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PubMed1993

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.

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PubMed2006

Prenatal diagnosis of achondroplasia presenting with multiple-suture synostosis: a novel association.

OBJECTIVE: We report an atypical case of a fetus presenting with a combined achondroplasia and multiple craniosynostosis phenotype. METHODS: Sonographic monitoring in conjunction with molecular genetic analysis was performed in a 32-gestational weeks fetus. RESULTS: Sonographic findings were consistent with a diagnosis of achondroplasia associated with multiple-suture synostosis. The most common G380R FGFR3 achondroplasia mutation was detected. CONCLUSION: The most common achondroplasia mutation should be considered for prenatal DNA testing in cases with ultrasound findings of achondroplasia and multiple-suture synostosis. This is crucial for the genetic counselling and perinatal management of the fetus.

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PubMed2004

Survey of the present status of sleep-disordered breathing in children with achondroplasia Part I. A questionnaire survey.

An achondroplasia is known to be the inherited disease causing a growth impairment of limb bones. Recently, as a symptom of achondroplasia, a sleep-disordered breathing has been reported. Considering the scientific evidence that the sleep-disordered breathing in children such as that due to tonsillar hypertrophy inhibits somatotropin secretion and causes growth retardation, sleep-disordered breathing in children with achondroplasia may aggravate growth/developmental retardation in addition to the bone growth impairment. However, the present status of the development of sleep-disordered breathing in children with achondroplasia has been unknown. Therefore, in order to clarify the present status of sleep-disordered breathing in children with achondroplasia (AP group), we carried out a questionnaire survey of the breathing state during sleep, growth/development history and the oral state at preschool age and school age in the AP group, and compared the results with previously reported data in healthy children (control group). 1. Among the questionnaire items, the incidences of snoring, apnea, mouth breathing, anterior cross bite, and open bite at preschool age were significantly higher in the AP group than in the control group (P < 0.01) At school age, the AP group showed significantly higher incidences of mouth breathing and cross/open bite (P < 0.01) and snoring and apnea (P < 0.05) than the control group. 2. Height and weight at birth and at the ages of 1.5 and 3 years, excluding birth weight, were significantly lower in the AP group than in the control group (P < 0.01). 3. The chronological age at the initiation of eruption of the deciduous or permanent teeth did not significantly differ between the two groups. Thus, the AP group showed higher incidences of sleep-disordered breathing and malocclusion than the control group, and development of sleep-disordered breathing at preschool age.

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PubMed1994

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.

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PubMed1994

Two sibs who are double heterozygotes for achondroplasia and pseudoachondroplastic dysplasia.

We report a family in which two sibs have both achondroplasia and pseudoachondroplastic dysplasia. The mother has achondroplasia and the father has pseudoachondroplastic dysplasia, which he had inherited from his father. Both children appeared typical of achondroplasia at birth. By 1 1/2 years they had developed a fixed lumbar kyphosis with gibbus and had additional x ray changes unusual for just achondroplasia and suggestive of pseudoachondroplastic dysplasia. Subsequently both children have shown characteristic features of both conditions and have grown less well than expected for achondroplasia. Radiographs show the striking synergistic effects of the two conditions. MRI in both sibs confirmed brain stem compression at the foramen magnum. This may be an important complication and should be actively sought in any double heterozygote.

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PubMedDate not supplied

Growth hormone (GH) treatment in achondroplasia.

Achondroplasia is one of the most commonly known types of skeletal dysplasia in the adult leading to short stature. Before beginning growth hormone (GH) treatment of short stature in patients with achondroplasia, we evaluated their growth pattern and their hypothalamic-pituitary function, including GH secretion. We studied 22 patients with achondroplasia (7 males and 15 females: age range, 3 to 12 years). The z-score of their height at admission was -5.4 +/- 1.2 (mean +/- SD), and that of their annual height gain before admission was -3.1 +/- 1.3 (mean +/- SD). GH response to provocative tests was normal in all patients except five: four showed subnormal (< 10 ng/ml) response to L-Dopa stimuli, and one patient showed subnormal (< 20 ng/ml) response to GRF stimuli. The mean GH concentration during sleep was found to be low (< 5 ng/ml) in three patients. These three patients were suspected to have latent GH deficiency, as they also showed a markedly low IGF-1 level and marked delay of bone age. LH, FSH, TSH, and cortisol response to provocative tests were normal in all the patients. We treated this group of patients with recombinant human GH (1 IU/kg/week). In 18 patients who were treated with GH for more than 6 months, height velocity during GH therapy was significantly increased compared to that before GH therapy (4.1 +/- 0.8 cm/year vs 7.2 +/- 1.4 cm/year). We conclude that parameters reflecting hypothalamic-pituitary function, particularly GH secretion, should be examined in achondroplasia patients, and that GH treatment may be beneficial in the treatment of short stature in achondroplasia.

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PubMed1998

Effect of growth hormone therapy in children with achondroplasia: growth pattern, hypothalamic-pituitary function, and genotype.

OBJECTIVE: Although there are a few reports on GH therapy in achondroplasia, these were based on a small sample and/or short-term observation. To clarify the effectiveness of GH treatment on short stature in achondroplasia and hypochondroplasia, a long-term treatment study in a larger number of patients was performed. METHOD: Forty-two children (16 males and 26 females, age 3-14 years) with achondroplasia were examined in this study. Initially, we evaluated hypothalamic-pituitary function and point mutation analysis as previously reported. After the evaluation, the children were treated with GH for more than 2 years; then post-treatment growth velocity and body proportion parameters were determined. RESULTS: The 35 typical variants of our achondroplasia patients showed previously reported point mutation in the fibroblast growth factor receptor 3 gene. The annual height gain during GH therapy was significantly greater than that before therapy (3.9 +/- 1.0 cm/year before treatment vs 6.5 +/- 1.8 cm/year for the first year and 4.6 +/- 1.6 cm/year for the second year of treatment). The body disproportion had not been aggravated during the treatment period. CONCLUSION: We conclude that GH might be beneficial in the treatment of short stature in children with achondroplasia in the first 2 years of treatment.

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PubMed1991

Analysis of the chondroitin sulfate proteoglycan core protein (CSPGCP) gene in achondroplasia and pseudoachondroplasia.

Achondroplasia and pseudoachondroplasia are autosomal dominant skeletal dysplasias resulting in short-limbed dwarfism. Histologic and ultrastructural studies of the cartilage in pseudoachondroplasia and in homozygous achondroplasia have suggested a structural abnormality in chondroitin sulfate proteoglycan (CSPG), a major structural protein in the extra-cellular matrix. The gene encoding CSPG core protein (CSPGCP) is thus a logical "candidate gene" for analysis in these conditions. cDNA probes encoding CSPGCP were used to identify restriction fragment length polymorphisms (RFLPs) in DNA from a panel of control individuals. No gross alterations at the CSPGCP locus were noted in DNA from 37 individuals with achondroplasia and 5 individuals with pseudoachondroplasia. In addition, allelic frequencies of the RFLPs were not significantly different among controls and patients with either condition. In one three-generation family with achondroplasia, close linkage of the CSPGCP locus and the skeletal dysplasia was excluded using a Bgl II polymorphism. Similarly, in a three-generation family with pseudoachondroplasia, the CSPGCP gene was not tightly linked to the disease phenotype. These results indicate that mutations at the chondroitin sulfate proteoglycan core protein locus do not cause achondroplasia or pseudoachondroplasia in these families.

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PubMed1989

[Prediction of body height and shortening of the lower part of the body in adults with achondroplasia].

The authors present the method of predicting the body height of patients with achondroplasia in adulthood and the method of predicting shortening of the lower segment of the body as compared to the trunk. They evaluate a group of 12 patients with achondroplasia at the age from 3 to 17 years. They compare the growth curves of patients with normal Czechoslovak population and with a group of American patients suffering with achondroplasia. The application of growth curves of American patients with achondroplasia appears to be the most suitable and simple graphical method for the prediction of the body height of the Czechoslovak patients suffering from achondroplasia. The method of the prediction of dwarfism of the lower segment of the body has been developed for the purpose of the rational indication of the stepwise prolongation therapy by the compression-distraction method. Analogically it will be possible to verify the growth curves for some other bone dysplasiae presented in literature and predict dwarfism of the lower segment of the body in adulthood, e.g. in hypochondroplasia, metaphyseal chondrodysplasia of the type of Schmid, Turner syndromes, etc.

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PubMed1985

A morphometric analysis of the craniofacial configuration in achondroplasia.

Human achondroplasia can be viewed as an experimental model for studying the effects of abnormal endochondral bone formation on the development of the skull as a whole. In this study, lateral cephalograms of 25 adult males and 26 adult females with achondroplasia were converted to a two-dimensional coordinate model of craniofacial morphology and analyzed using 66 linear, angular, and area variables. Lateral cephalograms of 951 normal adults were used for comparison. Two sample t-tests were used to compare achondroplastic cephalograms with normal cephalograms. Multivariate statistical analysis included Hotelling's T2 and discriminant function analysis. Selected variables were graphed as profile patterns in which mean values were expressed as standard deviation units (Z scores) relative to the norm. Finally, Calcomp plots were used for visual inspection and for comparison of the average cephalometric tracings of male and female achondroplastic subjects with normal male and female subjects, respectively. Significant findings in achondroplasia included enlarged calvaria, frontal bossing, large frontal sinuses, occipital prominence, normal anterior cranial base length, strikingly shortened posterior cranial base length, an acute cranial base angle, a short nasal bone that was deformed and depressed, short upper facial height, recessed maxilla, posterior tilt of the nasal floor, and a prognathic mandible that was anteriorly displaced but of normal size with a normal gonial angle and a high coronoid process. The finding of normal anterior cranial base length in achondroplastic subjects was surprising since the cranial base is preformed in cartilage and hypoplasia and shortening would be expected. Since the brain is enlarged in achondroplasia, the expanding frontal lobes may possibly influence the growth of the anterior cranial base, since it is known to follow a neural pattern of growth. Cribriform plate length was strikingly reduced, but anterior sphenoidal length was strikingly increased, compensating for the shortened cribriform plate length and suggesting that growth in the length of the anterior cranial base takes place primarily by adaptation at one site--namely, the sphenoethmoidal synchondrosis. Strikingly short posterior cranial base length was interpreted as resulting from hypoplasia of bone that is preformed in cartilage with possible early closure of the spheno-occipital synchondrosis. The exaggerated closure of the cranial base angle in achondroplasia may be related to an increased brain size and possibly earlier than normal closure of the intersphenoidal synchondrosis.(ABSTRACT TRUNCATED AT 400 WORDS)

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PubMed1996

Standard curves of chest circumference in achondroplasia and the relationship of chest circumference to respiratory problems.

Several pathogenetic factors, alone or in combination, may contribute to the increased frequency of respiratory complications in achondroplasia. It has been suggested that relatively small chest circumference sometimes may contribute. However, there are no published curves of chest circumference for age in achondroplasia with which to compare patients. Nor are there data relating chest circumference to overall size in achondroplasia. We present curves of chest circumference for males and females with achondroplasia from birth through age 7 years. Additional curves for chest circumference against height are also provided. Finally, we report some preliminary data regarding the possible association of chest size with respiratory signs and symptoms.

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PubMed1984

Achondroplasia: unexpected familial recurrence.

We review six families in which recurrence of achondroplasia, inexplicable through autosomal dominant inheritance, has occurred. The clinical and radiographic characteristics of affected individuals in these families are identical to those usually seen in achondroplasia. Family histories and parental characteristics likewise seemed not to set this group apart from others with achondroplasia. While various mechanisms for these occurrences of achondroplasia in family members related through unaffected relatives can be postulated, the hypothesis that these recurrences were simply the result of two independent chance events cannot, at least for the moment, be excluded.

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PubMed1995

A common FGFR3 gene mutation is present in achondroplasia but not in hypochondroplasia.

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. Recent studies mapped the achondroplasia gene on chromosome region 4p16.3 and identified a common mutation in the gene encoding the fibroblast growth factor receptor 3 (FGFR3). In an analysis of 19 achondroplasia families from a variety of ethnic backgrounds we confirmed the presence of the G380R mutation in 21 of 23 achondroplasia chromosomes studied. In contrast, the G380R mutation was not found in any of the 8 hypochondroplasia chromosomes studied. Furthermore, linkage studies in a 3-generation family with hypochondroplasia show discordant segregation with markers in the 4p16.3 region suggesting that at least some cases of hypochondroplasia are caused by mutations in a gene other than FGFR3.

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PubMed2003

Mesomelic and rhizomelic short stature: The phenotype of combined Leri-Weill dyschondrosteosis and achondroplasia or hypochondroplasia.

We studied two children with combined genetic skeletal disorders. Both had Leri-Weill dyschondrosteosis (LWD); one also had achondroplasia and the other had hypochondroplasia. Both had severe short stature and evidence of rhizomelia and mesomelia as well as other phenotypic features of their individual genetic disorders. Achondroplasia was due to the G380R FGF3R mutation and hypochondroplasia to a N540K mutation in the same gene. The patient with hypochondroplasia had a heterozygous SHOX deletion; no SHOX mutation was identified in the child with achondroplasia. The phenotypes of combined LWD and achondroplasia or hypochondroplasia appeared to be less than additive, suggesting that SHOX and FGFR3 act on overlapping pathways of bone growth and development.

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PubMed2004

Living with achondroplasia: quality of life evaluation following cervico-medullary decompression.

Achondroplasia is the most common of the heritable skeletal dysplasias. Cervico-medullary compression is a frequently encountered and potentially lethal neurological complication. Cervico-medullary decompression (CMD) at the foramen magnum is often employed to relieve the pressure on the emerging cervical cord. Given the inherent risks associated with major surgery, there has been a substantial debate regarding the best criteria for CMD. Our objectives for this study are to explore the quality of life of patients who had undergone CMD, and to assess whether surgery is associated with mortality and increased long-term morbidity. A Medical Outcome Study 36-item Short Form General Health Survey designed to evaluate eight general health concepts as well as achondroplasia-related issues, was administered to patients assessed in the neurosurgery department in Johns Hopkins Hospital between 1977 and 1998. One hundred and sixty-seven patients were eligible for inclusion. Forty-three could not be contacted, and two refused consent. One hundred and twenty-two patients were assessed. Fifty-six (46%) individuals had CMD and 66 (54%) did not. There was 1 case of mortality in the CMD group and 12 cases in the non-CMD group. In the non-CMD group, all deaths, as far as we know, were unrelated to cervico-medullary compression. In this cohort of surviving patients (n = 109), the quality of life of the 55 (50.5%) who had undergone CMD is comparable to that of the 54 (49.5%) who did not have surgery, controlled for age and sex. CMD is indicated for patients with achondroplasia with significant symptomatic foramen magnum compression. It can be life saving. It can abolish profound central apnea that may cause sudden death and alleviate neurological complications associated with damage of the significantly compressed spinal cord. With regards to long-term outcome evaluation, the quality of life of individuals with achondroplasia who had CMD is similar to those age- and sex-matched patients who did not have this surgery. Moreover, CMD, with all its inherent surgical risks, does not appear to be associated with higher mortality or increased long-term morbidity.

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PubMed2006

Aspects of achondroplasia in the skulls of dwarf transgenic mice: a cephalometric study.

Achondroplasia, the most common short-limbed dwarfism in humans, results from a single nucleotide substitution in the gene for fibroblast growth factor receptor 3 (FGFR3). FGFR3 regulates bone growth in part via the mitogen-activated protein kinase pathway (MAPK). To examine the role of this pathway in chondrocyte differentiation, a transgenic mouse was generated that expresses a constitutively active mutant of MEK1 in chondrocytes and exhibits dwarfing characteristics typical of human achondroplasia, i.e., shortened axial and appendicular skeletons, mid-facial hypoplasia, and dome-shaped cranium. In this study, cephalometrics of the MEK1 mutant skulls were assessed to determine if the MEK1 mice are a good model of achondroplasia. Skull length, arc of the cranial vault, and area, maximum and minimum diameters of the brain case were measured on digitized radiographs of skulls of MEK1 and control mice. Cranial base and nasal bone length and foramen magnum diameter were measured on midsagittal micro-CT sections. Data were normalized by dividing by the cube root of each animal's weight. Transgenic mice exhibited a domed skull, deficient midface, and (relatively) prognathic mandible and had a shorter cranial base and nasal bone than the wild-type. Skull length was significantly less in transgenic mice, but cranial arc was significantly greater. The brain case was larger and more circular and minimum diameter of the brain case was significantly greater in transgenic mice. The foramen magnum was displaced anteriorly but not narrowed. MEK1 mouse cephalometrics confirm these mice as a model for achondroplasia, demonstrating that the MAP kinase signaling pathway is involved in FGF signaling in skeletal development.

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PubMed1995

A glycine 375-to-cysteine substitution in the transmembrane domain of the fibroblast growth factor receptor-3 in a newborn with achondroplasia.

Achondroplasia, the most common form of chondrodysplasia, has been associated with mutations in the gene of the fibroblast growth factor receptor-3 (FGFR-3) on chromosome 4p. All 39 achondroplasia alleles studied so far carried point mutations which caused the same amino acid exchange, a substitution of glycine by arginine at position 380 (G380R) in the transmembrane domain of the receptor. We report on a newborn with achondroplasia who does not carry a G380R mutation but has a mutation causing substitution of a nearby glycine with a cysteine (G375C). This observation indicates allelic heterogeneity and confirms the role of mutations in the transmembrane domain of FGFR-3 in the pathogenesis of achondroplasia.

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PubMed2006

Achondroplasia and enchondromatosis: report of three boys.

We report on three boys suffering from achondroplasia concurrent with enchondromatosis-like metaphyseal changes. Two boys who were examined by molecular analysis harbored a mutation of FGFR3, which occurs in most achondroplastic individuals. Given the prevalence of achondroplasia and enchondromatosis, the metaphyseal changes in these patients are less likely to represent the coincidence of both disorders, but rather to result from a rare consequence of the FGFR3 mutation. Impaired FGFs/FGFR3 signaling pathway in achondroplasia inhibits chondrocytic proliferation, which accounts for most characteristics of achondroplasia. On the other hand, it causes conflicting biological consequences that can suppress or stimulate chondrocytic maturation. In a small subset of achondroplastic individuals, the suppression of chondrocytic maturation may outweigh the stimulation, which leads to cartilaginous overgrowth into the metaphysis, eventually causing the metaphyseal dysplasia found in the present patients.

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