Foreword

This review was elaborated by our team at ALPE and is based on the current scientific and medical knowledge about achondroplasia at diverse levels. It also includes our vision based on a holistic care for achondroplasia. This document has been peer-reviewed by Dr. Morrys Kaisermann and Dr. Karen Heath to whom we want to thank and acknowledge for their valuable assistance.

 

WHAT IS ACHONDROPLASIA?

Introduction

In the 2015 revision of the list of genetic disorders of the skeleton, 436 different skeletal dysplasias have been recognized (Bonafé L et al., 2015) and this number keeps growing. Achondroplasia is one these skeletal dysplasias. It is a genetic disorder that affects the bone growth plate (Bouali H and Latrech H, 2015).

Achondroplasia is considered a rare disease. Rare diseases are those which affect less than 1 in 2000 of the general population. There are more than 7000 rare diseases identified to date and they are believed to affect 30 million European Union citizens. Overall, eighty percent of all rare diseases have a genetic origin and are often chronic and life-threatening (EURORDIS, 2016).

Achondroplasia is inherited as an autosomal dominant disease with essentially complete penetrance (Bouali H and Latrech H., 2015) (see next section for more information). Achondroplasia occurs with a similar frequency in both genders and in all ethnic groups (Horton W et al., 2007), affecting approximately 250,000 individuals worldwide (Narayana J and Horton W, 2013). The global prevalence is approximately 1 in 25,000 live births (Orphanet, 2017).

The term achondroplasia was first used by Jules Parrot in 1878, and in 1900, Pierre Marie described the main features in children and adults (Baujat G et al.,2008). Although the genetic defect causing achondroplasia was only identified in 1994, archaeological evidence of this disorder has been found in ancient Egypt (2500 BC) and in ancient American (300 BC) populations (Rodríguez C et al., 2012). The discovery of skeletons of apparently chondrodystrophic individuals between 7000 and 3000 BC in England and in the United States, reveal that this genetic anomaly goes back at least to the Neolithic period (Ortega A and Hernandez J, 2008).

The basic cause of achondroplasia is an alteration in the endochondral ossification. Bone is never formed as a primary tissue: it always replaces a preexisting support tissue, cartilage, and the process by which bone is formed is called osteogenesis or ossification. Longitudinal growth results in height increase and this occurs by endochondral ossification. During this process, new cartilage is formed at one side of the epiphyseal growth plate, a specific growth center, and is gradually replaced by bone. Chondrocytes, located in the growth plate, are the key cells in the long bone growth. They differentiate through proliferative, pre-hypertrophic and hypertrophic stages as the bone grows (Figure 1, Alman B, 2015).


 

 

Figure 1.The differentiation of chondrocytes in the growth plate, which results in long bone growth (Alman B, 2015).

 

Clinical features of achondroplasia

The clinical and radiological features of achondroplasia can be easily identified: disproportionate short stature with rhizomelic (upper part) shortening of the arms and legs, thoracolumbar kyphosis (early age, before walking) and lumbosacral hyperlordosis (with walking) (Bouali H and Latrech H, 2015), large head (macrocephaly), prominent forehead, depressed nasal bridge, maxillary hypoplasia, dysfunction of the upper respiratory system and foramen magnum stenosis (Shirley E and Ain M, 2009). Hands and fingers are short with a trident appearance in early life due to the inability to fully oppose the third and the fourth digits (Baujat G et al., 2008), (Harris H, 2012).

Children with achondroplasia commonly present motor development delay more evident in acquiring standing position and walking, due to muscle hypotonia and ligamentous laxity (Unger S et al., 2017).

 

Infancy (birth to 2 years old)

At birth, children with achondroplasia frequently have normal height (mean birth lengths are 47.7 cm and 47.2 cm for males and females, respectively). They present with macrocephaly and frontal bossing. The macrocephaly may be secondary to ventriculomegaly and benign external hydrocephalus (del Pino M et al., 2011; Zahl et al., 2011). There is a small risk of ventricular hydrocephalus caused by increased intracranial venous pressure.

Due to the shortening of proximal limb segments, children with achondroplasia often have redundant skin folds (Baujat G et al., 2008).

Spinal cord compression at the level of the foramen magnum (the opening in the base bone of the skull, the occipital bone) can be found in infancy and early childhood causing central apnea, developmental delay, and neurological signs such as clonus, muscle spasticity or neurogenic bladder dysfunction (the inability of the urinary sphincter to appropriately increase or decrease its pressure in response to increased bladder pressure that usually indicate a lesion in the middle or upper parts of the spinal cord or in the brain) (Ireland P et al., 2014; Dorsher P and McIntosh P, 2012). The spinal cord compression has also been linked to cases of sudden death during the first year of life. Population-based studies suggest that this increased risk of death may be as high as 7.5% (Pauli R, 2012).

Children with achondroplasia usually develop thoracolumbar kyphosis in the first few months of life (Misra S and Morgan W, 2003), which is observed as a bulging in the spine occurring due to general muscular hypotonia and macrocephaly (Ireland P et al., 2014). Nevertheless, in the majority of children, this deformity will correct spontaneously as the spinal muscle groups get stronger and increased power.

As mentioned above, the midface area and its internal structures are underdeveloped. The upper airways are narrow, which may cause obstructive sleep apnea. This may be exacerbated by enlarged tonsils and adenoids. The rib cage may be narrow and constricted, reducing lung capacity which can also result also in breathing problems (Ottonello G et al.,2007).

 

Childhood (3 to 12 years old)

Craniofacial features in children with achondroplasia include upper airway stenosis; retruded position of the chin (micrognathia); increased lower facial height that occurs due to an increased mandibular angle that at its turn, exists due to partial early ossification of cranial bones (Zaffanello M et al., 2017). These features can also lead to dental malocclusion and tongue thrusting. The midface hypoplasia in combination with adenoid and tonsil hypertrophy is still there and can lead to obstructive sleep apnea (Krakow D and Rimoin D, 2010). Dental overcrowding is typical due to the smaller maxilla and mandibular bone (Al-Saleem A and Al-Jobair A, 2010).

Recurrent otitis media is common, and often associated with conductive hearing loss and adenotonsillar hypertrophy (Wrigth M and Irving M, 2011).

As already seen, motor and speech development milestones are often delayed. When children begin to walk, the thoracolumbar kyphosis usually changes to lumbar lordosis (Wright M and Irving M, 2011). Most infants present generalized muscular hypotonia, usually moderate, which seem to be the cause of motor skills’ development delay. When untreated, this muscular weakness along with the oversize head and weight tends to lead to originate a hyperflexion of the spine, favouring the wedging of the first and second lumbar vertebrae (Barreal C, 2008). When untreated, a permanent or progressive thoracolumbar kyphosis may develop. Also tibial bowing and symptomatic lumbar spinal stenosis may occur (Wright M and Irving M, 2011).

Children with achondroplasia may present hyper extensible joints and genu varum (or bowing legs) (Krakow D and Rimoin D, 2010). Approximately 10% of children present marked tibial bowing by the age of five and over 40% of adults might present tibial bowing. Tibial bowing has been associated with recurrent leg pain and discomfort (Hunter AG el at., 1998).

Limitation of elbow extension is common due to a posterior convex deformity of the distal humerus. In patients with associated dislocation of the radial head the loss of extension is more severe (Haga N, 2004).

Both children and adults with achondroplasia uniformly display hip flexion contractures that have been postulated to contribute to the well-recognized lumbosacral lordosis and may be a contributing factor to the back pain and muscle fatigue reported by individuals with achondroplasia. Hyper mobility is typically observed in the knees and fingers of children with achondroplasia (Ireland P et al., 2014).

Obesity becomes also a common issue, as children with achondroplasia usually have more restricted physical activities, and may present with increased body mass index (BMI). Moreover, in children of average stature, distinct BMI patterns occur during growth and may predict sentinel events of puberty and risk adult obesity, but the relevance of these patterns to the achondroplasia population is unknown (Hoover-Fong J et al., 2008). Further information and the BMI curves for achondroplasia are found in the section “Managing Achondroplasia”.

 

Adolescence and adulthood

The average height in adulthood is 131±5.6 cm (men) and 124±5.9 cm (women)(Orphanet, 2017)

Lower lumbar spinal stenosis with accompanying neurological deficits like lower limb paresthesias, claudication, clonus, and bladder or bowel dysfunction become more common in adulthood (Krakow D and Rimoin D, 2010).

There is an increase in the prevalence of cardiovascular diseases in achondroplasia compared to the general population. Increased mortality in adults with achondroplasia has been reported, with a tenfold increase in heart disease-related mortality between the ages 25 and 35. The overall life expectancy appears to be decreased by about ten years compared to the general population (Pauli R, 2012).

Regarding fertility in women, certain gynaecological problems have been associated to achondroplasia, such as infertility, menorrhagia, dysmenorrhoea (menstrual cramps), benign uterin masses and early menopause. Problems associated with pregnancy and labour, reported in literature; include pre-eclampsia, polyhydramnios, respiratory compromise, contracted and small pelvis necessitating lower caesarean section, prematurity and fetal loss, etc. General anaesthesia is preferred to regional anaesthesia because of the spinal abnormalities. There is increased neonatal mortality due to hydrocephalus and thoracic cage abnormality. A pregnant woman with achondroplasia is considered to be a high risk patient in terms of anaesthesia and obstetric outcome so it is important to deliver prenatal counselling and diagnosis (Ghumman S et al., 2005; Orphanet 2017).

 

References

Alman B. The role of hedgehog signalling in skeletal health and disease Nat. Rev. Rheumatol. 2015: 11 (9): 552-60. Review.

Bonafe L. Et al. Nosology and classification of genetic skeletal disorders: 2015 revision. Am J Med Genet A 2015:167 A (12): 2869-92.

Bouali H, Latrech H. Achondroplasia: Current Opinions and Future Perspective. Pediatr Endocrinol Rev 2015: 12 (4): 388395.

del Pino M, Fano V Lejarraga H. Growth references for height, weight, and head circumference for Argentine children with achondroplasia. Eur J Pediatr 2011;170:453-459.

Dorsher P, McIntosh P. 2012. Neurogenic Bladder. Adv in Urology ;2012:816274.

Ghumman S, Goel N, Rajaram S, Singh KC, Kansal B, Dewan P. Pregnancy in an achondroplastic dwarf: a case report. J Indian Med Assoc. 2005; 103 (10): 536-538.

Haga N. Management of disabilities associated with achondroplasia. J Orthop Sci 2004; 9: 103-107.

Harris H. Advances in Human genetics, Springer Science & Business Media 2012.

Hecht JT, Hood OJ, Schwartz RJ, Hennessey JC, Benhardt BD, Horton WA. Obesity in achondroplasia. Am J Med Genet 1988; 31 (3): 597-602.

Histology Laboratory Manual, Bone Development: Endochondral Ossification, Columbia CNMTL, 2017.

Horton WA, Hall JG, Hecht JT. Achondroplasia. Lancet. 2007; 370 (9582): 162-72.

Hoover-Fong J, Schulze K, McGready J, Barnes H, Scott C. Age-appropriate body mass index in children with achondroplasia: interpretation in relation to indexes of height. Am J Clin Nutr 2008; 88 (2): 364-371.

Hunter AG, Bankier A, Rogers JG, Sillence D, Scott CI Jr. Medical complications of achondroplasia: a multicentre patient review. J Med Genet. 1998; 35 (9): 705-712.

Ireland P, Pacey V, Zankl A, Edwards P, Johnston M, Savarirayan R. Optimal management of complications associated with achondroplasia. Appl Clin Genet. 2014; 7: 117-125.

Narayana J, Horton WA. Molecular Genetics of Achondroplasia. eLS, 2013

Krakow D, Rimoin L. The skeletal dysplasias. Genet Med. 2012; 12, 327-341.

Mackie E et al., Endochondral ossification: How cartilage is converted into bone in the developing skeleton, Int J Biochem Cell Biol, 2008; 40(1): 46-62.

Misra S, Morgan H. Thoracolumbar spinal deformity in achondroplasia. Neurosurg Focus 2003; 14 (1): 4.

Ortega A, Hernández J, Fuentes Luis A. La acondroplasia, algo más que una cuestión de altura. AFAPA 2008.

Orphanet 2017, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=15

Ottonello G , Villa G, Moscatelli A , Diana M , Pavanello M. Noninvasive Ventilation in a Child Affected by Achondroplasia Respiratory Difficulty Syndrome. Paediatr Anesth 2007; 17: 75-79.

Pauli RM. Achondroplasia. Updated 2012. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® University of Washington, Seattle; 1993-2017.

Rodrigues C, Isaza C, Pachajoa H. Achondroplasia among ancient populations of mesoamerica and South America: Iconographic and Archaeological Evidence. Colomb Med (Cali) 2012; 43(3):212-215..

Al-Saleem A, Al-Jobair A. Achondroplasia: Craniofacial manifestations and considerations in dental management. Saudi Dent J. 2010; 22 (4): 195-199.

Shirley ED, Ain MC. Achondroplasia: manifestations and treatment. J Am Acad Orthop Surg. 2009; 17 (4): 231-41.

Unger S, Bonafé L, Gouze E. Current Care and Investigational Therapies in Achondroplasia. Curr Osteoporos Rep. 2017; 15 (2): 53-60.

Wright M, Irving M. Clinical management of achondroplasia. Arch Dis Child, 2012; 97 (2): 129-134.

Zaffanello M, Cantalupo G, Piacentini G, Gasperi E, Nosetti L, Cavarzere, Ramaroli D, Mittal A, Antoniazzi F. Sleep disordered breathing in children with achondroplasia. World J Pediatr. 2017; 13: 8-14.

Zahl S, Egge A, Helseth E, Wester K. Benign external hydrocephalus: a review, with emphasis on management. Neurosurg Rev. 2011; 34 (4): 417-432.

 

WHAT IS THE CAUSE OF ACHONDROPLASIA?

Achondroplasia is a genetic autosomal dominant disorder due to a defect in the maturation of the cartilage growth plate of long bones. It is linked to a missense mutation in the transmembrane domain of the fibroblast growth factor receptor 3 gene (FGFR3), which results in the substitution of the amino acid glycine to arginine, at position 380 (p.Gly380Arg or p.G380R), in 98% of cases (Figure 2). FGFR3 is a receptor tyrosine kinase that plays an important role in long bone development (He L et al., 2010).

 

 

 

 

Figure 2. Structure of the FGFR3 protein indicating the major mutations in skeletal dysplasias. ACH=achondroplasia. HYP=hypochondroplasia, TD=thanatophoric dysplasia. SADDAN=severe achondroplasia with developmental delay and acanthosis nigricans. Ig=Immunoglobulin loop. TKp/d=proximal and distal tyrosine kinase domains. TM=transmembrane. Credits: Horton W et al., 2007 

 

FGFR3 is expressed mainly in proliferating chondrocytes in the growth plates of developing long bones and acts as a negative regulator of endochondral bone growth by reducing the bone growth velocity in individuals with achondroplasia (Lee YC et al., 2017). FGFR3 transmits signals to the cellular machinery that regulates proliferation, maturation and survival of chondrocytes, the cells responsible for bone growth, which are found within the growth plates of growing bones.

The predominant signaling output involves a cascade of tyrosine kinase enzymes collectively referred to as the mitogen-activated protein kinase (MAPK) signaling pathway (Figure 3). The achondroplasia mutation increases the MAPK signaling (Narayana J and Horton W, 2013).


 

 

Figure 3. FGFR3 signaling pathway in the chondrocytes. Credits: Tratando acondroplasia, 2012

 

In 80% of cases, achondroplasia is due to a spontaneous mutation from average height parents, also known as a new or “de novo” mutation (Faruki T et al., 2014). De novo mutations can be associated with advanced paternal age (35 years or over) due to errors during spermatogenesis (Natacci F et al., 2008). For average stature couples who have a child with achondroplasia, the risk of recurrence is very small (<1%) but not negligible. This is due to the risk of germline mosaicism which is when the mutation is only present in the egg or sperm cell (Wright M and Irving M, 2011).

A person with achondroplasia who is planning to have children with a partner who does not have achondroplasia has a 50% chance of having a child with achondroplasia (Figure 4). When both parents have achondroplasia, their chance of having a child with normal stature is 25%, 50% of having a child with achondroplasia and 25% of having a child who inherits the gene mutation from both parents (called homozygous severe achondroplasia (SADDAN), a very severe condition that is incompatible with life) (Pauli R, 2012)


 

 

Figure 4. Autosomal dominant inheritance pattern. Credits: Genetics Home reference, 2012

 

References

Faruqi T, Dhawan N, Bahl J, Gupta V, Vohra S, Tu K, Abdelmagid S. Molecular, Phenotypic Aspects and Therapeutic Horizons of Rare Genetic Bone Disorders. BioMed Research International 2014;2014:670842.

He L, Horton W, Hristova K. Physical Basis behind Achondroplasia, the Most Common Form of Human Dwarfism. J Biol Chem 2010;285(39):30103-30114.

Horton W, Hall J, Hecht J. Achondroplasia. Lancet 2007;370: 162-72.

Lee YC, Song IW, Pai YJ, Chen SD, Chen YT. Knock-in human FGFR3 achondroplasia mutation as a mouse model for human skeletal dysplasia. Sci Rep 2017;7:43220.

Narayana J, Horton WA. Molecular Genetics of Achondroplasia. eLS, 2013 DOI: 10.1002/9780470015902.a0024296.

Natacci F, Baffico M, Cavallari U, Bedeschi MF, Mura I, Paffoni A, Setti P, Baldi M, Lalatta F. Clinical Report Germline Mosaicism in Achondroplasia Detected in Sperm DNA of the Father of Three Affected Sibs. Am J Med Genet A 2008;146A:784-786-

Pauli RM. Achondroplasia. 1998 Oct 12 [Updated 2012]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® University of Washington, Seattle; 1993-2017

Wright M, Irving M. Clinical management of achondroplasia. Arch Dis Child, 2012; 97 (2): 129-134.

 

HOW IS ACHONDROPLASIA DIAGNOSED?

The features of achondroplasia are very distinctive so that they can be easily identified both clinically and radiologically (Baujat G et al., 2008). Even so, confirming the diagnosis of achondroplasia by molecular genetic testing is essential to distinguish it from other skeletal dysplasias, to plan therapeutic options, and to offer genetic counseling. Molecular genetic testing allows prenatal diagnosis for achondroplasia in high-risk families at about 11-13 weeks of gestation (Nahar R et al., 2009)

 

Prenatal diagnosis (in utero)

A prenatal ultrasonography during the late second trimester or the third trimester may trigger the suspicion of the presence of achondroplasia, because limb growth disproportion becomes more evident (Chitty L et al., 2011). Other prenatal features include wide metaphyses, narrowing of the interpedicular distance of the lower lumbar vertebrae and an abnormal pelvis with small square iliac wings and narrow sacrosciatic notch. Other features may be observed as low nasal bridge, frontal bossing, with normal size of head and abdominal circumference. Even then, misdiagnosis is common by the use of 2D ultrasound. Several case series reports have speculated that the accurate diagnosis rate ranges from 30% to 70% (Yang PY et al., 2012). Three-dimensional helical computed tomography scan (3D HCT scan) after 30 weeks of gestation can show these specific features of achondroplasia dysplasia (Baujat G et al., 2008). However, this kind of imaging test is not performed routinely (Yang PY et al., 2012).

Achondroplasia can also be diagnosed during pregnancy through non-invasive prenatal diagnosis using cell-free fetal DNA (cffDNA) circulating in maternal blood. The maternal blood sample is analyzed by next-generation genetic sequencing, which provides an accurate, flexible approach to de novo and paternally inherited mutations (Chitty L et al., 2015). Positive results are then confirmed by a second test, an invasive test, CVS or amniocentesis.

 

Postnatal diagnosis (after birth)

The diagnosis is based on the presence of typical clinical features, such as frontal bossing, depressed nasal bridge, deep set eyes and skin folds. This should be complemented by radiographs of the cranium, column, hip, long bones and hands will help to identify   rhizomelic bone shortening, bullet shaped proximal phalanges and vertebra; and by molecular diagnosis (Jagadeesh S et al., 2015). Currently, skeletal dysplasias are screened using Next generation sequencing. The exception is in the case of achondroplasia where direct testing for the common p.Gly380Arg mutation (caused by c.1138G>A and c.1138G>C mutations). If these are negative, but the suspicion of achondroplasia based on clinical and radiographic grounds is high, a complete sequence analysis of the gene FGFR3 can be performed (Pauli R, 2012).

 

Differential diagnosis

While there are 436 skeletal dysplasias (Bonafé L et al., 2015), most 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: This distinction is sometimes the most difficult to make. In fact, there is some overlap between the radiologic and clinical phenotypes of these two conditions.

. Thanatophoric dysplasia: This is a lethal form which is detected during the early stages of the second trimester.

. Pseudoachondroplasia: a clinically and genetically distinct skeletal dysplasia.  People with pseudoachondroplasia have similar body features and proportions but normal head size and facial features.

. Other metaphyseal dysplasias.

(Pauli R, 2012).


 

References

Baujat G, Legeai-Mallet L, Finidori G, Cormier-Daire V, Le Merrer M. Achondroplasia. Best Pract Res Clin Rheumatol. 2008;22(1):3-18.

Chitty LS, Griffin DR, Meaney C, Barrett A, Khalil A, Pajkrt E, Cole TJ. New aids for the non-invasive prenatal diagnosis of achondroplasia: dysmorphic features, charts of fetal size and molecular confirmation using cell-free fetal DNA in maternal plasma. Ultrasound Obstet Gynecol. 2011;37(3):283-9.

Jagadeesh S, Kandasamy S, Gayathri J. Prenatal Diagnosis of Achondroplasia. Online 2015

Nahar R, Saxena R, Kohli S, Puri R, Verma I. Molecular studies of achondroplasia.Indian J Orthop. 2009; 43(2):194-196.

Pauli RM. Achondroplasia. 1998 Oct 12 [Updated 2012]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® University of Washington, Seattle; 1993-2017

Renna M, Pisani P, Conversano F, Perrone E, Casciaro E, Renzo G, Di Paola M, Perrone A, Casciaro S. Sonographic markers for early diagnosis of fetal malformations. World J Radiol. 2013; 5 (10): 356-371.

 

MANAGING ACHONDROPLASIA

Current management of achondroplasia consists essentially in the prevention and treatment of complications, although there is no consensus regarding the type and frequency of surveillance because of the lack of prospective controlled clinical studies (Unger S et al., 2017). Given the wide range of clinical conditions and medical issues that may accompany this skeletal dysplasia, ideally the healthcare for achondroplasia should have a long-term focus and be organized with access to relevant specialists in the fields of respiratory physiology, paediatric neurology, neurophysiology, neurosurgery, neuroradiology and orthopaedic surgery (van Dijk JM et al., 2007). Anticipatory care should be directed at identifying children who are at high risk to help preventing serious complications (Trotter T and Hall J, 2005).

In assessing the growth and development of a child with achondroplasia, it is important that appropriate comparisons are used. As highlighted before, children with achondroplasia may have distinct development milestones and their progress should be assessed accordingly (Wright M and Irving M, 2011).

Fundación ALPE developed infographics based on the clinical follow-up for achondroplasia proposed by Trotter T and Hall J, 2005 and reviewed by our medical team, with the purpose of facilitating access to this protocol. We will now focus on age-specific health surveillance and management of patients with achondroplasia.

 

Infancy

Growth

Recommendations for follow-up include measurements of growth and head circumference using growth curves standardized for achondroplasia. The occipital frontal circumference (OFC) is physiologically larger in achondroplasia and should be monitored regularly (monthly during the first year of life) in order to detect any unusual acceleration as a possible sign of hydrocephaly. Head circumference (Figure 5 and 6), height (Figure 7 and 8) and weight references for children with achondroplasia can also contribute to growth assessment and quality of healthcare.

 

 

Figure 5. Head circumference for age curves for achondroplasia with 3rd, 10th, 25th, 50th, 75th, 90th, and 97th percentiles for boys 0–6 years (del Pino M et al.,2011). Printable graphics here

 

 

Figure 6. Head circumference for age curves for achondroplasia with 3rd, 10th, 25th, 50th, 75th, 90th, and 97th percentiles for girls 0–6 years. (del Pino M et al.,2011). Printable graphics here

 

Figure 7. Height curves for boys with achondroplasia compared with normal standard curves (Horton W et al, 1978)

 

Figure 8. Height curves for girls with achondroplasia compared with normal standard curves (Horton W et al, 1978).

 

Neurologic complications

Careful neurological evaluation may include imaging studies such as computed tomography (CT), magnetic resonance (MRI), somatosensory evoked potentials (SEP) and polysomnography (PSN), also known by sleep study (McKusick V and O'Neill M, 2016).

Somatosensory evoked potentials (SEPs), an important non-invasive method that gives information about the function of the sensory pathway of the central nervous system, helps to localize possible lesions and provides a prognostic guide (Fornarino S et al., 2016).

In cases of a rapid increase in the head size or symptoms associated with increased cranial pressure such as irritability or a bulging fontanel, the child should be promptly evaluated by a pediatric neurologist or neurosurgeon, as hydrocephalus may be developing, leading to the need for ventricular shunting (Ireland P el al., 2014). In cases of severe foramen magnum stenosis, surgical repair is recommended (McKusick V and O'Neill M, 2016).

By appropriate assessment and intervention, the risk of unexpected infant death due to high cervical myelopathy secondary to the common small foramen magnum can be minimized (Trotter T and Hall J, 2005).

For infants not diagnosed in the newborn period, neuroimaging (MRI) and polysomnography (sleep study) should be arranged at the time of diagnosis (Trotter T and Hall J, 2005).

 

ENT complications

Children with achondroplasia often have breathing problems, especially during sleep due to the craniofacial features that can lead to snoring and obstructive sleep apnea syndrome (OSAS). Foramen magnum stenosis is present in 28% of the patients with OSAS, suggesting a link between hydrocephalus and breathing problems during sleep (Zaffanello M et al., 2017). MRI and SEPs are the main tools to evaluate the need for neurosurgery and myelopathy, respectively, while the sleep study enables the identification of children who have OSAS and to classify its severity (Zaffanello M et al., 2017). Treatment of obstructive sleep apnea may include adenotonsillectomy and/or continuous positive airway pressure (CPAP) (Orphanet, 2017).

Ear infections and serous otitis media can be recurrent and may cause hearing problems. Regular hearing assessments are therefore needed. Audiometric and tympanometric assessments should be completed approximately at 8-12 months of age and then every 6-12 months throughout preschool years (Cassidy S and Allanson J, 2011). In order to address this complication, orofacial myofunctional therapy (OMT) can be applied. OMT is a resource to correct breathing, swallowing and chewing disorders, normalize free airway space; helps stabilize the bite and eliminate noxious oral habits such as tongue thrusting and thumb-sucking (AOMT, 2017).

 

Motor skills

Most infants present generalized muscular hypotonia, usually moderate, which seem to be the cause of motor skills’ development delay. As we have seen above, in section “What is achondroplasia - Childhood” if left untreated, the thoracolumbar kyphosis may require orthotic treatment later (Barreal C, 2008). In order to address the muscular weakness and hypotonia, physical therapy can be started as soon as possible, from the first months of life. It is an important preventive strategy against motor delay and limitations (Barreal C, 2008). For more information on the development of motor skill in achondroplasia, see Figure 13 in section “Impact in life and common challenges”.

As it is not recommended that babies and young toddlers, unsupported sitting must be avoided to minimize the risk of developing permanent thoracolumbar kyphosis (Orphanet, 2017). Physiotherapy may be helpful for the child to improve right posture and motor skills before free walking is achieved (Unger S et al., 2017). Physical therapy also improves fine psychomotricity, contributing to manual coordination, stimulation of tactile perception as well as improving hand muscular strength. It can also be applied at the cervical spine level to improve muscular strengthening and head control. It may also contribute to achieve a better trunk control before the child can maintain the sitting position and also allows the correction of the standing position and walking (Barreal C, 2008).

Physical therapy also allows the development of energy-saving actions to optimize daily life tasks (Richardson N, 2016). In the work written by González A et al., 2010 for ALPE, the authors present specific exercises for babies and children with achondroplasia.

Aquatic or water therapy allows the improvement of mobility, especially in children whose heads have a larger circumference (see Figure 5 and 6) (Barreal C, 2010).

 

Nutrition

Birth weight is comparable between babies with achondroplasia and term infants of average stature. The reduced body area on which to distribute a greater body mass means that any minor increases in weight after birth can have an impact in life such as worsening obstructive sleep apnea, or contributing to cardiovascular disease later in life (Hoover-Fong J et al., 2008).

Regarding this, is important to work on good nutrition habits from an early age. Garde L, 2008, developed a document with information on feeding tips for children with achondroplasia from the ages of 0 to 24 months old. A well balanced diet can contribute to a better quality of life in the adulthood, preventing many health problems related with poor eating habits.

ALPE has also developed an infographics series for the health control of children with achondroplasia. This work was based on Trotter T and Hall J, 2005, the clinical report for Health Supervision for Children with Achondroplasia that has been one of the main guidelines for clinicians and caregivers since its publication. The infographics intend to facilitate the access to primary line information and advised assessments.

ALPE health control Infographic - 1 month to 1 year of age

 

Childhood

Most children with achondroplasia reach all normal developmental milestones and have no neurological or intellectual impairment. Access to physiotherapy, occupational therapy, and speech therapists with experience in working with achondroplasia may significantly improve timing of autonomy (Unger S et al., 2017).

It is also relevant to mention that a greater-than-average sweating is common in children with achondroplasia and is not indicative of serious medical problems (Trotter T and Hall J, 2005).

Also is important to refer that physical activities which may lead to a risk of injury to the craniocervical junction should be avoided (Orphanet, 2017).

 

ENT complications

In the case of language or speech problems, and with swallowing difficulties, the child should be examined by an ENT specialist and/or speech therapist. Regular ear examinations and hearing tests should be performed (Collins W and Choi S, 2007).

Due to the typical midface hypoplasia and other cranial abnormalities, it is not uncommon the onset of respiratory symptoms caused by upper airway obstruction, adenotonsillar hypertrophy and otitis media, which may be accompanied by hearing loss and delayed speech (Collins W and Choi S, 2007). Otitis media in achondroplasia occurs most probably due to the orientation and size of the Eustachian tube (ventilation tube in the middle ear), impairment of nasal airflow and temporal bone abnormalities. The middle ear ossicles (malleus, incus and staples, Figure 9) undergo endochondral ossification, which are impaired in achondroplasia (Jung J et al., 2013). These ossicles may be fused to the surrounding bony structures. Other abnormalities include the formation of dense, thick trabeculae without islands of cartilage in the endochondral bone and periosteal bone. In the inner ear, the associated abnormalities may include a deformed cochlea and thickened intracochlear partitions (Bluestone C, 2013)

 

 

Figure 9. Ear anatomy. Credits: MedicineNet.inc, 2014

 

Due to altered craniofacial morphology it has been suggested that there is a higher incidence of otitis media in children with achondroplasia. This suggestion makes it likely that myringotomies with the insertion of ventilation tubes would be performed on children with achondroplasia at a probably greater rate than the normal paediatric population (Williams J et al., 2006).

Hearing loss in achondroplasia is mostly a conductive hearing loss but sensorineural hearing loss and mixed hearing loss are also observable. Sensorineural hearing loss can be expected in achondroplasia because of the sequelae of frequent/persistent otitis media or cochlear abnormalities. The exact rate of hearing loss has not been evaluated, nor is the main cause of hearing loss in achondroplasia (Jung J et al., 2013). In cases of impaired hearing, the child will need hearing rehabilitation and speech therapy may be useful (Trotter T and Hall J, 2005).

The midface hypoplasia, one of the hallmarks of achondroplasia, also reflects in the abnormal development of the maxilla and the palate, which is unusually high and narrow, leading to dental malocclusion. Therefore, orthodontic treatment may be necessary to ensure a normal dental occlusion (Al-Saleem A and Al-Jobair A, 2010). These abnormalities in the oral cavity may cause certain eating problems such as difficulties in controlling swallowing which require assessment and treatment (Ireland P et al., 2014).

To help swallowing can be applied orofacial myofunctional therapy (OMT) can also improve orthodontic, surgical and dental results. This therapy can also bring benefits when hearing problems arise (AOMT, 2017). Help with developing oral motor skills, as well as language training with speech therapy may be useful in some children with delayed speech and language development (Trotter T and Hall J, 2005).

ALPE holistic approach to achondroplasia includes speech therapy and OMT as important resources for children with achondroplasia.

 

Orthopedics

Due to the several skeletal abnormalities present in children with achondroplasia, orthopedics follow-up is essential. Avoid the use of walkers, jumpers or backpack carriers (Trotter T and Hall J, 2005). As the child starts bearing weight by walking, any kyphosis should disappear. At the spinal level, follow-up should include evaluation of the thoracolumbar kyphosis (gibbus).

Angular deformities of the lower limbs are a common clinical problem. As observed in Figure 10, the genu varus deformity (bowing legs) and misalignment is common in achondroplasia patients because of the fibulae (thinner and external bone in the leg) grow faster than the tibiae (thicker and internal bone in the leg) (Kaissi AA et al., 2013).

 

 

Figure 10. Development of genu varum in achondroplasia. Credits Lee ST et al., 2007

 

Surgical treatment to re-align the lower limbs is usually indicated for cases that present either a severe, aesthetically difficult to overcome or clinically symptomatic limb deformity. Surgical realignment can generally be achieved by gradual correction using external fixation devices (Kaissi AA et al., 2013). Limb lengthening elective surgery conducted with the aim to increase the final height will be approached in the section “Potential treatments for achondroplasia”.

 

Nutrition

Children with achondroplasia have a reduced body area on which to distribute a greater body mass and minor increases in weight may potentially worsen motor skills, cause or worsen obstructive sleep apnea or contribute to cardiovascular disease later in life (Hoover-Fong J et al., 2008). As obesity is also an additional risk factor for orthopedic deformities (Unger S et al., 2017), is important to control weight starting in childhood (Hoover-Fong J et al., 2008). Nutritional counseling should be implemented early to help reduce the later effects of excessive weight in adult life (Ireland P et al., 2014). A simple and practical measure could be to adopt smaller meal portions (Garde L, 2008).

Pediatric Body Mass Index (BMI) for-age curves for children with achondroplasia (Figures 11 and 12) can be used in daily clinical care as a screening tool to identify children who are at the extremes of the population distribution of body mass, thereby prompting more intensive nutritional and physical assessment and intervention (Hoover-Fong J et al., 2017).


 

Figure 11. Mean height for age comparison between original (Horton et al., 1978) and new height for age curves for males. Credits: Hoover-Fong J et al., 2017

 

Figure 12. Mean height for age comparison between original (Horton et al., 1978) and new height for age curves for females. Credits: Hoover-Fong J et al., 2017

 

ALPE health control Infographic – 1 year to 5 years

ALPE health control Infographic – 5 years to 13 years

 

Adulthood

Appropriate follow-up should be implemented for young adults with achondroplasia leaving the remit of paediatric services (Wright M and Irving M, 2011).

Joint laxity is common, most frequently in the knees and shoulders, and manifests as progressive hyperextension of the knees and chronic inferior dislocation of the shoulder (Malcolm T et al., 2015)

 

Muscular and Neurologic complications

Adults with achondroplasia can face lumbar spinal stenosis which can manifest by lower limb paresthesias, claudication, clonus and bladder or bowel dysfunction. Regular monitoring for signs of spinal stenosis should be carried out by a spinal surgeon, every third to fifth year in adults (Wright M and Irving M, 2011; Karol L, 2012).

MRI and/or CT scans of the spine are essential to assess the degree of compression, and neurophysiological tests of nerve conduction in the spinal cord can be performed. The investigations should also include bladder function through urodynamic testing (Karol L, 2012). It is critical that signs of spinal compression are addressed promptly, since without appropriate decompression surgery, the spinal stenosis could progress to paraplegia and other neurological complications, hypertension and orthopedic problems, with associated significant morbidity (Krakow D and Rimoin D, 2010).

Frequently the spine nerve compression is located between the first and fourth lumbar vertebrae (L1-L4), but it may also be present in the thoracic vertebrae. A laminectomy is the spine decompression surgery where a portion of the vertebral bone is removed, which alleviates the problem in many cases (Carlisle ES et al., 2012).

 

Pregnancy

Abnormal pelvic morphology and high cervical length are responsible for high-risk pregnancies in women with achondroplasia. Early ultrasonographic assessment can indicate an unusually long cervical length, as consequence of the abnormal anatomy of the pelvis. There is a need for routine cesarean section because of foreseeable dystocia (abnormally slow progress in labor), that is a mismatch between the size of the fetal head and size of the maternal pelvis, resulting in "failure to progress" in labor due mechanical reasons (Maharaj D, 2010).

The anatomic variations and consequent effects on organ systems and airway management can create major challenges in anesthesia in patients with achondroplasia. In this matter, careful preparation and communication of the anesthetic plan with the surgical team are essential components of perioperative management (Spiegel J and Hellman M, 2015).

 

References

Al Kaissi A, Farr S, Ganger R, Hofstaetter J, Klaushofer K, Grill F. Treatment of Varus Deformities of the Lower Limbs in Patients with Achondroplasia and Hypochondroplasia. Abra Orthop J. 2013; 7: 33-39.

Al-Saleem A, Al-Jobair A. Achondroplasia: Craniofacial manifestations and considerations in dental management. Saudi Dent J. 2010;22(4):195-199.

Barreal C. Physical rehabilitation guidance for achondroplasia. Fundación ALPE. 2008

Bluestone and Stool´s. Pediatric Otolaryngology. PMPH-USA, 2013.

Carlisle ES, Ting BL, Abdullah MA, Skolasky RL, Schkrohowsky JG, Yost MT, Rigamonti D, Ain MC. Laminectomy in patients with achondroplasia: the impact of time to surgery on long-term function. Spine (Phila Pa 1976). 2011;36(11):886-92.

Cassidy S, Allanson J. Management of Genetic Syndromes. Ed:John Wiley & Sons, 2010.

Collins W, Choi S. Otolaryngologic Manifestations of Achondroplasia. Arch Otolaryngol Head Neck Surg. 2007;133:237-244.

del Pino M, Fano V Lejarraga H. Growth references for height, weight, and head circumference for Argentine children with achondroplasia. Eur J Pediatr 2011;170:453-459.

Fornarino S, Rossi DP, Severino M, Pistorio A, Allegri M, Martelli S, Doria Lamba L, Lanteri P. Early impairment of somatosensory evoked potentials in very young children with achondroplasia with foramen magnum stenosis. Dev Med Child Neurol 2017;59:192-198.

Hoover-Fong J, Schulze K, McGready J, Barnes H, Scott C. Age-appropriate body mass index in children with achondroplasia: interpretation in relation to indexes of height. Am J Clin Nutr August 2008;88(2):364-371.

Hoover-Fong J, McGready J, Schulze K, Alade AY, Scott CI. A height-for-age growth reference for children with achondroplasia: Expanded applications and comparison with original reference data. Am J Med Genet A. 2017;173(5):1226-1230.

Jung J, Yang C, Lee S, Choi J. Bilateral Ossiculoplasty in 1 Case of Achondroplasia. Korean J Audiol. 2013; 17(3):142–147.

Kaissi A, Farr S, Ganger R, Hofstaetter J, Klaushofer K, Grill F. Treatment of Varus Deformities of the Lower Limbs in Patients with Achondroplasia and Hypochondroplasia. Open Orthop J. 2013;7:33-39.

Karol L. Spinal Deformity in Children with Achondroplasia,2012

Krakow D, Rimoin L. The skeletal dysplasias. Genet Med 2010; 12: 327-341.

S. T. Lee, H. R. Song, R. Mahajan, V. Makwana, S. W. Suh, S. H. Lee. Development of genu varum in achondroplasia. J Bone Joint Surg Br. 2007;89:B(1):157-161.

Malcolm TL, Phan DL, Schwarzkopf R. Concomitant achondroplasia and developmental dysplasia of the hip. Arthroplasty in patients with rare conditions. Arthroplasty today. 2015;1(4):111–115.

Maharaj D. Assessing cephalopelvic disproportion: back to the basics. Obstet Gynecol Surv. 2010;65(6):387-395.

Richardson N. Achondroplasia. Physiopedia, 2016 (http://www.physio-pedia.com/Achondroplasia)

Spiegel J, Hellman M. Achondroplasia: Implications and Management strategies in anesthesia. Anesthesiology news special edition. October 2015

Trotter T, Hall J. Health Supervision for Children with Achondroplasia. Pediatrics 2005; 116(3):771-83.

Unger S, Bonafé L, Gouze E. Current Care and Investigational Therapies in Achondroplasia. Curr Osteoporos Rep. 2017;15(2):53-60.

van Dijk JM, Lubout CM, Brouwer PA. Cervical high-intensity intramedullary lesions without spinal cord compression in achondroplasia. J Neurosurg Spine. 2007 Apr; 6(4):304-8.

Williams J, Sharma A, Prinsley P.Bilateral jugular bulb dehiscence in achondroplasia. Int J Ped Otorhinolaryng Ext 2006;1:164-166.

Wright M, Irving M. Clinical management of achondroplasia. Arch Dis Child, 2012; 97 (2): 129-134.

Zaffanello M, Cantalupo G, Piacentini G, Gasperi E, Nosetti L, Cavarzere, Ramaroli D, Mittal A, Antoniazzi F. Sleep disordered breathing in children with achondroplasia. World J Pediatr. 2017.13:8-14.

 

IMPACT IN LIFE AND COMMON CHALLENGES

Achondroplasia can directly impact in activity limitation or restrictions including communication, self-care and mobility in respect to architectural barriers as access to toilets, public desks, ATMs, public transports (Ireland P et al., 2014; Unger S et al., 2017). These barriers vary according to the age.

 

Infancy

In the first few months after diagnosis in a newborn or young child, parents often experience extreme anxiety about the long-term outcome for their child in addition to concerns about the risk of immediate complications (Wright M and Irving M, 2011).

Following figure 13, by Trotter T and Hall J, 2005, infants have at pre-school age a specific profile of physical developmental sequences in the acquisition of gross motor skills, which differs from typical development, but is relatively consistent within the group (Trotter T and Hall J, 2005, Ireland P et al., 2014). Only, approximately 50% of infants will sit alone by 9 months and just over 50% will walk alone by 18 months (Trotter T and Hall J, 2005, Wright M and Irving M, 2011).

 

Figure 13. Developmental screening tests in achondroplasia. The bar scale shows the percentage of achondroplastic children passing the item; the black triangle on top of the bar shows the age at which 90% of normal children pass the same item. Credits: Trotter T e Hall J, 2005

 

Psychological support should be offered to parents of affected infants to help acceptance of the condition in order to promote establishment of appropriate affective links (Unger S et al., 2017). Support groups and organizations as Fundación ALPE, can be helpful for patients and families to share experiences and reinforce positive individual resources. ALPE has highly contributed for social empowerment of families and children with achondroplasia, through families meetings and making bridges through in social media.

 

Childhood

The child and family require follow up as soon as possible with an early intervention team, made up of professionals with special expertise in how disability affects everyday life, health and development. Support and follow-up should take place within several domains: medical, educational, psychological and social (WHO, 2011).

Joint contractures and hypermobility are factors contributing to the delayed independent self-care skills (Ireland P et al., 2014). Also the upper limb shortening and limited elbow extension with consequent reduced upper arms span is likely to restrict children from reaching the top of their head for hair brushing, adjusting clothes for upper body dressing and completing perianal hygiene when bathing and toileting, and may account for the ongoing need for assistance. At the self-care domain, children should have access to physiotherapy or occupational therapy services before primary school in order to maximize independence in transfer skills and longer distance mobility. In order to find new skills strategies, therapists can also collaborate in appropriate school facility modification, equipment prescription or task analysis and problem solving (Ireland P et al., 2011) (Unger S et al., 2017). Nevertheless, children show a significant increase in overall function and most individual functional skill domains between the ages of 3 and 5 years (Ireland P et al., 2011).

Another common concern in children with achondroplasia is exercise intolerance or exercise-induced fatigue when compared with general population. This may influence a number of participation areas, including self-care performance and leisure pursuits. Children present reduced muscle strength in almost all muscular groups, what may be caused by a decrease in muscle mass, reduced neuromuscular coordination and altered bio-mechanics. Nevertheless, physical exercise is highly important to strengthen muscles (Ireland P et al., 2011).

 

School

Children with achondroplasia are usually included in the regular education program. Nevertheless, transition to a new school is a time of anxiety for the child, parents and school staff. Educational guidance for parents of children with achondroplasia should be offered to prevent overprotection, limited autonomy and excessive anxiety (Unger S et al., 2017).

The challenges of children in school include mobility, self-care, education and performance (Wright M and Irving M, 2011). In this matter, when entering preschool or beginning primary school, it is important that both at home and at school, some adaptations can be made in order to adjust them as early as possible to the child needs (Trotter T and Hall J, 2005). ALPE developed series of adaptations for children in preschool and primary school as guidelines for primary school, chair adaptation or accessible folder.

A very important point is that when conducting general adaptations in school, these should be generalized and normalized, in the way to be useful and usable by all children and not only by the child with achondroplasia (APROSUBA, 2010).

It is also important to prepare the child for other children questions and curiosity. Be sure the child can explain why he or she is short and can ask for help in an appropriate way (Trotter T and Hall J, 2005). In this matter, ALPE developed a letter for the school teachers and a letter for the school classmates’ parents.

 

Psychosocial and cultural aspects

The psychosocial burden of achondroplasia depends on several factors as personal, familiar, ethnic and cultural. Some families will have a strong perception of disability of their child with achondroplasia, while others will not perceive the condition as a problem (Unger S et al., 2017).

Psychological assessment and support should be provided to children (Orphanet, 2017). Even at young ages, most children are aware that they are shorter than their friends of the same age. Some may require a more continued psychological support as they are growing up (Yeo M and Sawyer S, 2005), and could be also important for teenagers facing frustration and rebellion toward diversity (Unger S et al., 2017).

In order for children with achondroplasia to grow into well-adjusted adults it is important that they are not overprotected, but are allowed to be like other children. Also, children with achondroplasia should be treated in a way appropriate to their age and in the same way as their peers (Yeo M and Sawyer S, 2005).

Notwithstanding, the self-esteem of most children with achondroplasia is not impaired although they tend to encounter short stature-related unpleasant experiences. They show a higher ability to surpass challenges compared with average height children (Nishimura N and Hanaki K, 2014) and social cognition appears to be a relative strength. However, in an observational study from Ireland P et al., 2011, 25% of children still required prompting for social comprehension (understanding and following commands) and expression (expressing basic needs and ideas) at the age of 7 years.

Puberty is another time of further challenges in psycho-social adaptation for many children. The support from other children and young adults with achondroplasia may be particularly helpful at this time (Wright M and Irving M, 2011).

For parents of children with achondroplasia, long term concerns often include questions about final adult height, likely employment prospects and life expectancy (Wright M and Irving M, 2011).

Children attitude may differ towards impairment and disability according to their cultural background. Low stature caused by achondroplasia is perceived differently in Mediterranean countries such as Italy and Spain, compared with countries such as the USA, Canada, UK and Australia. While in Italy and Spain children with achondroplasia frequently undergo surgical limb lengthening, in the other mentioned countries, people tend to consider the preservation of their natural height as a primary aspect of psychological development and identity building (Cortinovis I et al., 2011).

 

Adulthood

A significant number of adults develop major physical limitations and pain, which impacts on their quality of life. It is possible that the onset of age related medical issues as spinal stenosis and leg pain could be exacerbated by physical access challenges related to the short stature, such as climbing stairs (Ireland P et al., 2011). Some adults with achondroplasia may require continued individually-designed rehabilitation or physiotherapy (Swedish Information Centre for Rare Diseases, 2013).

Adults with achondroplasia, like most average height adults, focus on building careers, achieving financial security and enjoying their homes, families, and friendship networks. In a study conducted by Cortinovis I et al., 2011, adults report experiences characterized by high challenges that also allow them to gain positive creativity and cognitive empowerment. Although for many adults, their condition has impact either on employment opportunities or social relations at work (Ireland P et al., 2011), which will depend in socio-cultural factors

achondroplasia gives a unique physical appearance and affected people may experience different barriers that can challenge their quality of life. One of the most important constraints in quality of life is the social devaluation and stigma around the short stature, still present in society (Fernández S, 2009). Nevertheless, people with achondroplasia try to live ordinary lives while coping with extraordinary circumstances (Cortinovis I et al., 2011).

 

References

Arregui S. The social stigma on dwarfism - consequences and coping techniques. Doctoral Thesis. UNED. 2009

Barreal C. Physical rehabilitation guidance for achondroplasia. Fundación ALPE. 2008

Cortinovis I, Luraschi E, Intini S, Sessa M, Delle Fave A.The Daily Experience of People with Achondroplasia. Applied psycology: health and well-being, 2011;3(2):207-227.

Hoover-Fong J, Schulze K, McGready J, Barnes H, Scott C. Age-appropriate body mass index in children with achondroplasia: interpretation in relation to indexes of height. Am J Clin Nutr 2008; 88 (2): 364-371.

Ireland P, McGill J, Zankl A, Ware R, Pacey V, Ault J. Savarirayan R, Sillence D, Thompson E, Townshend S, Johnston L. Functional performance in young Australian children with achondroplasia. Developmental medicine and child neurology 2011;53 (10):944-950.

Ireland P, Pacey V, Zankl A, Edwards P, Johnston M, Savarirayan R. Optimal management of complications associated with achondroplasia. Appl Clin Genet. 2014; 7: 117-125.

Trotter T, Hall J. Health Supervision for Children with Achondroplasia. Pediatria 2005; 116 (3)

Wright M, Irving M. Clinical management of achondroplasia. Arch Dis Child, 2012:

Unger S, Bonafé L, Gouze E. Current Care and Investigational Therapies in Achondroplasia. Curr Osteoporos Rep. 2017:

OMS. Relatório mundial sobre deficiências - Reabilitação. Capítulo 4. 2011

 

 

POTENTIAL TREATMENTS FOR ACHONDROPLASIA

There is currently no cure or pharmacological treatment available for achondroplasia. Current care for achondroplasia manages the symptoms and alleviates the consequences of complications (Unger S et al., 2017) (as seen above). However, there are potential drugs under development aiming to improve bone growth and decrease the rate of complications seen in achondroplasia (Ireland P et al., 2014).

The major goal in developing treatments for achondroplasia has been to safely reduce the output of FGFR3 signals close to normal. Strategies have ranged from blocking receptor activation, inhibiting FGFR3 tyrosine kinase activity, accelerating the degradation of the active receptor to antagonizing signals downstream of the receptor. These strategies are based on the understanding of relevant molecular events that lead to this skeletal dysplasia (Narayana J and Horton W, 2013).

 

Medicines

The strategy to treat achondroplasia that is currently in a more advanced stage of development is Vosoritide, a C-natriuretic peptide (CNP) analogue, developed by BioMarin Pharmaceutical. This CNP antagonizes the MAPK signals initiated by FGFR3. Vosoritide is currently being investigated in a Phase III clinical trial, a study in children with achondroplasia between 5 and 14 years old (Narayana J and Horton W, 2013).

Recently a new approach was presented by the company Ascendis Pharma, through their innovative TransCon technology with the TransCon CNP for achondroplasia. This technology combines the benefits of a prodrug and a sustained-release technology. A prodrug is a masked form of an active drug. In this case, the prodrug is capable to increase the efficiency of the CNP, decrease associated toxicity and reduce the frequency of administration. The TransCon CNP is currently under pre-clinical trials (Beyond Achondroplasia, 2017).

Another example of the potential therapies in development for achondroplasia is TA-46 from the Therachon, a biotech company. TA-46 is a soluble form of human FGFR3 (sFGFR3), which acts as a trap for FGFs, the factors that bind to FGFR3, which prevents FGFR3 to be activated (Garcia S et al., 2013). This compound is currently undergoing laboratory studies.

Also under evaluation is meclozine (also known by meclizine), an over-the-counter drug for motion sickness. In studies conducted by Matsushita M et al., 2015, meclozine inhibited the elevated FGFR3 signaling in chondrocytes, suggesting potential clinical utility of this drug for the improvement of short stature in achondroplasia.

Another approach comes from Ribomic, a Japonese biotechnology company working with aptamers for innovative therapeutics. In Ribomic pipeline there are several aptamers and among them is RBM 007, under investigation for 5 conditions including achondroplasia, that is about to enter the Toxicological Good Laboratory Practices (Beyond Achondroplasia, 2016).

 

Limb lengthening

Distraction osteogenesis is a surgical technique consisting of a controlled osteotomy (straight cut in the bone) followed by gradual and controlled distraction (separation) of the two bone ends utilizing a mechanical stretch of the vascularized bone surfaces to stimulate new bone (Figure 14). This technique involves several temporal phases to complete the process (Lamm B et al., 2015).

This technique has been used successfully to increase limb length in achondroplasia. Limb lengthening has mostly been performed in pre-adolescents and adolescents, when the child´s assent is possible. (Chilbule S et al., 2016; Krakow D and Rimoin D, 2010). But the surgery outcome differs among patients and the body image change is limited.


 

 

Figure 14. Description of the distraction osteogenesis technique. (A) Showing the tibial bone that need to be lengthened. (B) Application of external fixator at the proximal and distal end. (C) Tibial and fibular osteomty. (D) Distraction phase. Note the new bone formation in the distraction gap (E) consolidation phase. Credits: Makhdom A et al., 2014

 

The rhizomelic pattern of achondroplasia lends itself favorably to limb lengthening to ameliorate body proportionality. Patients with achondroplasia usually have normal joint structures, so the height gained from limb lengthening can improve function and appearance. Moreover, due to the increased ligament and joint laxity, the muscle length exceeds bone length before lengthening, which facilitates the lengthening process ((Donaldson J, Aftab S, Bradish C, 2015).

The Ilizarov technique using external fixation was the best option for limb lengthening for many years. More recently, the use of an adjustable intramedullary nail that eliminates the need for external fixator has been introduced. External fixation frames are commonly associated with pin site infections and other complications (Fragomen A and Rozbruch, 2007).

Bilateral lower-limb lengthening, when both legs are under surgical intervention at the same time, has been commonly performed for patients with achondroplasia as it improves the quality of life (QOL) in selected patients (Park KW et al., 2015). Here is possible to view a case from Dr. Dror Paley, an orthopedic surgeon highly recognized by limb lengthening in achondroplasia.

Nevertheless, limb lengthening is performed over a 2-year period that includes surgery, recovery and rehabilitation period (Krakow D and Rimoin D, 2010) and may lead to some complications such as pin site infections, weak bone regeneration, delayed consolidation, non union at the regenerate point, joint contracture, joint deformity, subluxation, articular cartilage damage, stiffness and neurological and vascular compromise (Chilbule S et al., 2016).

 

Recombinant growth hormone (rhGH)

Recombinant human growth hormone (rhGH) is not approved to treat short stature of achondroplasia (ACH). Some studies suggested growth improvement in children with achondroplasia during short-term treatment with rhGH, but there is insufficient data available on both the effects on adult height and the changes of body proportions (Micolli M et al., 2016).

 

References

Beyond Achondroplasia, 2016 and 2017

Chilbule SK, Dutt V, Madhuri V. Limb lengthening in achondroplasia. Indian J Orthop 2016;50:397-405.

Donaldson J, Aftab S, Bradish C. Achondroplasia and limb lengthening: Results in a UK cohort and review of the literature. J Orthop. 2015;12(1):31-34.

Fragomen AT, Rozbruch SR. The mechanics of external fixation. HSS J 2007; 3(1):13-29.

Klag KA, Horton WA. Advances in treatment of achondroplasia and osteoarthritis. Hum Mol Genet. 2016; 25: R2acho

Lamm B, Knight J, Kelley S. A Closer Look At The Potential Of Bone Lengthening Distraction Osteogenesis. Podiatry today.2015;28(5). (http://www.podiatrytoday.com/closer-look-potential-bone-lengthening-distraction-osteogenesis)

Miccoli M, Bertelloni S, Massart F. Height Outcome of Recombinant Human Growth Hormone Treatment in Achondroplasia Children: A Meta-Analysis. Horm Res Paediatr 2016;86:27-34.

Park KW, Garcia R,Rejuso C, Choi JW, Song HR. Limb Lengthening in Patients with Achondroplasia. Yonsei Med J. 2015; 56(6):1656-1662.

Paley P. PRECICE intramedullary limb lengthening system. Expert Rev. Med. Devices Early online, 1–19 (2015)

Krakow D, The skeletal dysplasias. Genet Med 2010;12:327-341