Achondroplasia and Other Dwarfisms

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CHAPTER 219 Achondroplasia and Other Dwarfisms

Hypochondroplasia, achondroplasia, and thanatophoric dysplasia are clinically related skeletal dysplasias caused by gain-of-function mutations of the fibroblast growth factor receptor 3 (FGFR3) gene. The phenotype, disproportionately short stature with rhizomelic shortening of the extremities, results from defective formation of endochondral bone.

Hypochondroplasia yields the mildest phenotype, which varies within and between families and frequently lacks the neurological complications often seen in achondroplasia, such as hydrocephalus, cervicomedullary compression, and spinal stenosis. Life expectancy in this group may approach normal. The pathologic features of micromelic short stature—reduced or unchanged interpedicular distances in the lumbar spine, disproportionately long fibulas, squared and shortened pelvic ilia, and reduced subischial leg length—are significantly less in hypochondroplasia than in achondroplasia. Achondroplastic patients have increased age-specific mortality rates at all ages, with the highest increase occurring in childhood. Cervicomedullary compression probably accounts for the excess deaths in children; however, cardiovascular causes of death appear to be increased in adults. Individuals with thanatophoric dysplasia seldom survive to adulthood.

Given our present understanding of the short-limb dysplasias, neurosurgical approaches to achondroplastic, thanatophoric, and hypochondroplastic patients are similar. Hydrocephalus and cervicomedullary compression are typically pediatric concerns, whereas spinal stenosis has traditionally been treated in adults; however, increased sensitivity to signs of spinal stenosis and improved surgical technology have allowed earlier treatment of clinically significant spinal compression. The initial symptoms frequently do not have strictly neurosurgical resolutions; thus, a comprehensive treatment plan involving a multidisciplinary team of physicians that includes a neurosurgeon, neurologist, pulmonary specialist, sleep specialist, geneticist, anesthesiologist, neuroradiologist, orthopedic surgeon, and otolaryngologist is useful.13 Because these patients are at risk for brainstem compression, comprehensive testing is directed toward the detection of central and obstructive apnea and cervicomedullary compression, all of which contribute to the risk for sudden death.

Several areas of research are leading to new initiatives in the management of skeletal dysplasias. First is the application of advanced diagnostic tools and imaging techniques.4 Second is an emphasis on outcome studies, a movement based on the well-supported assumption that different operative strategies can yield marked long-term differences in the patient’s health.4,5 Third, a better understanding of molecular biology has led to fresh ideas for targeted molecular treatment of achondroplasia, namely, those that inhibit the excess FGFR3 signals that are present in these individuals. A fourth area, the use of recombinant growth hormone to treat pediatric patients, is outside the scope of this chapter. Here, we describe our current approach to the evaluation and management of short-limb dysplasias and summarize the molecular biology, diagnostic findings, and outcome studies, mostly from our own institution.

Genetics and Epidemiology

Achondroplasia is an autosomal dominant disorder that results from a guanine (G)-to-adenine (A) mutation at base 1138 (G1138A) in the FGFR3 gene on chromosome 4 at 4p16.3.68 The gene codes for a tyrosine kinase receptor expressed in developing bones. The nucleotide (missense) mutation results in an amino acid glycine (Gly)-to-arginine (Arg) substitution at amino acid 380 (Gly380Arg) in the transmembrane domain of the protein. Penetrance of the Gly380Arg mutation is 100%; in other words, all individuals with the mutation will have achondroplasia. A few patients with achondroplasia have been demonstrated to instead have a Gly375Cys mutation of the FGFR3 gene.9 Achondroplasia appears to be genetically homogeneous. No significant racial difference has been detected in North America, Spain, Korea, Japan, China, or Sweden.1015

The FGFR3 hypochondroplasia mutation pattern is more diverse than that for achondroplasia.14,1618 In many patients, a C1620G or C1620A mutation results in an asparagine-to-lysine substitution at amino acid 540 (N450K) in the FGFR3 proximal tyrosine kinase domain. In a substantial number of patients who express a mild phenotype, the mutation has yet to be identified.16 The phenotypic diversity confounds estimates of incidence data. Accurate prenatal ultrasonographic diagnosis is rare.19 Before identification of the specific nucleotide mutations, some achondroplasia case reports probably included patients with hypochondroplasia. This overlap should be considered in efforts to compare current and past case series.

An arginine-to-cysteine (R248C) substitution in the extracellular domain of the receptor has been found in thanatophoric patients. Other mutations are likely because at least two phenotypes have been identified, thanatophoric dwarfism type I and type II. Less is known about this dysplasia because the mutation is almost always lethal neonatally.20

Compound mutations for achondroplasia and hypochondroplasia have been reported in children whose achondroplastic father or mother had the G380R mutation and the other parent had the hypochondroplasia N450K mutation.21,22 The phenotypic expression of the compound mutation appears to be more severe than that of achondroplasia.22

New mutations account for about 80% of children born with achondroplasia. In other words, most infants with FGFR3 mutations are born to parents without FGFR3 mutations. As in many autosomal dominant conditions, a positive correlation exists between advanced paternal age and the occurrence of new mutations. It was initially thought that factors influencing DNA replication or repair during spermatogenesis, but not during oogenesis, may predispose to occurrence of the G1138A mutation in the FGFR3 gene.23 However, more recent evidence suggests that sperm with the FGFR3 mutation have a selective advantage over sperm with a normal FGFR3 gene, thereby increasing the number of affected sperm with age.2426 Offspring of couples who are both affected by achondroplasia have a 25% chance of inheriting both parental achondroplasia alleles, thereby resulting in homozygous achondroplasia, which is almost universally fatal within the first year of life.27 The skeletal features of achondroplasia are highly exaggerated in the homozygous condition: significantly shorter limbs, a smaller chest size, and a smaller foramen magnum. A brief summary of medical complications by age is presented in Table 219-1.

Approximately 150 skeletal dysplasias have been identified, a number of which are associated with neurological symptoms.28 Achondroplasia is the most common in clinical series. Although frequency estimates cluster between 1 in 10,000 and 1 in 35,000 live births, the true frequency must be recalculated because these data were generated before the FGFR3 mutations were identified.6,7,29,30

The FGFR3 gene encodes one of four tyrosine kinase receptors for fibroblast growth factor (FGFR1 to FGFR4) in mammals.31 Mutations of FGFR3 in achondroplasia have been shown to cause a gain of function, which correlates with the severity of the clinical phenotype.32,33 FGFR3 normally functions as an inhibitor of linear bone growth by acting negatively on both the proliferation and differentiation of growth plate chondrocytes.34,35 In achondroplasia, the normal function of FGFR3 is exaggerated. Numerous cellular mechanisms have been proposed that describe the increase in receptor tyrosine kinase activity that is common in all of the FGFR3 mutations in achondroplasia.32

Medical Complications

Most individuals with achondroplasia have normal intelligence. A cross-sectional survey (using self-reported 36-item short form health survey [SF-36] data) of the functional health status of adults with achondroplasia revealed that the mental component summary scores did not differ significantly from scores in the general population. In contrast, the physical component summary scores were significantly lower starting in the fourth decade of life.36 In children, motor milestones are delayed, partly because of generalized hypotonia and partly because of the mechanical disadvantage imposed by short limbs.1,27,3739 Psychosocial problems arising from short stature include lack of acceptance by peers and the tendency for adults, including parents and teachers, to treat children with achondroplasia appropriately for their height rather than their age.40,41 Quality-of-life issues on which the patient’s perceived status is suboptimal require special attention during adolescence.42 Involvement in support groups with other families who have children of short stature can improve self-esteem and assist parents in guiding their achondroplastic children through the difficulties of growing up in a culture that often equates stature with status.

Reproductive difficulties have not been conclusively documented, but reduced fertility, frequent fibroid cysts, and early menopause have been reported. The decreased reproductive rates in achondroplastic individuals may have been due in part to the social stigma present in those with reduced height in finding potential mates. However, with the establishment of organizations for those with reduced height, such as Little People of America, these individuals are now more likely to marry and have children.32 Women with achondroplasia must deliver their infants by cesarean section because of cephalopelvic disproportion,43 and the administration of spinal anesthesia is strongly discouraged.44

Obstructive sleep apnea, or sleep-disordered breathing secondary to a small upper airway, is common. Tonsillectomy and adenoidectomy decrease the degree of upper airway obstruction in most children. The majority do not have significant obstructive or central apnea, but a considerable minority are severely affected.4548 The cause of different patterns of sleep disorders may be related to localized alterations in chondrocranial development.46 Many infants sleep with their necks in a hyperextended position, which functionally increases the size of the upper airway. Although the hyperextended neck position relieves intermittent obstruction, it can also exacerbate the neurological sequelae of cervicomedullary compression related to a small foramen magnum. Abnormal respiratory sinus arrhythmias may be present.49 A small thoracic cage can result in restrictive pulmonary disease in infancy. Respiration may be further compromised by aspiration secondary to gastroesophageal reflux, swallowing dysfunction, or both, and result in recurrent pneumonia. Anesthesia can be given safely to children, with special consideration for limited neck extension and the use of appropriately sized endotracheal tubes.47

A relatively high rate (about 3%) of jugular bulb dehiscence—complete absence of the roof over the jugular bulb—was identified in a series of 126 achondroplastic children. This increased incidence may account for unexplained hearing loss, tinnitus, and self-audible bruits in these children and poses a risk for difficult-to-control bleeding at myringotomy.50

Evaluation and Diagnosis

Cervicomedullary Compression

Clinical Findings and Pathology

Cervicomedullary compression stems primarily from a reduction in the diameter of the foramen magnum in both the sagittal and coronal dimensions, a reduction that is sometimes more than 5 SD less than normal.5156 Cervicomedullary compression warrants early and aggressive treatment because it results in high cervical myelopathy and increases the risk for sudden death by central respiratory failure.5760 A prospective evaluation of achondroplastic infants found radiographic evidence of craniocervical stenosis in 58% of the patients studied, and a diagnosis of cervicomedullary compression was made in 35%.61 Although these figures are derived from a selected population and are therefore higher than for the general population, they are a strong argument for careful evaluation and treatment of achondroplastic children. A retrospective study found increased mortality (in comparison to population standards) in achondroplastic children younger than 4 years, with sudden death from brainstem compression identified as the cause of half of the deaths. The same study also found a 7.5% risk for sudden death in the first year of life.27

Chronic medullary and upper cervical cord compression may exist as a neurologically asymptomatic lesion and exhibit neither signs of root compression in the arms nor symptoms of cranial nerve impairment. Nonetheless, microcystic histopathologic changes, cervical syringomyelia, necrosis, and gliosis have been reported in autopsies of achondroplastic children who died unexpectedly. Presumably, lesions of this type interrupt the neural respiratory pathways from the nucleus tractus solitarii to the phrenic nerve nucleus, thereby arresting the muscles of inspiration and resulting in sudden death in some cases. We therefore consider infants with a history of sleep apnea or other severe respiratory or neurological abnormalities to be at increased risk for respiratory complications resulting from occult cervicomedullary compression. Some authors have recommended performing sleep and imaging studies on all children with achondroplasia.62 We believe that a careful history and neurological examination should precede costlier and more uncomfortable diagnostics. A composite profile of patients with cervicomedullary compression includes upper or lower extremity paresis, apnea or cyanosis, hyperreflexia or hypertonia, and delay in motor milestones beyond achondroplastic standards. These patients can present a striking contrast to the usual floppy, hypotonic achondroplastic infant.63

Indications for Surgery

Concerns have been expressed about the indications for surgical decompression of the foramen magnum in this population.6567 Radiographic studies during the first years of life show some degree of compression at the foramen magnum level. MRI evidence of spinal cord compression, such as indentation or narrowing of the upper cervical cord, is a common finding that is usually graded as “marked” or “severe” in the MRI report.65 In one report, myelomalacia was observed in 13 of 30 achondroplastic children.55 Yet other than the routinely observed generalized hypotonia seen in the achondroplastic population, the majority of these children are asymptomatic and outgrow their developmental delays.66,6870 Cervicomedullary decompression (CMD) as a standard routine prophylactic measure is therefore not warranted.

Several groups have published guidelines for surgical intervention.68,69,71 Our indications are based on lower limb symptoms, polysomnography, and MRI flow studies. The underlying principle must be to identify patients who are at risk for neurological damage or sudden death. We recommend that patients with cervicomedullary compression be identified and treated prophylactically, before abrupt and irreversible changes occur. For the purpose of diagnosis, we define clinically significant cervicomedullary compression to be (1) neurological evidence of upper cervical myelopathy or chronic brainstem compression (apnea, lower cranial nerve dysfunction, swallowing difficulties); (2) evidence of stenosis on imaging studies, including the absence of flow above and below the foramen magnum; and (3) frequently an otherwise unexplained respiratory or developmental abnormality.

Hunter and coworkers conducted a multicenter review of 193 patients with chondrodysplasias. The study reported data on rates of medical complications at specific age intervals (see Table 219-1). At age 4 the rate of cervicomedullary compression was 6.8%. The authors emphasized the important role of surgery, primarily because progressive neurological symptoms continue into adulthood. Ultimately, about 17% of the patients in the series underwent CMD.72

Hydrocephalus

Clinical Findings and Pathology

Hydrocephalus in an achondroplastic patient is probably secondary to deformation of the cranial base. Constriction of the basal foramina, particularly the jugular foramina, is thought to reduce venous drainage and potentially raise intracranial venous pressure. Investigators have demonstrated a correlation between the degree of venous narrowing at the jugular foramina and the degree of hydrocephalus in achondroplaasia.73 In theory, absorption of CSF into the sagittal venous sinus is thus reduced and results in hydrocephalus.56 However, identifying patients at high risk for hydrocephalus is currently not possible. Hydrocephalus may resolve in some patients with continued growth of the skull base during puberty.

It is easy to suspect hydrocephalus in a patient with achondroplasia, given that macrocrania is a morphologic hallmark of the disease. Concerns about hydrocephalus may also arise because of the enlarged ventricles and the delayed acquisition of gross motor skills. Although hydrocephalus is associated with enlarged ventricles in the achondroplastic population, it generally resolves through growth and maturation of the cranial bones.74 An achondroplastic child typically displays transient hypotonia, but the papilledema that is expected with symptomatic hydrocephalus is rare. Radiographically, mild to moderate ventricular enlargement, prominent cortical sulci, and an increased frontal subarachnoid space are apparent. Hydrocephalus severe enough to require shunting is often discovered after craniocervical decompression, when CSF leaks often complicate wound healing.

Indications for Surgery

Stenosis of the jugular foramina contributes to the altered CSF dynamics in achondroplasia.56 Jugular foramen decompression is an option.77 However, we believe that this option should be used only in children with severe jugular stenosis and debilitating hydrocephalus in whom conventional ventriculoperitoneal shunting is contraindicated. Given the high percentage of complications, shunting is best reserved for those in whom the symptoms are severe and threatening.54 CSF pressure profiles can be determined with an external transducer attached to an open fontanelle, with an epidural pressure monitor, or with an intraventricular catheter in older patients. If no critical pressure elevations are detected during a 48-hour period, shunt placement is not required, ventriculomegaly notwithstanding. However, the presence of severe clinical stigmata for hydrocephalus obviates such demonstrations.

For patients who have undergone craniocervical decompression, we expect sustained intracranial pressure (ICP) to be less than 20 mm Hg during the immediate postoperative period. Transient increases above this level can be associated with activity or irritation in normal individuals. In situations in which ICP is abnormally elevated, we proceed with shunting. In situations in which the interpretation is equivocal, we extend the period of monitoring for 1 or 2 days. Occasionally, even when no elevation in ICP is documented, a persistent CSF leak or subgaleal collections of CSF develop soon after the ventriculostomy is removed but are not necessarily indicative of hydrocephalus. We take a more aggressive approach to shunting, however, if subcutaneous collections develop over the site of craniocervical decompression.