Thanatophoric dwarfism. A condition confused with achondroplasia in the neonate, with brief comments on achondrogenesis and homozygous achondroplasia.
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Achondroplasia↗
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Genetics clinics of The Johns Hopkins Hospital. Surgical intervention in achondroplasia. Cervical and lumbar laminectomy for spinal stenosis in achondroplasia.
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Genetics clinics of The Johns Hopkins Hospital. Surgical intervention in achondroplasia. Correction of bowleg deformity in achondroplasia.
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Living with achondroplasia in an average-sized world: an assessment of quality of life.
Mutations in the gene encoding fibroblast growth factor receptor 3 cause achondroplasia, the most common form of inherited skeletal dysplasia. Although there are more than 10,000 individuals with achondroplasia living in the United States, there has been little study of their quality of life (QOL). For this study, surveys were collected from 189 individuals affected with achondroplasia (ACH) and 136 unaffected first-degree relatives (FDRs) of affected individuals. Individuals affected with achondroplasia had lower annual income, less education, and were less likely to be married than FDRs. They also differed significantly in their perceptions of achondroplasia, with FDRs believing that achondroplasia is a more serious condition. Total QOL indices and indices in each of four QOL subdomains were significantly lower in affected individuals than in relatives. When controlling for demographic characteristics and affected status, having lower self-esteem scores and perceiving achondroplasia as more serious were the independent factors most highly associated with lower QOL. A qualitative analysis of open responses to questions about the advantages and disadvantages of achondroplasia revealed that individuals were as likely to cite disadvantages relating to social barriers as they were to cite those relating to health and functioning. We interpret the low QOL scores to reflect the social challenges that individuals with achondroplasia regularly experience in the average-sized world. Genetics professionals should consider sources of lower QOL for affected individuals in their counseling sessions to acknowledge the relative importance of non-medical contributions.
Achondroplasia↗
Living with achondroplasia: attitudes toward population screening and correlation with quality of life.
OBJECTIVES: Since the discovery of the gene that causes achondroplasia, population-wide prenatal screening for this condition has become a possibility. This study sought to assess attitudes toward screening for achondroplasia and correlation with quality of life in a population of individuals affected with achondroplasia and first-degree relatives. METHODS: Surveys were collected from 189 individuals affected with achondroplasia and 136 average-statured first-degree relatives. RESULTS: While 87% of all respondents would support the use of prenatal screening by affected parents at risk of having a fetus with the homozygous, lethal form of achondroplasia, 29% would support general population prenatal screening for achondroplasia. Attitudes supporting general population screening were more likely to be held by those people with less education, who were affected with achondroplasia, who supported abortion, and who believed that achondroplasia is a serious condition without any accompanying advantages (p<0.01). Those respondents who felt positively toward offering the prenatal test for individuals at risk for homozygous achondroplasia were more likely to have lower mean quality of life scores and to support abortion in general (p<0.05). CONCLUSION: These data suggest that opinions about prenatal screening are heterogeneous within this study population and are related to individuals' experiences and perceptions of the condition. Future research is needed to assess attitudes toward population screening and quality of life in communities of individuals affected with genetic conditions, both to support policy decisions and to inform the education and counseling provided in the prenatal setting.
Achondroplasia↗
Issues surrounding prenatal genetic testing for achondroplasia.
OBJECTIVES: Mutations in the gene encoding fibroblast growth factor receptor 3 cause achondroplasia, the most prevalent form of dwarfism. Since the discovery of the mutations and gene in 1994, commercial testing has been available for use in prenatal diagnosis. This study sought to determine the awareness of, interest in and use of prenatal genetic testing for achondroplasia. METHODS: Surveys were collected from both individuals affected with achondroplasia (n = 189) and their average statured relatives (n = 136). RESULTS: The majority of participants were aware of the prenatal genetic testing at the time they were surveyed, but less than 10% had actually used the testing. Affected individuals were much more interested in using the testing if they became pregnant (62%) than were their relatives (28%). The groups were remarkably similar in their interest in using the testing to identify the lethal, homozygous form of achondroplasia and in their unwillingness to consider termination of pregnancies based on a diagnosis of either achondroplasia or average stature. Affected status and perception of the condition were correlated with the importance placed on knowing the prenatal diagnoses of achondroplasia and average stature. Views on abortion were highly correlated with all aspects of interest in prenatal diagnosis for achondroplasia. CONCLUSION: These results elucidate the role of selected attitudes and beliefs that contribute to reproductive decision making about achondroplasia. Furthermore, the findings provide insights into education and counseling issues for families and health care practitioners.
Abortion, Induced↗
Sleep and upper airway obstruction in children with achondroplasia.
OBJECTIVE: The features of achondroplasia, the most common form of dwarfism, includes short cranial base and midface hypoplasia; both abnormalities increased the risk of upper airway obstruction during sleep. The aim of our study was to evaluate sleep and respiratory function of children with achondroplasia and to differentiate central from obstructive apnea. We also wanted to correlate apneic events with foramen magnum stenosis. STUDY DESIGN: Sixteen children with achondroplasia (mean age, 4.7 years) were studied by noctumal polysomnography and brain computed tomography or magnetic resonance imaging. A comparison of sleep and respiratory findings was made between the study group and 25 children with adenotonsillar hypertrophy. RESULTS: The study revealed no significant difference between groups with respect to sleep architecture. We also found no relationship between apnea type and foramen magnum stenosis. Twelve children (75%) with achondroplasia had significant upper airway obstruction during sleep, with symptoms of continuous snoring and periods of brief obstructive apnea, hypopnea, or both. The mean apneahypopnea index (per hour of sleep) did not differ significantly between the two groups. However, the breathing rate during sleep was increased in children with achondroplasia. These findings indicate that the most important breathing disorder during sleep in children with achondroplasia is upper airway obstruction. CONCLUSION: We conclude that polysomnography with detailed scoring of breathing abnormalities is a useful tool in evaluating sleep-disordered breathing in children with achondroplasia.
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Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia.
Achondroplasia, the most common cause of chondrodysplasia in man (1 in 15,000 live births), is a condition of unknown origin characterized by short-limbed dwarfism and macrocephaly. More than 90% of cases are sporadic and there is an increased paternal age at the time of conception of affected individuals, suggesting that de novo mutations are of paternal origin. Affected individuals are fertile and achondroplasia is transmitted as a fully penetrant autosomal dominant trait, accounting for rare familial forms of the disease (10%). In contrast, homozygous achondroplasia is usually lethal in the neonatal period and affects 25% of the offspring of matings between heterozygous achondroplasia parents. The gene responsible for achondroplasia has been mapped to chromosome 4p16.3 (refs 7, 8); the genetic interval encompassing the disease gene contains a member of the fibroblast-growth-factor receptor (FGFR3) family which is expressed in articular chondrocytes. Here we report the finding of recurrent missense mutations in a CpG doublet of the transmembrane domain of the FGFR3 protein (glycine substituted with arginine at residue 380, G380R) in 17 sporadic cases and 6 unrelated familial forms of achondroplasia. We show that the mutant genotype segregates with the disease in these families. Thus it appears that recurrent mutations of a single amino acid in the transmembrane domain of the FGFR3 protein account for all cases (23/23) of achondroplasia in our series.
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Nonrandom association of a type II procollagen genotype with achondroplasia.
Achondroplasia is an autosomal dominant disorder that involves defective endochondral bone formation. Type II collagen is the predominant collagen of cartilage. We found a HindIII polymorphic site in the normal Caucasian population by using the type II procollagen gene probe pgHCol(II)A. The presence of this site yields a 7.0-kilobase (kb) band; its absence yields a 14.0-kb band. We found a significant deviation in genotype distribution and allele frequencies in a population of unrelated individuals with sporadic achondroplasia, compared with the normal control population. The HindIII genotype frequencies in 32 individuals with achondroplasia are 0.41 for the 7/7 genotype (controls, 0.08), 0.34 for the 7/14 genotype (controls, 0.54), and 0.25 for the 14/14 genotype (controls, 0.37). The apparent equilibrium excess of the "7" allele in individuals with achondroplasia may reflect either a predisposition for the mutation that causes achondroplasia or it could be the result of the achondroplasia-causing mutation. In either case, these findings suggest an association of the type II procollagen gene with achondroplasia.
Achondroplasia↗
Mutations in fibroblast growth-factor receptor 3 in sporadic cases of achondroplasia occur exclusively on the paternally derived chromosome.
More than 97% of achondroplasia cases are caused by one of two mutations (G1138A and G1138C) in the fibroblast growth factor receptor 3 (FGFR3) gene, which results in a specific amino acid substitution, G380R. Sporadic cases of achondroplasia have been associated with advanced paternal age, suggesting that these mutations occur preferentially during spermatogenesis. We have determined the parental origin of the achondroplasia mutation in 40 sporadic cases. Three distinct 1-bp polymorphisms were identified in the FGFR3 gene, within close proximity to the achondroplasia mutation site. Ninety-nine families, each with a sporadic case of achondroplasia in a child, were analyzed in this study. In this population, the achondroplasia mutation occurred on the paternal chromosome in all 40 cases in which parental origin was unambiguous. This observation is consistent with the clinical observation of advanced paternal age resulting in new cases of achondroplasia and suggests that factors influencing DNA replication or repair during spermatogenesis, but not during oogenesis, may predispose to the occurrence of the G1138 FGFR3 mutations.
Achondroplasia↗
Fibroblast growth factor receptor-3 as a therapeutic target for Achondroplasia--genetic short limbed dwarfism.
Achondroplasia, the most common form of human dwarfism is a sporadic autosomal dominant condition that occurs in approximately 1:20,000 births. The major clinical outcome of Achondroplasia is attenuated growth, rhizomelic shortening of the long bones and craniofacial abnormalities. As of today there is no pharmacological treatment for Achondroplasia. Some improvement in the patients well being and daily function can be achieved by a surgical limb lengthening procedure. Growth hormone treatment seems to have only modest short term success and to lack long term benefits. Achondroplasia results from a single point mutation in Fibroblast Growth Factor Receptor 3 (FGFR3). In 97% of the patients, there is a Glycine to Arginine substitution at position 380 within the FGFR-3 transmembrane domain leading to receptor overactivation. This FGF receptor tyrosine kinase is expressed by chondrocytes in the growth plate of developing long bones and plays a crucial role in bone growth. Genetic disruption of the FGFR-3 gene in mice leads to a remarkable increase in the length of the vertebral column and long bones. This suggests that overaction of FGFR3 signaling may specifically impair chondrocyte function within the epiphyseal growth plates and cause Achondroplasia. Reconstituted normal bone growth may therefore be achieved by attenuation of FGFR3 signaling in the appropriate cells within the growth plate. It is highly conceivable that drug development strategies aimed either towards blocking extracellular ligand binding or towards intracellular checkpoints along the FGF signal transduction cascade, may prove successful in the treatment of Achondroplasia. This review focuses on the possible approaches for developing a drug for Achondroplasia and related skeletal disorders, using chemical, biochemical and molecular strategies.
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Do parents and grandparents of patients with achondroplasia have a higher cancer risk?
Several studies, performed according to hypotheses based on teratogenesis and carcinogenesis have tried to answer the question: Do parents of children with congenital anomalies have a higher cancer risk? If the general answer is no, however, a higher risk for cancer was reported in the parents of children with cleft lip/palate (Zhu et al. [2002: Br J Cancer 87:524-528]). In achondroplasia, the neo-mutations are from paternal origin raising the hypothesis of the existence of a "mutator" gene acting in male meiosis and in somatic, mitotic cells in both sexes which may favor also the occurrence of cancer. In order to test this hypothesis, a questionnaire was sent to people with non-familial achondroplasia, asking for cancer, lymphoma, and leukemia in their parents and grandparents. In the hypothesis tested, the maternal lineage was the control. One hundred forty eight answers were obtained from 76 males and 72 females with achondroplasia. Out of them 68 had parents and/or grandparents with cancer. Among the grandparents of people with achondroplasia there were 36 cancers including two lymphomas in the paternal grandparents, 20 cancers including two chronic myeloid leukemia (CML) in the paternal grandmothers, 22 cancers including two CML in the maternal grandfathers, and two cancers in the maternal grandmothers. Paternal grandfathers and grandmothers had significantly more cancers (56) than maternal grandfathers and grandmothers (24) (chi(2)-test = 14.80, P < 0.001). In conclusion, paternal grandfathers and grandmothers of people with achondroplasia had significantly more cancers than maternal grandfathers and grandmothers. This result raises hypotheses in relationship with the paternal origin of neo-mutations in achondroplasia.
Achondroplasia↗
Posterior fossa decompression without duraplasty in infants and young children for treatment of Chiari malformation and achondroplasia.
Some children with Chiari malformation and achondroplasia require posterior fossa decompression that typically includes expansion of the dural tube with duraplasty. Infants and young children, however, may have a more distensible dura mater than do older patients. Furthermore, the structures that compress the hindbrain of young patients may be the bone and abnormally thickened atlantooccipital membrane, i.e., dural band, rather than the dura mater. We have treated 7 children who had Chiari malformation or achondroplasia with posterior fossa decompression without duraplasty. All children were symptomatic; 3 had Chiari-I malformations, 2 Chiari-II malformations, and 2 achondroplasia. The age range was 3 months to 2.5 years (mean 15.1 months). The exent of tonsillar herniation and other hindbrain anomalies was assessed on preoperative magnetic resonance imaging. The infants with Chiari-II malformations underwent cervical laminectomies, whereas the other young children with Chiari-I malformations or achondroplasia underwent suboccipital craniectomy as well as cervical laminectomy. In Chiari malformation, the dural band was divided; in achondroplasia, there was no identifiable dural band. Following bony decompression and division of the identifiable dural band, immediate expansion of the stenotic region with visible cerebrospinal fluid space posterior to the neural elements could be ascertained by intraoperative ultrasonography. During a follow-up period ranging from 4.5 months to 4 years (mean 22 months), all patients made improvements in their symptoms, 3 having complete resolution of their symptoms. This preliminary experience indicates that in children 2 years of age or younger, posterior fossa bony decompression without duraplasty can be effective treatment for Chiari malformations or achondroplasia.
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Achondroplasia-hypochondroplasia complex in a newborn infant.
We describe the case of an 8-month-old girl with achondroplasia-hypochondroplasia complex. The diagnosis was suggested antenatally when obstetrical ultrasonography at 27 weeks of gestation showed short limbs, small chest, and macrocephaly. The father has achondroplasia due to the common G1138A (G380R) mutation in the fibroblast growth factor receptor 3 (FGFR3) gene, while the mother has hypochondroplasia due to the C1620G (N450K) mutation in the FGFR3 gene. Neither had had genetic counseling or molecular testing prior to the pregnancy. Antenatal ultrasound study at 29 weeks of gestation showed a large head, very short limbs, and a small chest; the findings were more severe than in achondroplasia or hypochondroplasia alone. The patient was born by cesarean section at 37 weeks of gestation and had rhizomelic shortness of limbs with excess skin creases, large head, and small chest, diagnostic of achondroplasia. Radiographs showed shortness of the long bones and flaring of the metaphyses. She had mild hypoplasia of lungs. Molecular testing showed both the G1138A and the C1620G mutations in FGFR3, confirming the diagnosis of achondroplasia-hypochondroplasia complex. At 8 months, she has disproportionate shortness of the long bones and a large head with frontal bossing and a depressed nasal bridge. Her chest remains small, and she is on home oxygen at times of respiratory stress. She has a large gibbus. She is delayed in her motor development and has significant head lag. To our knowledge, there is only one previously published report of achondroplasia-hypochondroplasia complex.
Abnormalities, Multiple↗
Achondroplasia in Turkey is defined by recurrent G380R mutation of the FGFR3 gene.
Achondroplasia, the most common form of skeletal dysplasia in man, has autosomal dominant inheritance and causes severe dwarfism. More than 90% of patients with achondroplasia have a G to A transversion or G to C transversion at position 1138 of the fibroblast growth factor receptor-3 (FGFR3) gene resulting in the substitution of an arginine for a glycine residue at position 380 (G380R) of the FGFR3 protein. In this study, 12 unrelated Turkish patients with achondroplasia were evaluated for the G to A and G to C transversion at position 1138 of the FGFR3 gene. Eleven of 12 patients carried the G to A mutation heterozygously. None of the patients had the G to C mutation at the same position. In conclusion, the vast majority of Turkish achondroplasia patients have the same mutation that has been most often defined in patients with achondroplasia from other countries. Our results give further support to the fact that the G380R mutation of FGFR-3 is the most common mutation causing achondroplasia in different populations.
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[Mutations in the Fibroblast Growth Factor Receptor 3 gene (FGFR3) in Chilean patients with idiopathic short stature, hypochondroplasia and achondroplasia].
BACKGROUND: Achondroplasia and hypochondroplasia are skeletal dysplasias of autosomal dominant inheritance that represent different degrees of severity of the same pathological entity. Both dysplasias are caused by mutations in the Fibroblast Growth Factor Receptor 3 (FGFR3) gene. In achondroplasia more than 95% of the cases studied to date carry the same mutation (G380R). Hypochondroplasia represents a greater clinical and genetic heterogeneity, possibly being confused with "idiopathic short stature". The N540K mutation has been detected in 50-70% of cases of hypochondroplasia and mutations at the 650 locus in approximately 2.8%. AIM: To assess the frequency of N540K and G380R mutations, and changes at the 650 locus in Chilean patients with idiopathic disproportionate short stature, hypochondroplasia and achondroplasia. PATIENTS AND METHODS: We studied 21 patients referred for idiopathic short stature, 5 with clinically suspected hypochondroplasia and 4 with achondroplasia. The G1138A, G1138C (G380R), and C1620, C1620A (N540K) mutations and the nucleotide changes at the 650 locus were studied using PCR and restriction analysis of genomic DNA. RESULTS: Three out of five hypochondroplasia patients were heterozygous for the N540K mutation. All of the 4 patients with achondroplasia presented the G1138A mutation. None of these mutations were found in patients with idiopathic short stature. CONCLUSION: Chilean patients with hypochondroplasia and achondroplasia have the same mutations described in other ethnic groups. The identification of mutations in 3 out of 5 patients with hypochondroplasia shows that this analysis is a useful tool for its diagnostic confirmation. In short stature the molecular study should only be indicated in those cases presenting other clinical and/or radiological features of hypochondroplasia.
Achondroplasia↗
Cognitive skills in achondroplasia.
Increased intracranial pressure and ventricular and subarachnoidal dilatation are common manifestations in achondroplasia. They rarely lead to major neurologic and/or psychomotor deficits and neurosurgical intervention is seldom needed. The present study was undertaken to detect signs of minor cerebral dysfunction and discuss possibilities of their prevention. Thirty children with achondroplasia were compared to 3 control groups: their next-born sibs, 30 children with other forms of dwarfism, and 30 children with normal height. Early development was assessed by means of questionnaires. Cognitive skills were evaluated with the German version of the Cognitive Abilities Test and the Lorge-Thorndike Intelligence Test. Personality data were tested using standardized neuroticism, extraversion, and anxiety scales. Children with achondroplasia had more frequent histories of delayed motor development, retarded speech development, and lower school grades in language-related specialties. Psychometric testing disclosed total and subtest scores in the population-based normal range. In comparison with their sibs and matched controls children with achondroplasia had significantly lower total scores mainly caused by low scores in the subtest "verbal comprehension." We conclude that verbal comprehension is significantly impaired in children with achondroplasia. This partial deficiency is probably related to frequent middle ear infections and resulting conductive hearing loss. Hypotonia with delayed oropharyngeal muscle coordination and parental response to an altered, more infantile instinctive releasing pattern may be contributing factors.
Achondroplasia↗
Localization of the achondroplasia gene to the distal 2.5 Mb of human chromosome 4p.
Achondroplasia has been mapped to 4p16.3 using 18 multigenerational families with achondroplasia and 10 short tandem repeat polymorphic markers from this region. No evidence of genetic heterogeneity was found. Analysis of a recombinant family localizes the achondroplasia locus to the 2.5 Mb region between D4S43 and the telomere. Multipoint linkage analysis favors placement telomeric of D4S412. The establishment of closely linked markers will facilitate positional cloning of the achondroplasia gene and permit prenatal diagnosis of homozygous achondroplasia for at risk couples.
Achondroplasia↗