This may be a serious consideration given concerns about the effects on synaptogenesis of anesthesia in young babies [ ]. This should be performed in a sleep center comfortable with assessing infants.
Interpretation can be complicated by restrictive pulmonary issues with decreased respiratory reserve. Emphasis, of course, should be on assessing central apnea and hypopnea. In our center, only in infants who have worrisome features based on these initial assessments is magnetic resonance imaging MRI completed. Generally, we now obtain the MRI in both flexion and extension [ , ].
MRI, too, requires careful interpretation specific to achondroplasia. All infants will have narrowing at the foramen magnum. Most infants with achondroplasia will have obliteration of the posterior subarachnoid fluid layer Fig. These features must be interpreted in light of clinical characteristics, since clearly some babies with all of these features do well and thrive without decompressive surgery personal observations.
Prudence commends that MRI studies be reviewed by a neuroradiologist with experience and expertise in achondroplasia in order to limit unneeded surgeries.
The presence of either a T-2 signal abnormality Fig. Sagittal views of magnetic resonance imaging of the cervical cord in four infants with achondroplasia. Various alternatives have been suggested and used. Such prospective investigations of what evaluation scheme is most helpful are desperately needed but very difficult to develop. Better visualization of neural tissue is forthcoming, but usually sedation or general anesthesia will be needed because of the length of the procedure. Often multiposition MRI is elected [ , ].
Flow studies may be of some help as well in determining whether surgical intervention is warranted [ , ]. Three dimensional CT might be another alternative [ ], as might be diffusion tensor MRI imaging [ ]. This obviates the need for anesthesia and the possible risks that this entails both immediate and, at least speculatively, long term [ ]. However, while sufficient for many purposes, detail obtained by fast-MRI is not sufficient to definitively determine the need for surgery related to the craniocervical junction.
It has even been suggested that no imaging at all be routinely done in infants with achondroplasia [ ]. However, this recommendation appears to be based on no objective, published evidence [ ]. Table 1 summarizes the advantages and disadvantages of various approaches to imaging in infancy. There is clear need to objectively assess which approach or approaches are most advantageous. At a minimum, standards for MRI or fast-MRI features and measurements in infants with achondroplasia need to be generated [ ], if this is to become the routine method of anatomic evaluation.
Some have also suggested a step-wise protocol. Bober, personal communication While logical, such stepwise assessment has not yet been rigorously assessed and should not be embraced without evidence to support it. Likewise, the suggestion that polysomnography is not predictive of craniocervical junction concern, and so implying that it is not an essential assessment [ ], is based on a small, retrospective series of patients, of whom many were well outside the age range of relevance, and is not worthy of further consideration.
Somatosensory evoked potentials could be of considerable benefit in identifying infants at high risk. Early experience, however, suggested that most infants with achondroplasia showed abnormalities of somatosensory evoked potentials, and that it failed to discriminate between those at high risk and others [ 8 ]. However, other investigations suggest that there may be a role of evoked potentials in the assessment of the craniocervical junction in infants with achondroplasia [ , , ]. Should any prospective studies of efficacy of evaluations be initiated in the future, somatosensory evoked potential testing should probably be included in such a protocol.
Counseling regarding cautions that should be exercised with every infant with achondroplasia are based, in part, on the presumed mechanism of injury at the craniocervical junction and, in part, on the circumstances that have been observed in instances of unexpected infant deaths.
As noted, risk likely is related to a combination of foramen magnum constriction, the typically large head of achondroplasia and poor head control, which often takes longer to develop in infants with achondroplasia. Uncontrolled head movement should, then, be avoided. There is anecdotal evidence that deaths are particularly likely to arise in babies who have been placed in vertical automatic swings [ 4 , ]; in fact, I am aware of at least six instances in which babies with achondroplasia have died in vertical automatic swings.
There also have been multiple instances of life-taking or life-threatening events in car seats [ ] and personal observations. Use of a neck roll in strollers, and, particularly, in car seats. When restrained, infants with achondroplasia, who have large and prominent occiputs, will have their necks in a forced flexed position.
In those infants where assessment demonstrates unequivocal cord compression resulting in clinical abnormalities, then suboccipital decompression should be completed urgently [ , ]. Operative intervention may be particularly challenging because of the unique anatomy of the skull in achondroplasia [ , ].
Major complications of decompressive surgery are rare [ ] and the quality of life of those undergoing decompression is not compromised long term [ ].
If, as suggested, such intervention is lifesaving, then with universal assessment and intervention 4—5 lives per year should be spared in the United States, and around per year worldwide. As noted, there is evidence that routine assessment and intervention as outlined does decrease mortality in infants with achondropasia [ ]. Infants with achondroplasia often have small chests [ 63 ]. In addition, there is increased compliance of the rib cage, sometimes dramatically so.
That excess compliance is manifest as paradoxical movement with inspiration in most young infants with achondroplasia — sinking inward principally of the inferolateral part of the chest, but also often substernally. Mild deformity of the chest may also be present [ ], including lateral indentations and pectus excavatum. The combination of these features — small chest, presumably but not certainly reflecting smaller anatomic lung volumes, inefficient chest mechanics, and chest deformity — together may result in smaller effective lung volumes.
Despite these features, most babies suffer no evident consequences. Predictably it does result in more rapid desaturations with physiologic sloppiness of central respiratory control or with minor obstructive events, making interpretation of polysomnography more challenging in young infants. In a small proportion this set of features can result in chronic hypoxemia.
This is particularly likely in those living at high altitude personal observations. Chronic hypoxemia can be of sufficient severity to result in failure to thrive presumably because of increased work of breathing , rarely respiratory failure, and, potentially, cor pulmonale if not addressed [ , , ]. Assessment is straightforward.
Clinically persistent marked tachypnea, secondary feeding difficulties because of that tachypnea, additional signs of chronic respiratory distress and failure to thrive may be present.
In all babies with achondroplasia polysomnography needs to be completed for other indications see above. This also will provide a long oximetry sample. Saturation dips into the high 80s are normal in infants with achondroplasia personal observation. In addition, daytime spot oximetries, both during active alert time and, particularly, during feedings for example, may be helpful.
Chest circumference measures compared with achondroplasia standards may also be of some help [ 63 ]. In those with restrictive pulmonary disease, the help of a pediatric pulmonologist should be sought. Oxygen supplementation alone may be sufficient to maintain saturations and reverse failure to thrive. If not, tracheostomy may be needed. In all, it has been temporary. Given that the activating mutation of FGFR3 that results in achondroplasia causes a general inhibition of endochondral bone growth, of course one would anticipate that all of the long bones of the body will grow slowly; and they do.
Small stature is the signal characteristic of achondroplasia. Although length at birth may be normal [ 61 , ], slow growth is evident shortly thereafter.
Moderate to marked short stature is present in all affected individuals. Remarkably few parents of average children understand the importance of routine measurement of growth — that growth is an excellent, nonspecific indication of general well-being.
Therefore, standard growth charts specific for achondroplasia [ 61 , ] should be used Fig. In addition to these hand-smoothed curves, statistically more rigorous growth curves for a U. Diagnostic specific linear growth charts for females left and males right with achondroplasia. Comparable curves for average statured individuals are shaded.
Clinton, SC: Jacobs [ ]. These standards are based on a U. Growth references for other populations are also available [ , , ]. The achondroplasia mutation modifies rather than negates other genetic determinants of growth [ ]. Height variability in individuals with achondroplasia seems to correlate just as strongly with parental heights as it is in average individuals.
That is, tall parents will tend to have tall achondroplastic offspring and short parents, shorter than average achondroplastic children.
There is uncertainty whether individuals with achondroplasia do [ ] or do not [ ] show a normal adolescent growth spurt. Small stature has substantial consequences for the affected individual.
There may be psychological sequelae, which possibility needs to be addressed with parents and the affected individual. Physical limitations result, as well, and there will be need for environmental adaptations, particularly in school see below. Note, however, that sitting height is near normal [ ]. This is of relevance with respect to, for example, safe transitions from carseat to booster and regarding adaptive needs for driving.
To date no treatment has been devised that will negate the effects on growth of achondroplasia but see also Possible future therapies below. A substantial number of studies have been published regarding the use of growth hormone therapy to enhance growth in children with achondroplasia for example [ , , ]. A transient increase in growth velocity is predictably found, but the effect diminishes with length of treatment.
Of the many published studies, virtually none has followed treated children to the completion of their growth [ ]. However, Harada et al. Most families recognize the disadvantages of both daily injections and the accompanying medicalization of small stature, and few elect to pursue growth hormone therapy.
Extended limb lengthening is offered as another option for height enhancement [ , , , ]. A variety of techniques have been used, generally through osteotomies and gradual distraction using external fixators. This is a long and arduous process.
High complication rates can be expected [ ]. It has been used in many patients with achondroplasia; most of these lived outside of the United States, perhaps because of different attitudes toward outwardly evident physical differences.
Most care providers and ethicists in this country have advocated that such surgery be postponed until the affected individual can participate in decision making that is, in preadolescence or later , and that it should only be completed in a center offering comprehensive, multidisciplinary care [ ].
Early in life feeding difficulties may arise because of tachypnea, gastroesophageal reflux, oromotor hypotonia or some combination of these. Together with increased work of breathing see above , failure to thrive may result.
Thereafter, however, obesity is prevalent, probably far more prevalent than in the population at large [ ]. Excess weight may be particularly problematic in persons with achondroplasia related to potential neurologic and orthopedic sequelae [ ]. Both weight for age [ ] Fig. The weight-by-height charts are helpful in caring for adults as well. Reproduced with permission from Hoover-Fong JE et al. Reproduced with permission from Hunter et al. Am J Med Genet — [ ]. For those who elect to use the Body Mass Index BMI to assess for obesity [ ], note should be made that standards for average individuals will incorrectly define most individuals with achondroplasia as being obese.
This arises because of the marked differences in body proportions [ ]. Diagnosis specific BMI standards are now available Fig. Diagnosis-specific body mass index standards for children with achondroplasia. Am J Clin Nutr — [ ]. All currently available ponderal standards are population based — they reflect what is , not necessarily what should be. Energy expenditure and caloric need appear to be less in those with achondroplasia [ ]. Although typical interventions to prevent or treat excess weight are usually effective, this means that efforts at weight loss may need to be more rigorous and aggressively supported.
Bariatric surgical procedures have been successfully carried out in obese adults with achondroplasia [ ] and personal observations. Cognitive function is normal in most persons with achondroplasia [ , ], although it has long been recognized that developmental delays, particularly motor delays, are common [ , ].
Of course, cognitive issues may arise secondary to other sequelae of achondroplasia — hydrocephalus, hypoxic injury and so forth. Furthermore, untreated obstructive sleep apnea may have serious developmental consequences in children with achondroplasia [ ]. The first attempt to provide standards for comparison of development in a child with achondroplasia to similarly affected peers was that of Todorov et al.
Furthermore, it addressed possible delays in development but not differences in development. Subsequent studies have emphasized the motor issues that are often present in young children with achondroplasia [ , ].
Children with achondroplasia are not only uniformly motor delayed, but display unusual patterns of motor development [ ]. A number of bioanatomic differences appear to underlie these differences — including marked rhizomelic shortening Fig. Together such features make typical pre-orthograde movement strategies senseless for a baby with achondroplasia. Although such strategies may elicit parental concern, in fact they should be viewed as normal and adaptive differences in children with achondroplasia.
Fowler et al. The occurrence of such unique movement strategies has been confirmed in a prospective study of Ireland et al. Position — remarkably, a comfortable one — illustrating the large joint hypermobility that is present in younger children with achondroplasia. As described in the text, movement is effected by pushing with the feet, sliding the head forward.
Reverse snowplowing. Here pushing with the heels propels the child who is also supported by the back of the head. Originally published in Fowler ES et al. J Dev Behav Pediatr — [ ]. Preorthograde motor movement strategies for infants with achondroplasia. Gross motor delays are substantial. Median age of walking independently is around 18 [ ] or 19 [ 9 ] months.
Those medians hide a remarkably broad range, so that first independent walking may not occur until well after the 2nd birthday [ 9 ]. Gross motor issues may be sufficient that with increasing age they result in greater caregiver dependence [ ]. Fine motor differences also appear to have biophysical bases, including brachydactyly and trident configuration of the fingers Fig. While fine motor issues are less marked and attainment of fine motor skills much less delayed than gross motor ones [ 9 , ], differences are frequently observed.
For example, because of brachydactyly and hypermobility of the wrists and fingers, there often is persistence of a four-finger grasp Fig.
As children get older there often are complaints of fine motor fatigability, inability to exert sufficient pressure with pencils, etc. Demonstration of wrist hypermobility in a school-aged child with achondroplasia. Four-finger grasp. Two-finger grasp taking advantage of the trident configuration gap between the third and fourth fingers. A larger than expected number of children with achondroplasia have language delays [ , ]. Documented delays are most often of expressive language [ 9 , ].
Unrecognized persistent or fluctuating hearing loss is common in those with achondroplasia see Ears and hearing , and may explain much of these expressive delays [ ].
It also may, in part, arise from how adults interact with children with achondroplasia [ 9 ]. It may in part be related to the expression of FGFR3 in the brain [ ].
It appears that quite infrequently, but still at a higher frequency than in the general population, children with achondroplasia may have autism spectrum disorders [ ]. This possibility has not yet been adequately documented or confirmed. Currently the most helpful screening tool is that of Ireland et al.
This, or other standards, should be used in screening every child with achondroplasia. A developmental screening tool developed by Ireland et al. It is currently the best alternative for developmental screening of children with achondroplasia.
Reproduced with permission from Ireland PJ et al. Dev Med Child Neurol — [ 9 ]. Most individuals with achondroplasia are macrocephalic [ 61 ]. Large head size appears to have multiple contributing factors. Megalencephaly of mild degree is typical [ ], perhaps because of direct effects of FGFR3 on brain morphogenesis [ 47 ]; typically there is both ventriculomegaly and excess extra-axial fluid [ ], presumably a result of a mechanism shared with the process that sometimes results in hydrocephalus [ ] — see below.
All children with achondroplasia should have head circumference measurements at every health care contact, with those plotted on achondroplasia specific head circumference standards [ 61 ] Fig. Plotting head circumferences on typical standards will give the spurious impression of accelerating head growth with crossing of centiles.
Head circumference reference standards for females left and males right with achondroplasia. Comparable measurements for average stature individuals are shaded. Although Hunter et al. A more recent study reported an incidence of 4. This is more in keeping with our own experience. In some individuals there is transient acceleration of head growth with few or no accompanying symptoms suggestive of increased intracranial pressure.
Then there may be re-equilibration, rechanneling of head growth Fig. This suggests that in symptom free individuals a period of watchful waiting is appropriate [ ], even if imaging demonstrates increasing ventriculomegaly compared with imaging obtained in early infancy. Sequential head circumference measurements in a boy with achondroplasia. Neuroimaging at that age did demonstrate increased ventricular size compared with imaging completed in the first year of life.
There was subsequent equilibration of head growth without intervention. Now an adult, the individual is of normal intelligence and without any indicators of any harmful effects of this transient acceleration and re-equilibration. In a few children it appears that there is intermittent, episodic increased intracranial pressure [ 25 , , ]. This may result in acute and severe symptoms, but without persistence.
Whether this is present and relevant can only be assessed with intracranial pressure monitoring [ ]. Rarely infants will have acute and dramatic signs and symptoms of hydrocephalus. More often, its development is more insidious, with mild and difficult to pinpoint symptoms such as lethargy, irritability, headache etc. In those instances signs become more important. Unlike the obstructive hydrocephalus typically encountered, the mechanism of development of hydrocephalus in achondroplasia is thought to be distinctive.
Just as the foramen magnum is of diminished size because the cranial base is endochondral bone, so, too, the jugular foramina on either side of the foramen magnum are smaller.
Evidently, this can lead to partial obstruction of venous flow through them [ ], which in turn results in increased intracranial venous pressure. Intracranial venous hypertension causes limitation of venous resorption of cerebrospinal fluid [ , ]. Along with causing increasing cerebrospinal fluid accumulation and, at some critical tipping point, increased intracranial pressure, the obstruction of venous outflow at the jugular foramina causes alternative flow to become more important.
The emissary veins assume that role of collateral channels [ , ] resulting in prominence of superficial veins of the scalp and skull Fig. Sudden increase in superficial venous prominence probably is indicative of worsening outflow obstruction at the jugular foramina and increased risk that hydrocephalus is developing.
Typical superficial venous prominence in an infant with achondroplasia. This arises from increased flow through emissary veins secondary to increased resistance to flow at the jugular foramina. Although this is likely the most important mechanism, there is also evidence that obliteration of cerebrospinal fluid flow at the craniocervical junction may be a factor in development of hydrocephalus, too [ , , , ].
It is not unreasonable to posit that there are two distinct processes that can give rise to increased intracranial pressure in those with achondroplasia. In those who clearly need treatment, ventriculoperitoneal shunting is standard [ 1 , 4 ]. Surgical and post-surgical care are no different than in others without achondroplasia who require shunting. One might think that jugular foramenotomy would be the logical approach, and this has been successfully done [ ].
However, this is challenging surgery and has not supplanted use of ventriculoperitoneal shunting. Third ventriculostomy has been carried out in a few children with achondroplasia, apparently successfully [ , ]. Good outcomes with this procedure which should not be effective if intracranial venous hypertension rather than obstruction is the mechanism of hydrocephalus could mean either that intervention was not really needed, or that a second, obstructive mechanism such as flow restriction at the craniocervical junction may sometimes be important [ ].
If there are, in fact, two distinct mechanisms giving rise to hydrocephalus in those with achondroplasia, distinguishing which mechanism or mechanisms is operative in an individual is not straightforward.
Distinguishing which intervention is most effective is, in theory, uncomplicated. Prospective randomization to two alternative treatment arms of patients presenting with signs and symptoms of hydrocephalus is easy to envisage.
However, in practice such a trial is virtually impossible. Over the course of 30 years, the largest specialty clinics assess around unique individuals with achondroplasia [ 10 ]. Each such clinic, then, would identify only around 0. The failed embryos were homozygous for the mutant agouti-allele suggesting that it is a recessive lethal allele. The agouti gene is responsible for the color of the coat in mice.
This gene codes for an agouti-signaling protein, which is responsible for melanin distribution in mammals. The wild-type allele gives rise to gray-brown coat color in mice, while the mutant allele gives rise to yellow coat color. In addition to coat color, the agouti gene is associated with the yellow mouse obesity syndrome, characterized by early onset of obesity and tumors. The progeny never showed the phenotypic ratio expected from a monohybrid cross.
Instead, they showed a phenotypic ratio of yellow to grey mice. Little demonstrated that the missing yellow mice were dying in the embryonic stage. The embryo carried both recessive mutant alleles, a homozygous condition that affects the differentiation of both the inner cell mass ICM and trophectoderm, the outer layer of the blastocyst. Some recessive lethal alleles cause genetic disorders in humans.
For example, achondroplasia is a genetic disorder that affects bone development resulting in short-limbed dwarfism. It is caused by a dominant allele, which means the presence of a single copy of the mutated allele causes the disorder.
However, when the same allele is present in homozygous form, it becomes lethal and causes death during embryonic development.
Even though the disease is caused by a dominant allele, the lethality is recessive; hence, it is called a recessive lethal allele. Similarly, dominant lethal alleles can also cause genetic disorders in humans.
Such lethal alleles cause death even if they are present in a single copy. Mostly, these alleles are hard to find in a population because it causes the early death of an organism. The onset of this disease is slow, which allows heterozygotes to survive after birth. If the person survives until the reproductive age, the genes are passed on to their offspring. This way, the allele persists in the population. To learn more about our GDPR policies click here. If you want more info regarding data storage, please contact gdpr jove.
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