Achondroplasia↗
PubMedDate not supplied

Multiplier method for prediction of adult height in patients with achondroplasia.

To date, the only way to predict adult height in achondroplastic dwarves has been to consult a growth chart. The purpose of this study was to ascertain whether the multiplier method of predicting adult height at skeletal maturity in healthy persons can be applied to persons with achondroplasia. Previous studies have shown that the multiplier method can be applied to lower limb length, upper limb length, total height, foot length, and foot height. It is therefore reasonable to suggest that the growth pattern for total height in achondroplastic dwarves might also be characterized by a multiplier. Total height multipliers for achondroplastic dwarves ("achondroplasia height multipliers") were calculated from two separate databases by dividing height at maturity by height at each respective age for both genders. Little variability was found among multipliers for each age and among multipliers calculated from different databases. Upper torso (sitting height) multipliers and lower limb multipliers were also derived for achondroplastic dwarves. Lower limb and total height growth rates were slower in achondroplastic dwarves compared with healthy persons. However, sitting height multipliers for achondroplastic dwarves were closely related to sitting height multipliers for healthy persons. Because these findings showed that the multiplier values were independent of population and percentile, the multiplier method may be a valid method for quickly predicting height at any age for achondroplastic dwarves.

Achondroplasia↗
PubMedDate not supplied

Analysis of lower extremity alignment in achondroplasia: interobserver reliability and intraobserver reproducibility.

This study was designed to evaluate the reliability and reproducibility of frontal plane malalignment measurements using the mechanical axis deviation method in achondroplasia and to determine whether the patient's age has any influence on these measurements. A total of 150 anteroposterior standing radiographs of the lower extremities were randomly selected for the study. Radiographs were divided into three groups according to age: group 1, younger than 6 years of age; group 2, 6 to 10 years of age; group 3, older than 10 years of age. Interobserver agreement for the medial proximal tibial angle and the lateral distal tibial angle measurements were poor (0.32 and 0.38, respectively) in group 1, but agreement increased between observers with increasing patient age. Good to excellent intraobserver reproducibility was found in all groups, except measurement of the medial proximal tibial angle in group 1, where the results were poor (0.36). Significant measurement errors in the proximal and distal tibial joint lines are possible in children less than 6 years of age with achondroplasia.

Achondroplasia↗
PubMedDate not supplied

Dynamic lower extremity alignment in children with achondroplasia.

The purpose of this study is to analyze lower extremity dynamic malalignment during gait using a 3-dimensional kinematics and kinetics in 13 children (3-17 years old) with achondroplasia and to compare measurements of alignment and malrotation between gait, radiographic, and clinical measures. Gait analysis in the coronal plane showed a varus malalignment of the knee (19 +/- 13 degrees) and variable tibial torsion abnormalities (13 [internal] +/- 15.7 degrees). Radiographs also showed knee varus malalignment (16 +/- 9 degrees); however, there was poor correlation with gait analysis measures (P > 0.05). In the sagittal plane, radiographs showed genu recurvatum deformity (23.5 +/- 13.2 degrees), although the sagittal plane knee kinematics were normal. Kinetic analyses of the knee showed high internal knee valgus moments (external varus moments, 0.48 +/- 0.25 N m/kg), which were significantly different from the normal population (P < 0.05). In conclusion, there is a 3-dimensional, complex, dynamic deformity of the lower extremity present in children with achondroplasia. We recommend a very careful assessment of the limb focusing on both the static and dynamic varus deformity and tibial torsion using a combination of radiographic, clinical, and gait analysis.

Achondroplasia↗
PubMedDate not supplied

Limb lengthening for achondroplasia: early experience.

Three adolescent patients underwent limb lengthening for achondroplasia by the DeBastiani technique. Average increase in length was 15.4 cm (37.7%) per limb. Bone formation was excellent, and there were no neurovascular complications or infections. Numerous problems were encountered during treatment, but there were only two residual complications in one patient. Soft tissue tension and contractures precluded further lengthening in each case. Thirty-five percent lengthening may be the maximum that can be safely achieved for achondroplasia, and though it may produce cosmetic and psychological benefits, the functional benefits may not justify the expense, morbidity, and risk of the procedure.

Achondroplasia↗
PubMed1982

Unexpected death of children with achondroplasia after the perinatal period.

This report describes six cases of achondroplasia, four of whom died unexpectedly in early childhood. Clinical details and pathological findings are reported. Unexpected death seems to be a feature of children with achondroplasia, and appears to be related to brain-stem lesions secondary to deformities of the foramen magnum and posterior fossa.

Achondroplasia↗
PubMed1993

Breathing abnormalities in sleep in achondroplasia.

Overnight sleep studies were performed in 20 subjects with achondroplasia to document further the respiratory abnormalities present in this group. Somatosensory evoked potentials (SEPs) were recorded in 19 of the subjects to screen for the presence of brainstem abnormalities, which are one of the potential aetiological mechanisms. Fifteen children aged 1 to 14 years, and five young adults, aged 20 to 31 years were included. All had upper airway obstruction and 15 (75%) had a pathological apnoea index (greater than five per hour). Other sleep associated respiratory abnormalities, including partial obstruction, central apnoea, and abnormal electromyographic activity of accessory muscles of respiration, also showed a high prevalence. SEPs were abnormal in eight (42%), but there was no correlation between abnormal SEPs and apnoea during sleep, either qualitatively or quantitatively. A high prevalence of both sleep related respiratory abnormalities and abnormal SEPs in young subjects with achondroplasia was demonstrated. However, the sleep related respiratory abnormalities do not always result in significant blood gas disturbances or correlate with abnormal SEPs in this group.

Achondroplasia↗