Achondroplasia is the most frequent form of short-limb dwarfism. Affected individuals exhibit short stature caused by rhizomelic shortening of the limbs, characteristic facies with frontal bossing and midface hypoplasia, exaggerated lumbar lordosis, limitation of elbow extension, genu varum, ... Achondroplasia is the most frequent form of short-limb dwarfism. Affected individuals exhibit short stature caused by rhizomelic shortening of the limbs, characteristic facies with frontal bossing and midface hypoplasia, exaggerated lumbar lordosis, limitation of elbow extension, genu varum, and trident hand.
The diagnosis is based on the typical clinical and radiologic features; the delineation from severe hypochondroplasia may be arbitrary.
The demonstration of a very limited number of mutations causing achondroplasia and the ease with which they ... The diagnosis is based on the typical clinical and radiologic features; the delineation from severe hypochondroplasia may be arbitrary. The demonstration of a very limited number of mutations causing achondroplasia and the ease with which they can be detected (1 PCR and 1 restriction digest) provides a simple method for prenatal diagnosis of ACH homozygotes in families at risk and in which the parents are heterozygous for either the 1138A or 1138C allele (Shiang et al., 1994). Shiang et al. (1994) expressed the opinion that other than the screening of at-risk pregnancies for homozygous ACH fetuses, any 'other application of the diagnostic test for ACH mutations should be prohibited.' Bellus et al. (1994) practiced prenatal diagnosis by chorionic villus sampling at 10 weeks and 4 days of gestation, both parents having achondroplasia. Both parents and the fetus were shown to be heterozygous for the more common G-to-A transition. Homozygous achondroplasia was excluded.
Whereas many conditions that cause short stature have inappropriately been called achondroplasia in the past, the phenotype of this osteochondrodysplasia is so distinctive and so easily identified clinically and radiologically at birth that confusion should not occur. It ... Whereas many conditions that cause short stature have inappropriately been called achondroplasia in the past, the phenotype of this osteochondrodysplasia is so distinctive and so easily identified clinically and radiologically at birth that confusion should not occur. It is characterized by a long, narrow trunk, short extremities, particularly in the proximal (rhizomelic) segments, a large head with frontal bossing, hypoplasia of the midface and a trident configuration of the hands. Hyperextensibility of most joints, especially the knees, is common, but extension and rotation are limited at the elbow. A thoracolumbar gibbus is typically present at birth, but usually gives way to exaggerated lumbar lordosis when the child begins to ambulate. Mild to moderate hypotonia is common, and motor milestones are usually delayed. Intelligence is normal unless hydrocephalus or other central nervous system complications arise. In 13 achondroplastic infants, Hecht et al. (1991) found that cognitive development was average and did not correlate with motor development which typically was delayed. It was noteworthy that reduced mental capacity correlated with evidence of respiratory dysfunction detected by polysomnography. In children, caudad narrowing of the interpediculate distance, rather than the normal caudad widening, and a notchlike sacroiliac groove are typical radiologic features. Also in children, epiphyseal ossification centers show a circumflex or chevron seat on the metaphysis. Limb shortening is especially striking in the proximal segments, e.g., the humerus; hence the description rhizomelic ('root limb'). The radiologic features of true achondroplasia and much concerning the natural history of the condition were presented by Langer et al. (1967) on the basis of a study of 101 cases and by Hall (1988). True megalencephaly occurs in achondroplasia and has been speculated to indicate effects of the gene other than those on the skeleton alone (Dennis et al., 1961). Disproportion between the base of the skull and the brain results in internal hydrocephalus in some cases. The hydrocephalus may be caused by increased intracranial venous pressure due to stenosis of the sigmoid sinus at the level of the narrowed jugular foramina (Pierre-Kahn et al., 1980). Hall et al. (1982) pointed out that the large head of the achondroplastic fetus creates an increased risk of intracranial bleeding during delivery. They recommended that in the management of achondroplastic infants ultrasonography be done at birth and at 2, 4, and 6 months of age to establish ventricular size, the presence or absence of hydrocephalus, and possible intracranial bleed. They stated the impression that some achondroplasts have only megalencephaly, others have true communicating hydrocephalus, and yet others have dilated ventricles without hydrocephalus. Nelson et al. (1988) concluded that brainstem compression is common in achondroplasia and may account in part for the abnormal respiratory function. Pauli et al. (1984) focused attention on the risk of sudden unexpected death in infants with achondroplasia. While uncontrolled and retrospective, their study demonstrated an excess of deaths in the first year of life, most or all of which were attributable to abnormalities at the craniocervical junction. Hecht et al. (1987) showed that the excess risk of death in infants with achondroplasia may approach 7.5%, largely because of cervical cord compression. Pauli et al. (1995) performed a prospective assessment of risk for cervical medullary-junction compression in 53 infants, 5 of whom were judged to have sufficient craniocervical junction compression to require surgical decompression. Intraoperative observation showed marked abnormality of the cervical spinal cord, and all operated-on children showed marked improvement of neurologic function. The best predictors of need for suboccipital decompression included lower-limb hyperreflexia or clonus on examination, central hypopnea demonstrated by polysomnography, and foramen magnum measures below the mean for children with achondroplasia. Lachman (1997) reviewed the neurologic abnormalities in the skeletal dysplasias from a clinical and radiologic perspective. Three important major groups were identified: (i) achondroplasia (cranio-cervical junction problems in infancy, spinal stenosis, and neurogenic claudication in adulthood); (ii) type II collagenopathies (upper cervical spine anatomic and functional problems); and (iii) craniotubular and sclerosing bone dysplasias (osseous overgrowth with foraminal obstruction problems). To detect myelopathy, Boor et al. (1999) recorded somatosensory evoked potentials (SEPs) after median nerve stimulation in 30 patients with achondroplasia. In addition to the conventional technique, they employed a noncephalic reference electrode recording the subcortical waveforms N13b and P13, generated near the craniocervical junction. The findings were correlated with the clinical status and MRI results. The sensitivities of the SEPs were 0.89 for cervical cord compression, 0.92 for myelomalacia, and 1.0 for the clinically symptomatic patients. There were no false-positive results. The subcortical SEPs were more sensitive than the conventional recordings. Hecht et al. (1988) reviewed the subject of obesity in achondroplasia, concluding that it is a major problem which, whatever its underlying cause, aggravates the morbidity associated with lumbar stenosis and contributes to the nonspecific joint problems and to the possible early cardiovascular mortality in this condition. Using data about 409 Caucasian patients with achondroplasia from different countries (1,147 observations), Hunter et al. (1996) developed weight for height (W/H) curves for these patients. They showed that to a height of about 75 cm, the mean W/H curves are virtually identical for normal and achondroplastic children. After this height, the W/H curves for achondroplastic patients rise above those for the general population. Hunter et al. (1996) contended that the best estimation of weight excess for achondroplastic patients aged 3 to 6 years is given by the Quetelet index, whereas that for patients aged 6 to 18 years is the Rohrer index. Homozygosity for the achondroplasia gene results in a severe disorder of the skeleton with radiologic changes qualitatively somewhat different from those of the usual heterozygous achondroplasia; early death results from respiratory embarrassment from the small thoracic cage and neurologic deficit from hydrocephalus (Hall et al., 1969). Yang et al. (1977) reported upper cervical myelopathy in a homozygote. Horton et al. (1988) found that the epiphyseal and growth plate cartilages have a normal appearance histologically, and the major matrix constituents exhibit a normal distribution by immunostaining; however, morphometric investigations have indicated that the growth plate is shorter than normal and that the shortening is greater in homozygous than in heterozygous achondroplasia, suggesting a gene dosage effect. Stanescu et al. (1990) reported histochemical, immunohistochemical, electron microscopic, and biochemical studies on upper tibial cartilage from a case of homozygous achondroplasia. No specific abnormality was defined. Aterman et al. (1983) expressed puzzlement at the striking histologic changes in homozygous achondroplasia despite the virtual absence of changes in the heterozygote. They pointed out that histologic studies in the heterozygote at a few weeks or months of age have not been done. They suggested that because of similarities between what they called PHA (presumed homozygous achondroplasia) and thanatophoric dwarfism (187600), some cases of the latter condition may be due to a particularly severe mutation at the achondroplasia locus. Young et al. (1992) described lethal short-limb dwarfism in the offspring of a father with spondyloepiphyseal dysplasia congenita (SEDC; 183900) and a mother with achondroplasia. Young et al. (1992) suggested that the infant was a double heterozygote for the 2 dominant genes rather than a compound heterozygote. It was considered unlikely that SEDC and achondroplasia are allelic because of the evidence that most, if not all, cases of SEDC result from mutation in the type II collagen gene (COL2A1; 120140), whereas this gene has been excluded as the site of the mutation in achondroplasia. Evidence that hypochondroplasia (146000) can be caused by an allele at the achondroplasia locus came from observations of a presumed genetic compound in the offspring of an achondroplastic father and a hypochondroplastic mother who exhibited growth deficiency and radiographic abnormalities of the skeleton that were much more severe than those typically seen in achondroplasia (McKusick et al., 1973; Sommer et al., 1987) and somewhat less severe than those of the ACH homozygote. Huggins et al. (1999) reported an 8-month-old girl with achondroplasia/hypochondroplasia whose father had the G380R achondroplasia mutation (134934.0001) in the FGFR3 gene and whose mother had the N450K hypochondroplasia mutation (134934.0010). Chitayat et al. (1999) simultaneously reported an infant boy with achondroplasia/hypochondroplasia whose mother had the G380R mutation and whose father had the N450K mutation. Molecular analysis confirmed the compound heterozygosity of both children, who displayed an intermediate phenotype that was more severe than either condition in the heterozygous state but less severe than homozygous ACH. In a presentation of adult genetic skeletal dysplasias found in the Museum of Pathological Anatomy in Vienna, Beighton et al. (1993) pictured the skeleton of a 61-year-old man with achondroplasia who died of transverse myelitis. Randolph et al. (1988) reported an achondroplastic patient who developed classic ankylosing spondylitis (106300). There is no fundamental connection between the 2 disorders. The importance of the observation is mainly to indicate that back problems in achondroplasts can be due to causes other than the underlying disease. Hunter et al. (1998) presented data from a multicenter study of 193 individuals with achondroplasia. They found that 89.4% of children had at least one episode of otitis media within the first 2 years of life; 24 of 99 children who had otitis media in the first year of life had several infections. All were observed to have chronic otitis media; 78.3% of individuals required the insertion of ventilation tubes at some point in their lives. Thirty of 85 patients aged 1 to 2 years and 26 of 70 patients aged 2 to 3 years had received at least one set of ventilation tubes. A degree of conductive hearing loss was found in 38.3% of individuals at sometime in their lives, the majority of these being found after 4 years of age Tonsillectomy was performed in 38.8% of individuals, with cumulative rates of 8.8% within the first 4 years of life and 25% by age 8 years. Speech delay was found in 18.6% of individuals, and 10.9% had articulation problems; only 9.5% of these individuals received speech therapy. Orthodontic problems were found in 53.8% of individuals; only 3.2% of these individuals presented within the first 10 years of life. Hunter et al. (1998) found that 10.5% of individuals had a ventricular shunt placed; all but one of these procedures were done in the preteenage years. Cervicomedullary decompression surgery had been performed in 6.8% of children by 4 years of age; however, this procedure was also performed in a number of older children, teenagers, and adults, with a total of 16.5% of individuals having this type of surgery. Apnea was reported in 10.9% of individuals by age 4 years and 16.1% of individuals overall. Hunter et al. (1998) defined tibial bowing as a distance of greater than 5 cm between the knees, with the legs straight and ankles apposed. Using these criteria, they found that 9.7% of individuals had tibial bowing by age 5 years. This continued to develop throughout childhood and into adult life, with a total of 41.6% of individuals being affected at some time. Tibial osteotomy had been performed on 21.6% of these individuals. By age 10 years, 8.9% of individuals had neurologic signs in the leg; however, by the sixth decade, 77.9% of individuals had these signs. A total of 24.1% had surgery for spinal stenosis, with an additional 18% in whom the diagnosis was made but surgery had not been performed. A majority of these surgeries were performed in individuals over 40 years of age. Hunter et al. (1998) concluded that middle ear disease with its attendant risk of hearing loss was more frequent than previously reported, and that while a significant number of patients with achondroplasia experience delayed speech, only a minority receive speech therapy. The rate of early cervicomedullary decompression was comparable to the previously reported series, but an equivalent proportion of patients require such intervention beyond childhood. Hunter et al. (1998) also concluded that a significant number of patients have neurologic complaints by their teenage years and that this becomes a majority in adulthood. Tasker et al. (1998) characterized cardiorespiratory and sleep dysfunction in 17 patients with achondroplasia referred to Great Ormond Street Hospital for Children, London. Three distinct etiologic groups were identified: group 1 had a mild degree of midfacial hypoplasia resulting in relative adenotonsillar hypertrophy; group 2 had jugular foramen stenosis resulting in muscular upper airway obstruction and progressive hydrocephalus due to jugular venous hypertension; and group 3 had muscular upper airway obstruction without hydrocephalus resulting from hypoglossal canal stenosis with or without foramen magnum compression. In addition, gastroesophageal reflux, which tended to occur in group 3 patients, was identified as a significant factor in the development of airway disease. Group 1 patients had obstructive sleep apnea only, and showed marked symptomatic improvement following adenotonsillectomy. Group 2 patients had central apnea responsive to surgical treatment of their hydrocephalus; obstructive sleep apnea in this group did not appear to respond to adenotonsillectomy, but to nocturnal continuous positive airway pressure. Group 3 patients had progressive cor pulmonale, obstructive and central sleep apnea, and gastroesophageal reflux with small airway pathology requiring multiple treatment modalities including foramen magnum decompression. In 4 (3.2%) of 126 children with achondroplasia undergoing periodic evaluations at a bone dysplasia clinic, Pauli and Modaff (1999) identified a right-sided temporal bone abnormality involving absence of a roof over the jugular bulb, with bulging of the bulb into the middle ear cavity. In 2 patients, dark bluish-gray discoloration behind the tympanic membrane was noted, and temporal bone CT scan confirmed the presence of unilateral jugular bulb dehiscence. In a third patient, a large dehiscent jugular bulb was observed during exploratory tympanotomy; in a fourth patient, after brisk bleeding during attempted myringotomy and tube placement, CT scan demonstrated the absence of the bony covering of the jugular bulb. Jugular bulb dehiscence was suspected in a fifth patient with dark bluish discoloration behind the inferior quarter of the tympanic membrane, but confirmatory studies had not been performed at the time of the report. Pauli and Modaff (1999) noted that dehiscence of the jugular bulb is of clinical relevance, particularly in regard to difficult-to-control bleeding at myringotomy, and is associated with otherwise unexplained hearing loss, tinnitus, and self-audible bruits in children with achondroplasia. Reynolds et al. (2001) retrospectively reviewed clinical and computed tomographic data in 71 infants with achondroplasia. They found no correlation between infantile hypotonia and foramen magnum size. These results suggested that there is no direct relationship and that foraminal size does not affect severity of hypotonia. They concluded that the only plausible explanation for the infantile hypotonia of achondroplasia is a primary effect of the causative mutation in FGFR3 (134934), which is expressed in brain. Van Esch and Fryns (2004) described acanthosis nigricans in a 9-year-old boy with achondroplasia due to the classic gly380-to-arg mutation (134934.0001) in FGFR3. Wynn et al. (2007) reported a 42-year follow-up study of mortality in achondroplasia. The study included 718 achondroplasia individuals from an earlier mortality study by Hecht et al. (1987) and 75 additional achondroplasia individuals. Rates of death were similar across the entire follow-up period. The overall mortality and age-specific mortality at all ages remained significantly increased. Accidental and neurologic disease-related deaths were increased in adults. Heart disease-related mortality, between ages 25 and 35, was more than 10 times higher than in the general population. Overall survival and the average life expectancy in this ACH population were decreased by 10 years.
Once the gene for achondroplasia was assigned to 4p16.3 by linkage analysis (Le Merrer et al., 1994; Velinov et al., 1994; Francomano et al., 1994), causative mutations were identified by the candidate gene approach and reported within 6 ... Once the gene for achondroplasia was assigned to 4p16.3 by linkage analysis (Le Merrer et al., 1994; Velinov et al., 1994; Francomano et al., 1994), causative mutations were identified by the candidate gene approach and reported within 6 months of the first mapping report. Mutations in the gene for fibroblast growth factor receptor-3 (134934) were identified by Shiang et al. (1994) and independently by Rousseau et al. (1994). The FGFR3 gene had previously been mapped to the same region, 4p16.3, as the ACH gene and the Huntington disease gene. The mutation in 15 of the 16 achondroplasia-affected chromosomes studied by Shiang et al. (1994) was the same, a G-to-A transition at nucleotide 1138 (134934.0001) of the cDNA. The mutation on the only other ACH-affected chromosome 4 without the G-to-A transition at nucleotide 1138 had a G-to-C transversion at this same position (134934.0002). Both mutations resulted in the substitution of an arginine residue for a glycine at position 380 of the mature protein, which is in the transmembrane domain of FGFR3. The mutation was located in a CpG dinucleotide. Rousseau et al. (1994) found the G380R mutation in all cases studied: 17 sporadic cases and 6 unrelated familial cases. Because of the high mutation rate, it might have been predicted that the achondroplasia gene is large and that any one of many mutations could lead to the same or a similar (hypochondroplasia) phenotype. Such is apparently not the case. The fact that there are no reports of Wolf-Hirschhorn syndrome (194190) patients with stigmata of achondroplasia may indicate that the phenotype is due to some mechanism other than haploinsufficiency, e.g., represents a dominant-negative or gain-of-function effect. (The independent work of Shiang et al. (1994) and Rousseau et al. (1994) was reported in the 29 July issue of Cell and the 15 September issue of Nature, respectively.) Bellus et al. (1995) found that 150 of 154 unrelated achondroplasts had the G-to-A transition (134934.0001) and 3 had the G-to-C transversion (134934.0002) at nucleotide 1138 of the FGFR3 gene. All 153 had the gly380-to-arg substitution; in one individual, an atypical case, the gly380-to-arg substitution was missing. Nucleotide 1138 of the FGFR3 gene was the most mutable nucleotide in the human genome discovered at that time. Superti-Furga et al. (1995) reported the case of a newborn with achondroplasia who did not carry the mutation at nucleotide 1138 changing glycine-380 to arginine but had a mutation causing substitution of a nearby glycine with a cysteine (134934.0003). The FGFR3 gene was isolated and studied in connection with a search for the Huntington disease gene. The distribution of FGFR3 mRNA in embryonic mouse tissues was found to be more restricted than that of FGFR1 (136350) and FGFR2 (176943) mRNA. Outside of the developing central nervous system, the highest level of FGFR3 mRNA was found to be in the prebone cartilage rudiments of all bones, and during endochondral ossification, FGFR3 was detected in resting but not hypertrophic cartilage (Peters et al., 1993). The glycine-to-arginine substitution would have a major effect on the structure, function, or both of the hydrophobic transmembrane domain and most likely would have a significant effect on the function of the receptor. Five of 6 ACH homozygotes were homozygous for the G-to-A transition and each of 6 sporadic cases, including the parents of 2 of the homozygotes, were heterozygous for the 1138A allele and the wildtype allele. The fact that FGFR3 transcripts are present in fetal and adult brain (which has the highest levels of any tissue) may have relevance in connection with the megalencephaly which is thought to occur in achondroplasia (Dennis et al., 1961). FGFR3 codes for at least 2 isoforms of the gene product by alternate use of 2 different exons that encode the last half of the third immunoglobulin domain (IgIII), which is primarily responsible for the ligand-binding specificity. The isoforms are preferentially activated by the various fibroblast growth factors. Rump et al. (2006) reported a Dutch infant with a severe form of achondroplasia caused by 2 de novo mutations in the FGFR3 gene on the same allele: the common G380R mutation (134934.0001) and L377R (134934.0027). Allele-specific PCR analysis confirmed that the 2 mutations were in cis. From birth, the child had severe respiratory difficulties with multiple hypoxic episodes due to a combination of upper airway obstruction, pulmonary hypoplasia, and cervicomedullary compression. He eventually became ventilator dependent and died at age 4 months. Horton (2006) reviewed work on the nature of the basic defect in achondroplasia. After mutations in FGFR3 were identified as the basis of achondroplasia in 1994, attention turned to how the mutation disturbed linear bone growth. Biochemical studies of the FGFR3 receptor combined with knockout experiments in mice revealed that FGFR3 is a negative regulator of chondrocyte proliferation and differentiation in the growth plate and that the mutations in achondroplasia and related disorders activate the receptor. Thus they can be viewed as gain-of-function mutations. Heuertz et al. (2006) screened 18 exons of the FGFR3 gene in 25 patients with hypochondroplasia and 1 with achondroplasia in whom the common mutations G380R and N540K had been excluded. The authors identified 7 novel missense mutations, including 1 in the patient with achondroplasia (S279C; 134934.0030). Heuertz et al. (2006) noted that 4 of the 6 extracellular mutations created additional cysteine residues and were associated with severe phenotypes.
Early estimates on the prevalence of achondroplasia are undoubtedly incorrect because of misdiagnosis. For example, Wallace et al. (1970) reported 2 female sibs as examples of achondroplasia; both died in the neonatal period and showed, in addition to ... Early estimates on the prevalence of achondroplasia are undoubtedly incorrect because of misdiagnosis. For example, Wallace et al. (1970) reported 2 female sibs as examples of achondroplasia; both died in the neonatal period and showed, in addition to chondrodystrophy, central harelip, hypoplastic lungs, and hydrocephalus. Without radiographic studies it is impossible to identify the nature of this condition, but it is certainly not true achondroplasia; Jeune asphyxiating thoracic dystrophy (208500), thanatophoric dwarfism (187600), and achondrogenesis are each possibilities. Using modern diagnostic criteria, Gardner (1977) estimated the mutation rate at 0.000014. Orioli et al. (1986) reported on the frequency of skeletal dysplasias among 349,470 births (live and stillbirths). The prevalence rate for achondroplasia was between 0.5 and 1.5/10,000 births. The mutation rate was estimated to be between 1.72 and 5.57 x 10(-5) per gamete per generation. The stated range is a consequence of the uncertainty of diagnosis in some cases. (The thanatophoric dysplasia/achondrogenesis group had a prevalence between 0.2 and 0.5/10,000 births. Osteogenesis imperfecta had a prevalence of 0.4/10,000 births. Only 1 case of diastrophic dysplasia was identified.) In the county of Fyn in Denmark, Andersen and Hauge (1989) determined the prevalence of generalized bone dysplasias by study of all children born in a 14-year period. The figures, which they referred to as 'point-prevalence at birth,' showed that achondroplasia was less common than generally thought (1.3 per 100,000), while osteogenesis imperfecta (21.8), multiple epiphyseal dysplasia tarda (9.0), achondrogenesis (6.4), osteopetrosis (5.1), and thanatophoric dysplasia (3.8) were found to be more frequent. Stoll et al. (1989) found a mutation rate of 3.3 x 10(-5) per gamete per generation. In Spain, Martinez-Frias et al. (1991) found a frequency of achondroplasia of 2.53 per 100,000 live births. Total prevalence of autosomal dominant malformation syndromes was 12.1 per 100,000 live births. Using data from 7 population-based birth defects monitoring programs in the United States, Waller et al. (2008) estimated the prevalence of achondroplasia and thanatophoric dysplasia and presented data on the association between older paternal age and these conditions. The prevalence of achondroplasia ranged from 0.36 to 0.60 per 10,000 live births (1/27,780-1/16,670 live births). The prevalence of thanatophoric dysplasia ranged from 0.21 to 0.30 per 10,000 live births (1/33.330-1/47,620). The data suggested that thanatophoric dysplasia is one-third to one-half as frequent as achondroplasia. The differences in the prevalence of these conditions across monitoring programs were consistent with random fluctuation. In Texas, fathers that were 25-29, 30-34, 35-39, and over 40 years of age had significantly increased rates of de novo achondroplasia and thanatophoric dysplasia among their offspring compared with younger fathers.
Both the clinical and radiologic features of achondroplasia have been well defined [Langer et al 1967], although no formal diagnostic algorithms have been published....
DiagnosisClinical DiagnosisBoth the clinical and radiologic features of achondroplasia have been well defined [Langer et al 1967], although no formal diagnostic algorithms have been published.The clinical features of achondroplasia include the following:Small statureRhizomelic (proximal) shortening of the arms and legs with redundant skin folds on limbsLimitation of elbow extensionShort fingersTrident configuration of the handsGenu varum (bow legs)Thoracolumbar kyphosis in infancyExaggerated lumbar lordosis, which develops when walking beginsLarge head with frontal bossingMidfacial retrusion and depressed nasal bridgeThe radiographic findings of achondroplasia in children include the following:Short, robust tubular bonesNarrowing of the interpediculate distance of the caudal spineRounded ilia and horizontal acetabulaNarrow sacrosciatic notchProximal femoral radiolucencyMild, generalized metaphyseal changesMolecular Genetic TestingGene. FGFR3 is the only gene in which mutations are known to cause achondroplasia.Clinical testingTable 1. Summary of Molecular Genetic Testing Used in AchondroplasiaView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityFGFR3Targeted mutation analysisc.1138G>A (p.Gly380Arg)~98%Clinical c.1138G>C (p.Gly380Arg) ~1%Sequence analysis of select exonsSequence variants in the selected exons 2, 3See footnote 4Sequence analysisSequence variants in the gene 2, 3>99% 51. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions, missense, nonsense, and splice site mutations.3. These methods should be used only when the suspicion of achondroplasia based on clinical and radiographic grounds is high and the two common mutations are not found. Typically, sequence analysis of selected exons is designed to detect the few reported mutations known to cause achondroplasia. Sequence analysis of the entire coding region detects these known mutations and also has the potential of detecting novel sequence variants, whose clinical significance may be unknown.4. Includes the two mutations detected by targeted mutation analysis5. Shiang et al [1994], Bellus et al [1995], Rousseau et al [1996]Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo confirm/establish the diagnosis in a proband. An individual with typical clinical and radiographic findings of achondroplasia does not generally need molecular confirmation of the diagnosis. In those in whom there is any uncertainty: Targeted mutation analysis for the two common mutations should be pursued first.Sequence analysis can be performed when the suspicion of achondroplasia based on clinical and radiographic grounds is high and targeted mutation analysis for the two common mutations is negative. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersOther phenotypes associated with mutations in FGFR3 include:HypochondroplasiaFGFR-related craniosynostosisThanatophoric dysplasia (types I and II)SADDAN (severe achondroplasia with developmental delay and acanthosis nigricans) dysplasia. SADDAN dysplasia is a rare disorder characterized by extremely short stature, severe tibial bowing, profound developmental delay, and acanthosis nigricans. Unlike individuals with thanatophoric dysplasia, those with SADDAN dysplasia survive past infancy. An FGFR3 Lys650Met mutation has been identified in affected individuals [Bellus et al 1999, Zankl et al 2008]. Note that acanthosis nigricans may also be seen in persons with classic achondroplasia [Alotzoglou et al 2009].
Other, extensive summaries of the natural history and appropriate interventions in individuals with achondroplasia have been published [Trotter et al 2005, Pauli 2010]....
Natural HistoryOther, extensive summaries of the natural history and appropriate interventions in individuals with achondroplasia have been published [Trotter et al 2005, Pauli 2010].Individuals with achondroplasia have short stature caused by rhizomelic shortening of the limbs, characteristic facies with frontal bossing and midfacial retrusion, exaggerated lumbar lordosis, limitation of elbow extension and rotation, genu varum, brachydactyly, and trident appearance of the hands. Excess mobility of the knees, hips, and most other joints is common. Average adult height for men with achondroplasia is 131±5.6 cm; for women, 124±5.9 cm. Obesity is a major problem in achondroplasia [Hecht et al 1988]. Excessive weight gain is manifest in early childhood. In adults, obesity can aggravate the morbidity associated with lumbar stenosis and contribute to nonspecific joint problems and possibly to early mortality from cardiovascular complications [Hecht et al 1988]. In infancy, mild to moderate hypotonia is typical, and acquisition of developmental motor milestones is delayed and also shows unusual, aberrant patterns [Fowler et al 1997, Ireland et al 2010]. Infants have difficulty in supporting their heads because of both hypotonia and large head size. Intelligence is normal unless hydrocephalus or other central nervous system complications occur.True megalencephaly occurs in individuals with achondroplasia and most children with achondroplasia are macrocephalic [Horton et al 1978]. Hydrocephalus requiring treatment, which probably occurs in 5% or fewer [Pauli 2010], may be caused by increased intracranial venous pressure because of stenosis of the jugular foramina [Pierre-Kahn et al 1980, Steinbok et al 1989]. Some infants with achondroplasia die in the first year of life from complications related to the craniocervical junction; population-based studies suggest that this excess risk of death may be as high as 7.5% [Hecht et al 1987]. The risk appears to be secondary to central apnea associated with damage to respiratory control centers [Nelson et al 1988, Pauli et al 1995], and can be minimized by comprehensive evaluation of every infant with achondroplasia [Trotter et al 2005] and selective neurosurgical intervention. In one study [Pauli et al 1995] all children undergoing surgical decompression of the craniocervical junction showed marked improvement of neurologic function. Quality of life indices determined up to 20 years after such surgery were comparable to quality of life indices in those for whom surgery was not indicated in childhood [Ho et al 2004].Obstructive sleep apnea, common in both older children and adults [Waters et al 1995, Sisk et al 1999], arises because of a combination of midfacial retrusion resulting in smaller airway size [Stokes et al 1983, Waters et al 1995], hypertrophy of the lymphatic ring and, perhaps, abnormal innervation of the airway musculature [Tasker et al 1998].Middle ear dysfunction is frequently a problem [Berkowitz et al 1991], which, if inadequately treated, can result in hearing loss of sufficient severity to interfere with language development. Bowing of the lower legs is exceedingly common in those with achondroplasia [Kopits 1988a]. More than 90% of untreated adults have some degree of bowing [Kopits 1988a]. ‘Bowing’ is actually a complex deformity arising from a combination of lateral bowing, internal tibial torsion and dynamic instability of the knee [Inan et al 2006].Kyphosis at the thoracolumbar junction is present in 90%-95% of infants with achondroplasia [Kopitz 1988b, Pauli et al 1997]. In about 10% it does not spontaneously resolve and can result in serious neurologic sequelae [Kopits 1988b]. Preventive strategies [Pauli et al 1997] may reduce the need for surgical intervention [Ain & Browne 2004, Ain & Shirley 2004].The most common medical complaint in adulthood is symptomatic spinal stenosis involving L1-L4 [Kahanovitz et al 1982]. Symptoms range from intermittent, reversible, exercise-induced claudication to severe, irreversible abnormalities of leg function and of continence [Pyeritz et al 1987].Increased mortality in adults with achondroplasia has been reported [Hecht et al 1987, Wynn et al 2007]. In the latter study, there was a tenfold increase in heart disease-related mortality between ages 25 and 35 and, overall, life expectancy appeared to be decreased by about ten years. Homozygous achondroplasia, caused by the presence of two mutant alleles at nucleotide 1138 of FGFR3, is a severe disorder with radiologic changes qualitatively different from those of achondroplasia. Early death results from respiratory insufficiency because of the small thoracic cage and neurologic deficit from cervicomedullary stenosis [Hall 1988].
While more than 100 skeletal dysplasias that cause short stature are recognized, many are extremely rare; and virtually all have clinical and radiographic features that readily distinguish them from achondroplasia. Conditions that may be confused with achondroplasia include the following:...
Differential DiagnosisWhile more than 100 skeletal dysplasias that cause short stature are recognized, many are extremely rare; and virtually all have clinical and radiographic features that readily distinguish them from achondroplasia. Conditions that may be confused with achondroplasia include the following:Hypochondroplasia (also usually caused by mutations in FGFR3). This distinction is sometimes the most difficult to make. In fact, there appears to be some overlap between the radiologic and clinical phenotypes of these two conditions [Almeida et al 2009].Thanatophoric dysplasiaCartilage-hair hypoplasia (metaphyseal chondrodysplasia, McKusick type)Pseudoachondroplasia (a clinically and genetically distinct skeletal dysplasia; the similar nomenclature, however, may cause confusion)Other metaphyseal dysplasiasNote to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
Clinical manifestations in achondroplasia vary modestly. In order to establish the extent of disease in an individual diagnosed with achondroplasia, the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisClinical manifestations in achondroplasia vary modestly. In order to establish the extent of disease in an individual diagnosed with achondroplasia, the following evaluations are recommended:Genetics consultation and, if feasible, consultation with a clinician experienced in caring for children with bone dysplasiasDocumentation of length, weight, and head circumference compared with achondroplasia-specific growth standardsAssessment of the craniocervical junction including neurologic history and examination, computerized tomography of the craniocervical junction, and polysomnographyBaseline computerized tomography of the brainTreatment of ManifestationsRecommendations for management of children with achondroplasia were outlined by the American Academy of Pediatrics Committee on Genetics [Trotter et al 2005]. The recommendations of the committee are meant to supplement guidelines available for treating the child with average stature. A recent review [Pauli 2010] updates the information available in Trotter et al [2005]. The recommendations include (but are not limited to) the following:Short statureA number of studies have assessed growth hormone (GH) therapy as a possible treatment for the short stature of achondroplasia [Seino et al 2000, Kanaka-Gantenbein 2001, Kanazawa et al 2003]. In general, these and other series show initial acceleration of growth, but with lessening effect over time. Only modest effects on adult stature seem to accrue. Extended limb lengthening using various techniques remains an option for some. Increases in height of up to 12-14 inches may be obtained [Peretti et al 1995, Ganel & Horoszowski 1996, Yasui et al 1997, Aldegheri & Dall’Oca 2001]. Although some have advocated performing these procedures as early as ages six to eight years, many pediatricians, medical geneticists, and ethicists have advocated postponing such surgery until the young person is able to participate in making an informed decision. At least in North America, only a tiny proportion of affected individuals elect to undergo extended limb lengthening. The Medical Advisory Board of Little People of America has published a statement regarding use of extended limb lengthening.Obesity. Measures to avoid obesity should start in early childhood. Standard weight and weight-by-height grids specific for achondroplasia [Hunter et al 1996, Hoover-Fong et al 2007] should be used to monitor progress. Note that the body mass index has not been standardized for individuals with achondroplasia and will yield misleading results; thus, body mass index should not be used in this population until normal ranges are established.HydrocephalusIf increased intracranial pressure arises, referral to a neurosurgeon is needed. Because of the presumed mechanism giving rise to hydrocephalus in this population, probably ventriculoperitoneal shunting, rather than third ventriculostomy, is appropriate.Craniocervical junction constrictionThe best predictors of need for suboccipital decompression include: Lower-limb hyperreflexia or clonusCentral hypopnea demonstrated by polysomnographyReduced foramen magnum size, determined by CT examination of the craniocervical junction and by comparison with the norms for children with achondroplasia [Pauli et al 1995]. If there is clear indication of symptomatic compression, urgent referral to a pediatric neurosurgeon for decompression surgery should be initiated [Bagley et al 2006].Obstructive sleep apneaTreatment may include the following:AdenotonsillectomyWeight reductionContinuous positive airway pressure Tracheostomy for extreme casesImprovement in disturbed sleep and some improvement in neurologic function can result from these interventions [Waters et al 1995]. In rare instances in which the obstruction is severe enough to require tracheostomy, surgical intervention to advance the midface has been used to alleviate upper airway obstruction [Elwood et al 2003].Middle ear dysfunctionRoutine management of frequent middle-ear infections, persistent middle-ear fluid, and consequent hearing loss should be undertaken as needed. Speech evaluation by age two years should be undertaken if any concerns arise on screening.Varus deformityCriteria for surgical intervention have been published previously [Kopits 1980, Pauli 2010]. Presence of progressive, symptomatic bowing should prompt referral to an orthopedist. Various interventions may be elected (e.g. valgus-producing and derotational osteotomies, guided growth using 8-plates).Kyphosis. A protocol to help prevent the development of a fixed, angular kyphosis is available [Pauli et al 1997]: In children in whom spontaneous remission does not arise after trunk strength increases and the child begins to walk, bracing is usually sufficient to prevent persistence of the thoracolumbar kyphosis. If a severe kyphosis persists, spinal surgery may be necessary to prevent neurologic complications [Ain & Browne 2004, Ain & Shirley 2004]. Spinal stenosisIf severe signs and/or symptoms of spinal stenosis arise, urgent surgical referral is appropriate. Extended and wide laminectomies [Pyeritz et al 1987, Lonstein 1988], need to be done as soon as possible [Carlisle et al 2011].Socialization Because of the highly visible nature of the short stature associated with achondroplasia, affected persons and their families may encounter difficulties in socialization and school adjustment. Support groups (see Resources), such as the Little People of America, Inc (LPA), can assist families with these issues through peer support, personal example, and social awareness programs. Information on employment, education, disability rights, adoption of children with short stature, medical issues, suitable clothing, adaptive devices, and parenting is available through a national newsletter, seminars, and workshops.Prevention of Secondary ComplicationsFor issues related to the secondary complications that may arise in achondroplasia, see Treatment of Manifestations and Surveillance.SurveillanceGuidelines for surveillance are incorporated into the American Academy of Pediatrics clinical report [Trotter et al 2005].Growth. Monitor height and weight at each physician contact using growth curves standardized for achondroplasia [Horton et al 1978, Hoover-Fong et al 2007]Development. Screening of developmental milestones throughout infancy and early childhood should be performed and compared with those specific for achondroplasia [Fowler et al 1997, Ireland et al 2010].Head growth and risk for hydrocephalusComplete baseline CT scan (or MRI) of the brain in infancyMonitoring of head circumference using growth curves standardized for achondroplasia [Horton et al 1978] throughout childhoodCraniocervical junctionEvery infant should have a CT scan (or MRI) of the craniocervical junction in infancy, with comparison of foramen magnum size to diagnostic-specific standards [Hecht et al 1989]. Overnight polysomnography should also be completed in infancy and interpreted with consideration of features important in assessing the craniocervical junction [Pauli et al 1995]. Neurologic examination including for signs of cervical myelopathy should be incorporated into each physical examination in infancy and childhood. Sleep apneaInquiry should be made regarding signs and symptoms of sleep apnea. If worrisome nighttime or daytime features arise, then polysomnography should be completed.Ears and hearingIn addition to newborn screening, each infant should have tympanometric and behavioral audiometric evaluation by age approximately one year. Evidence for middle ear problems or hearing loss should be sought throughout childhood.KyphosisThe spine of the infant and child should be clinically assessed every six months until age three years. If severe kyphosis appears to be developing, radiologic assessment is needed (lateral in sitting or standing, depending on age, and lateral cross-table prone or cross-table supine over a bolster).Legs. Clinical assessment for development of bowing and/or internal tibial torsion should be part of each physical assessment.Spinal stenosis. Because adults with achondroplasia are at increased risk for spinal stenosis, a clinical history and neurologic examination is warranted every three to five years once the person with achondroplasia reaches adulthood.Adaptation to difference. Inquiry regarding social adjustment should be part of each primary physician contact.Agents/Circumstances to AvoidParticularly in childhood, care must be taken to limit risk for injury to the spinal cord at the craniocervical junction. This should include proscription of activities including collision sports (e.g., American football, ice hockey, rugby), use of a trampoline, diving from diving boards, vaulting in gymnastics, and hanging upside down from knees or feet on playground equipment. Protocols have been published regarding positioning that should be avoided in order to decrease the likelihood of development of a fixed, angular kyphosis [Pauli et al 1997].There is no increased risk for bone fragility or joint degeneration, and no circumstances to avoid related to these. Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy Management Cephalo-pelvic disproportion may necessitate delivery by Caesarian section when the pregnant woman is of average stature and the fetus has achondroplasia.Pregnant women with achondroplasia must always be delivered by Caesarian section because of the small size of the pelvis.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Achondroplasia: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDFGFR34p16.3Fibroblast growth factor receptor 3FGFR3 @ LOVDFGFR3Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Achondroplasia (View All in OMIM) View in own window 100800ACHONDROPLASIA; ACH 134934FIBROBLAST GROWTH FACTOR RECEPTOR 3; FGFR3Normal allelic variants. The 4.3-kb cDNA has 19 exons and encodes an 806-residue protein (isoform 1).Pathologic allelic variants. More than 99% of individuals with achondroplasia have one of two mutations in FGFR3. Two different substitutions at nucleotide 1138 both result in the amino acid change p.Gly380Arg (Table 2). Several exceptions with mutations at other nucleotides have been reported. (For more information, see Table A, HGMD database.)Table 2. Selected FGFR3 Pathologic Allelic Variants in AchondroplasiaView in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequencesc.1138G>A p.Gly380ArgNM_000142.4 NP_000133.1c.1138G>Cp.Gly380ArgSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). Normal gene product. Fibroblast growth factor receptor 3. The mature FGFR3 protein, like all of the FGFRs, is a membrane-spanning tyrosine kinase receptor with an extracellular ligand-binding domain consisting of three immunoglobulin (Ig) subdomains, a transmembrane domain, and a split intracellular tyrosine kinase domain [Laederich & Horton 2010]. Alternative splice sites in the FGFR genes result in tissue-specific isoforms [Chellaiah et al 1994].FGFR3 is activated by various fibroblast growth factors (FGFs) [Ornitz 2005]. Binding appears to result in receptor dimerization, transactivation of tyrosine kinase and transphosphorylation of tyrosine residues [Plotnikov et al 1999] These modifications result in activation of a number of downstream signaling pathways, including signal transducer and activator of transcription (STAT) and mitogen-activated protein kinase (MAPK) [Deng et al 1996, Eswarakumar et al 2005]. Overall, these secondary pathways cause slowing of proliferation and differentiation of chondrocytes [Dailey et al 2003].Abnormal gene product. The p.Gly380Arg mutation resulting in achondroplasia causes constitutive activation of FGFR3, which is, through its inhibition of chondrocyte proliferation and differentiation, a negative regulator of bone growth [Horton & Degnin 2009]. Indeed, the members of the family of bone dysplasias that includes hypochondroplasia, achondroplasia, SADDAN dysplasia, and thanatophoric dysplasia type I and II [Spranger 1985] are the result of allelic FGFR3 mutations that result in a graded series of such activating mutations [Naski et al 1996, Vajo et al 2000]. Although the precise consequences of the achondroplasia mutation in FGFR3 are still uncertain, the net result is excess inhibitory signaling in growth plate chrondrocytes [Ornitz 2005], principally, it appears, through the MAPK pathway [Zhang et al 2006]. A variety of therapeutic approaches are suggested by current understanding of FGFs, FGFRs, MAPK, and proteins interacting with the MAPK pathway, such as C-type natriuretic peptide [Yasoda et al 2004, Kake et al 2009, Laederich & Horton 2010].