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International Birth Defects Information Systems

International Birth Defects Information Systems

(Harold Chen, M.D. and Wladimir Wertelecki, M.D.)

Topics: Chondrodystrophia fetalis | Chondrodysplasia fetalis | Chondrodystrophic dwarfism | Heterozygous achondroplasia | Homozygous achondroplasia |

Service Related: Support Groups | Professional Associations | Key Information Sources |

Languages: | English |

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Major Criteria : Symptoms | Signs | Associated Findings
Imaging Signs : MRI | Radiologic Features
Laboratory Findings: Histology | Molecular genetics
Prenatal Diagnosis : Ultrasonography | Molecular testing
Differential Diagnosis : Hypochondroplasia | Hypochondroplasia-achondroplasia compound heterozygote | Thanatophoric dysplasia (TD) | Pseudoachondroplasia
Age of Detectability: Childhood/Adulthood/Fertility/Aging
Sex Ratio

Major Criteria

Delayed motor milestones during infancy and early childhood (Todorov et al, 1981)

Sleep disturbances can be the result of both neurological and respiratory complications.

A high prevalence (75%) of breathing disorders during sleep. The most significant and very common breathing abnormality in children with achondroplasia is upper airway obstruction causing obstructive apnea (Zucconi et al, 1996). The majority of respiratory complaints are due to restrictive lung disease secondary to diminished chest size or upper airway obstruction and rarely due to spinal cord compression (Reid et al, 1987).

More than 50% of patients with spinal stenosis as a consequence of a congenitally small canal develop symptoms. These include back pain, lower extremity sensory changes, incontinence, and paraplegia (Kahanovitz et al, 1982; Fortuna et al, 1989). Symptoms usually do not appear until the 20s or 30s. Lutter and Langer (1977) devised a classification scheme based on neurologic severity and presentation of spinal stenosis:

Type I (back pain with sensory and motor change of an insidious nature)
Type I (intermittent claudication limiting ambulation)
Type III (nerve root compression)
Type IV (acute onset paraplegia)

Foramen magnum stenosis can present as respiratory difficulty, feeding problems, cyanosis, quadriparesis, and poor head control.

Pain, ataxia, incontinence, apnea, progressive quadriparesis, and respiratory arrest may be caused by cervicomedullary compression (Gordon, 2000).

Disproportionate short stature (dwarfism)

Hypotonia during infancy and early childhood

All patients have relative stenosis of the foramen magnum, documented by CT (Wang et al, 1987). Foramen magnum stenosis is considered the cause of increased incidence of hypotonia, sleep apnea and sudden infant death syndrome. Symptomatic hydrocephalus in infancy and early childhood can rarely be due to narrowing of the foramen magnum.

Disproportionately large head with frontal bossing, depressed nasal bridge, midfacial hypoplasia, narrow nasal passages, prognathism, and dental malocclusion

A normal trunk length

A thoracolumbar kyphosis or gibbus is usually present at birth.

Exaggerated lumbar lordosis when the child begins to ambulate.

Prominent buttocks and protuberant abdomen secondary to increased pelvic tilt in children and adults

Generalized joint hypermobility, especially the knees

Rhizomelic micromelia (relatively shorter proximal segment of the limbs compared to the middle and the distal segments)

Limited elbow and hip extension Trident hands (inability to approximate the third and fourth fingers in extension produces a ‘trident' configuration of the hand)

Short fingers (brachydactyly)

Bowing of legs (genu varum) due to lax knee ligaments

Excess skin folds about thighs

Associated Findings:
Recurrent otitis media during infancy and childhood (Hunter et al, 1998). Otitis media can cause conductive hearing loss and delayed language development.

Dental crowding


Psychosocial problems related to body image

Imaging Signs

Diagnostic imaging consists of standard radiographs, MRI, and CT-myelography MRI:
Craniocervical MRI may reveal narrowing of the foramen magnum, effacement of the subarachnoid spaces at the cervicomedullary junction, abnormal intrinsic cord signal intensity, and mild to moderate ventriculomegaly (Keiper et al, 1999).

Radiologic Features:
Skull: Relatively large calvaria, prominent forehead, depressed nasal bridge, small skull base, small foramen magnum

Spine: Caudal narrowing of interpedicular distances in the lower lumbar spine, short vertebral pedicles, wide disc spaces, dorsal scalloping of the vertebral bodies in newborn, concave posterior aspect of the vertebral bodies in childhood and adulthood, different degree of anterior wedging of the vertebral bodies causing gibbus

Pelvis: lack of iliac flaring, narrow sacroiliac notch, horizontal acetabular portions of the iliac bones

Limbs: rhizomelic micromelia, square or oval radiolucent areas in the proximal humerus and femur during infancy, tubular bones with widened diaphyses and flared metaphyses during childhood and adulthood, markedly shortened humeri, short femoral neck, disproportionately long fibulae in relation to tibiae

Laboratory Findings

Epiphyseal and growth plate cartilages have a normal appearance histologically but the growth plate is shorter than normal and that the shortening is greater in homozygous than in heterozygous achondroplasia, suggesting a gene dosage effect (Horton, 1988).

Molecular genetics:
About 98% of achondroplasia have G-to-A transition and about 2% have G-to-C transversion at nucleotide 1138 (Bellus et al, 1995). Both mutations resulted in the substitution of an arginine residue for a glycine at position 380 of the mature protein in the transmembrane domain of fibroblast growth factor receptor 3 (FGFR3) (Shiang et al, 1994; Rousseau et al, 1994). A rare mutation causing substitution of a nearby glycine 375 with a cysteine has also been reported (Superti-Furga et al, 1995).

Prenatal diagnosis

In cases of parents with normal heights, achondroplasia may be suspected on routine ultrasound examinations revealing a fall-off in limb growth usually during the third trimester of pregnancy. About one third of cases are suspected by this way. However, one must be careful because disproportionately short limbs are observed in a variety of conditions. Specific diagnosis of achondroplasia usually cannot be made with certainty with ultrasonography unless by radiography late in gestation or after birth.

An affected parent, having 50% risk of having a similarly affected child, may request prenatal diagnosis by ultrasonography to optimize obstetric management.

If both parents are affected, the pregnancy is at risk for heterozygosity (50%) and homozygosity (25%). The pregnancy should be followed by a femoral growth curve in the second trimester by serial ultrasound scans to enable prenatal distinction between homozygous, heterozygous, and unaffected fetuses (Patel and Filly, 1995).

Molecular testing:
The number of mutations causing achondroplasia is very limited and the methodology is simple requiring only one PCR and one restriction digest. Molecular technology can be applied to prenatal diagnosis of a fetus suspected of or at risk for having achondroplasia.

Prenatal diagnosis of achondroplasia homozygotes in families at risk and in which parents are heterozygous for either the 1138A or 1138C allele can be made by amniocentesis or chorionic villus sampling (Shiang et al, 1994; Bellus et al, 1994).

Differential Diagnosis

Hypochondroplasia is an autosomal dominant disorder. Short stature is evident by school age. The facial appearance is usually normal, although mild macrocephaly may be present. The limbs are disproportionately short compared with the length of the trunk. The hands and feet are short and broad; there is no trident hand deformity. Slight lumbar lordosis, with a sacral tilt, mild limitation of elbow extension, and genu varum may be present. Spinal stenosis and neurologic complications are rare. Skeletal features are usually similar but milder to achondroplasia. Radiographic criteria are available for hypochondroplasia (Hall and Spranger, 1979).

Two mutations (C1620A and C1620G) result in a lysine for asparagines substitution at codon 540 of FGFR3 have been recently described in hypochondroplasia (Bellus et al, 1995; Prinos et al, 1995). About 70% of affected individuals are heterozygous for a mutation in the FGFR3 gene.

Hypochondroplasia-achondroplasia compound heterozygote:
A hypochondroplastic parent and achondroplastic parent may have a child with hypochondroplasia-achondroplasia, a genetic compound. The severity of the child is intermediate between heterozygous and homozygous achondroplasia. Both the hypochondroplasia (Asn540Lys) and achondroplasia (Gly380Arg) mutations have been demonstrated at the FGFR3 locus in a patient with the genetic compound.

Severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN) dysplasia (Bellus et al, 1999)

FGFR3 mutation results in severe disturbances in endochondral bone growth in SADDAN dysplasia. The phenotype overlaps that of thanatophoric dysplasia type I, but most often is compatible with survival into adulthood. Unusual bone abnormalities include femoral bowing with reverse (i.e., posterior apex) tibial and fibular bowing and “ram's horn” bowing of the clavicle. In addition to skeletal dysplasia, progressive acanthosis nigricans, and central nervous system structural anomalies, seizures and severe developmental delays are observed in surviving SADDAN patients. Despite its location within the same FGFR3 codon as the thanatophoric dysplasia type II mutation (Lys650Glu) and a similar effect on constitutive activation of the FGFR3 tyrosine kinase, the Lys650Met is not associated with cloverleaf skull or craniosynostosis.

Thanatophoric dysplasia (TD):
Thanatophoric dysplasia is probably the most common lethal neonatal dwarfism. The head is disproportionally large, with frontal bossing, bulging eyes, and severely depressed or indented nasal bridge. A cloverleaf anomaly of the skull can be associated with thanatophoric dysplasia. The neck is short. The chest is extremely narrow due to short ribs. The abdomen appears protuberant. Severe respiratory distress, caused by hypoplastic lungs and constricted thoracic cage, lead to early death. Limbs are extremely short, with thickened skin and excessive skin folds. The arms are usually outstretched and the legs are externally rotated, with abducted thighs.

Characteristic radiographic findings include relatively large calvarium, a small foramen magnum, trilobed skull with a towering calvarium and bitemporal bulging in the cloverleaf skull type, very short ribs with cupped anterior ends, diminished heights of vertebral bodies, increasing interverteral disc spaces, “inverted U-shaped or H-shaped” vertebral bodies, narrow interpedunculate distance at the lumbar level, short pelvis with small sacrosciatic notches, extremely shortened long bones of the limbs, flared metaphyses, and "telephone-receiver"-like curved femora in the non-cloverleaf type.

The hallmark of the histologic findings is a generalized disruption of endochondral ossification. The physis is characterized by a lack of column formation, with minimal proliferation or hypertrophy.

Two forms (TD1, TD2) of thanatophoric dysplasia have been postulated based on subtle differences in skeletal radiographs. Patients with TDI have mutations in Arg248Cys (Tavormina et al, 1995a), Ser249Cys (Tavormina et al, 1995b), and stop codon (807) (Rousseau et al, 1995); patients with TD II have Lys650Glu mutations (Tavormina et al, 1995a).

Pseudoachondroplasia, a short-limbed dwarfism, is inherited in an autosomal dominant fashion. Clinically, it has little resemblance to achondroplasia.

Other short-limbed dwarfisms

Autosomal dominant disorder with complete penetrance

About 80% of the cases are sporadic, the result of a de novo mutation

Paternal age effect (advanced paternal age in sporadic cases) (Penrose, 1955)

Gonadal mosaicism (two or more children with classic achondroplasia born to normal parents) (Bowen, 1974; Fryns et al, 1983; Philip et al, 1988)

Clinical findings, radiographic features, and FGFR3 mutation analysis detect carriers.

The basic defect is in the zone of chondroblast proliferation in the physeal growth plates. As a consequence, the bones preformed in cartilage are markedly foreshortened in length, compared to the bones formed by membranous ossification (skull, facial bones) or by apophyseal growth (ilium, os clcis) are normal. The remaining physeal growth mechanisms, such as columnization, hypertrophy, degeneration, calcification and ossification, take place normally although the amount formed is significantly less (ref?).

Achondroplasia is, thus, the result of a quantitative loss rather than the formation of abnormal tissue. Since the subperiosteal membranous ossification of tubular bones is normal, the diameter of the bones is normal. The results are production of short, thick tubular bones, leading to short stature with disproportionately shortened limbs.

The specific mechanisms by which FGFR3 mutations disrupt skeletal development in achondroplasia remain elusive.

Age of Detectability

Achondroplasia can be detected prenatally or at birth.

Large head of the affected infant may cause obstetrical problems and also creates an increased risk of intracranial bleeding during delivery (Hall et al, 1982).

Marked obstetrical difficulties secondary to very narrow pelvis of achondroplastic women

Neurological complications including, small foramen magnum, cervicomedullary junction compression causing sudden unexpected death in infants with achondroplasia (Pauli et al, 1984), apnea, communicating hydrocephalus, spinal stenosis, paraparesis, quadriparesis, and infantile hypotonia

Thoraco-lumbar gibbus

Osteoarthropathy of the knee joints

Obesity is a major problem by aggravating the morbidity associated with lumbar stenosis and contributes to the nonspecific joint problems and to the possible early cardiovascular mortality in this condition (Hecht et al, 1988)

Sex Ratio:
No sexual predilection

Achondroplasia is the most common form of short-limbed dwarfism.

Gene frequency is estimated to be 1/16,000 and 1/35,000 (ref).

There are about 5,000 achondroplasts in the U.S.A. and 65,000 on Earth (Warkany, 1971).

The prevalence rate for achondroplasia is between 0.5 and 1.5 in 10,000 births.

The mutation rate is high and is estimated to be between 1.72 and 5.57 x 10-5 per gamete per generation (Orioli et al, 1986). Most infants with achondroplasia are born unexpectedly to parents of average stature.

Achondroplasia is caused by mutations in the gene of the FGFR3 (Shiang et al, 1994; Rousseau et al, 1994) on chromosome 4p16.3 (Francomano et al, 1994; Velinov et al, 1994).

Measurements of growth and head circumference using growth curves standardized for achondroplasia (Horton et al, 1978).

Careful neurologic examinations, including CT, MRI, somatosensory evoked potentials and polysomnography

No therapy is necessary for early motor delay (poor head control until 3 or 4 months, delay walking until 2 or 3 years of age) since motor development will eventually be normal.

Dorsal kyphosis during infancy secondary to hypotonia – Avoid sitting position and encourage ventral position until good trunk strength is obtained to prevent a permanent gibbus or kyphosis due to anterior wedging of the first two lumbar vertebrae. Kyphosis in achondroplasia is probably preventable (Hall, 1988). Bracing with a modified thoracolumbosacral orthoses (TLSO) should be implemented for thoracolumbar kyphosis persisting after 3 years of age (Winter and Herring, 1983).

Management of recurrent middle ear infections and associated conductive hearing loss and dental crowding

Obstructive sleep apnea may be improved by adenotonsillectomy, weight loss, and nasal-mask continuous positive airway pressure (CPAP) (Waters et al, 1995). Adenoidectomy and/or tonsillectomy are effective, but recurrent symptoms are common, particularly when the initial procedure is adenoidectomy. General anesthesia can be given safely to these patients with special consideration for limited neck extension and appropriate endotracheal tube size (Sisk et al, 1999). Central apnea may be improved by surgical treatment of hydrocephalus; progressive cor pulmonale, obstructive and central sleep apnea, and gastroesophageal reflux with small airway pathology may require multiple treatment modalities including foramen magnum decompression (Tasker et al, 1998).

Avoid neurosurgical interventions on a latent hydrocephalus unless sudden increase in head size and presence of increased intracranial pressure

Infants with achondroplasia are at risk for potentially lethal sequelae of craniocervical junction abnormalities. Neurosurgical referral may be needed if there is any evidence of central apnea, reflex asymmetry, extreme hypotonia, or early hand preference. The best predictors of need for suboccipital decompression for cervicomedullary-junction compression include lower limb hyperreflexia or clonus, central hypopnea demonstrated by polysomnography, and foramen magnum measures below the means for children with achondroplasia (Pauli et al, 1995). Only rarely, decompression of the foramen magnum is necessary when clinical and imaging examinations reveal spinal cord compression.

The most common complication during adulthood is related to lumbosacral spinal stenosis with compression of the spinal cord or nerve roots (Hecht and Butler, 1990; Pyeritz et al, 1987). Surgical decompression is needed to manage this complication, especially when there is sufficient craniocervical junction compression (Pauli et al, 1995)

Tibial osteotomies or epiphysiodesis of the fibular growth plate to correct severe genu varum, preferably deferred until after cessation of growth

Dietary restriction and regular exercise for obesity should begin in early childhood. Obesity occurs in about one-third of patients with achondroplasia and often develops by mid to late childhood. It may aggravate lumbar lordosis, spinal stenosis, obstructive apnea, and other respiratory problems. A person with achondroplasia may only need half of the calories of an average-sized individual of the same age.

Surgical lengthening of limb bones may provide additional increase in height of up to 12-14 inches over an 18-24 month period (Yasui et al, 1997; Ganel and Horoszowski, 1996). Complications of this procedure include pain, pin infections, and neurologic and vascular compromise resulting from rapid lengthening. Currently, it is advisable to postpone such procedure until an affected individual is old enough to make an informed decision.

Recombinant human growth hormone treatment has been shown to increase growth rate in achondroplasia but there may be individual variability in the response to growth hormone treatment (Weber et al, 1996). Growth hormone therapy is also shown to increase growth rate, serum insulin-like growth factor (IGF)-I, IGF-binding protein-3, and osteocalcin without adverse effect. Growth hormone therapy appears to be a useful method for improvement of severe growth retardation of achondroplasia (Seino et al, 2000).

The fertility in achondroplasia is normal. However, achondroplastic pregnant women are considered at high risk. Respiratory compromise is common during the third trimester and baseline pulmonary function studies should be carried out before pregnancy to aid in evaluation and management. A small pelvic outlet usually requires Cesarean section under general anesthesia since the spinal or epidural approach is contraindicated because of spinal stenosis (Allanson and Hall, 1986).

Anticipatory guidance: Patients and their families can benefit greatly from anticipatory guidance published by American Academy of Pediatrics Committee on Genetics (1995).

Adaptations of patients to the environment to foster independence include lowering faucets and light switches, use of a step stool to keep feet from dangling when sitting, use of step stools, an extended wand for toileting, and adaptations of toys for short limbs (Milisa and Pearson, 1998).

Support groups: Many families find it beneficial to interact with other families and children with achondroplasia through local and national support groups.

Little people of America
P.O. Box 745
Lubbock, Texas 79408
Tel: (888) LPA-2001

The Billy Barty Foundation
929 W. Olive Ave., Suite C
Burbank, CA 91506
Tel: (818) 953-5410

MAGIC Foundation for Children Growth
1327 North Harlem Avenue
Oak Park, IL 60302
Tel: (800) 362-4423

The vast majority of individuals with achondroplasia have normal intelligence and lead healthy, independent, and productive lives (Rogers et al, 1979). Rarely, intelligence may be affected secondary to hydrocephalus or other CNS complications.

Mean adult height is approximately 131 cm + 5.6 for males and 124 cm + 5.9 for females. Presence of severe disproportionate short stature can cause a number of psychosocial problems.

Life span for heterozygous achondroplasia is usually normal unless there are serious complications. A mean life expectancy is approximately 10 years less than the general population (Hecht et al, 1987).

Homozygous achondroplasia is a lethal condition with severe respiratory distress caused by rib-cage deformity. Radiographic changes are much more severe than the heterozygous achondroplasia. The patients die soon after birth.

An affected individual (heterozygous) has a 50% risk of transmitting the disorder to offspring.

Recurrence risk of achondroplasia in the sibs of achondroplastic children with unaffected parents is presumably higher than twice the mutation rate because of gonadal mosaicism. Currently, the risk is estimated as 1 in 443 (0.02%) (Mettler and Fraser, 2000).

If both parents are affected, there is a 25% risk for the offspring to be homozygous for the achondroplasia allele, resulting in a much more severe phenotype that is usually lethal early in infancy. There is also a 50% risk of having achondroplasia (heterozygous) offspring. There is still a 25% chance that the offspring will be normal.

In case of prenatally diagnosed achondroplasia, one should explore the options available to the family for the management and rearing of the child using a nondirective approach. This includes discussion of pregnancy interruption, as well as continuation of pregnancy and rearing of affected child at home, foster care, or adoption.

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