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Home , Bone health, Hypochondrogenesis, Hypochondroplasia, Idiopathic short stature, Osteopetrosis

Curr Osteoporos Rep DOI 10.1007/s11914-017-0392-x

PEDIATRICS (L WARD AND E IMEL, SECTION EDITORS)

Skeletal Dysplasias: What Every Health Clinician Needs to Know

Sarah M. Nikkel1

# Springer Science+Business Media, LLC 2017

Abstract the first international nomenclature of constitutional Purpose of Review This review highlights how skeletal dys- of was published [1]. There have been numerous revi- plasias are diagnosed and how our understanding of some of sions over the years, with the last coming out in 2015 [2]. The these conditions has now translated to treatment options. Nosology and Classification of Genetic Skeletal Disorders Recent Findings The use of multigene panels, using next- divides the conditions into 42 groups based on gene families generation sequence technology, has improved our ability to (i.e., the FGFR3 group), phenotypic presentation (i.e., quickly identify the genetic etiology, which can impact man- acromicric dysplasia), and pathophysiology (i.e., lysosomal agement. There are successes with the use of disorders), among others. There are 436 disorders with 364 in individuals with SHOX deficiencies, asfotase alfa in genes described, indicating that for a number of conditions a , and some promising data for c-type natri- genetic etiology has yet to be found. However, this is not the uretic peptide for those with . full explanation as one gene may be responsible for more than Summary One needs to consider that a patient with short stat- one condition (COL2A1 mutations cause ure has a skeletal dysplasia as options for management may be type 2, , spondyloepiphyseal dysplasia available. congenital, Kniest and Stickler syndromes) or a condition may be due to more than one gene (multiple epiphyseal dys- Keywords Skeletal dysplasias . Enzyme replacement plasia is caused by mutations in SLC26A2, COMP, MATN3, therapy . Gene panels . Radiographs . C-type natriuretic COL9A1, COL9A2,andCOL9A3, with the gene(s) for some peptide individuals yet to be found). The nosology allows for consis- tency when diagnosing the conditions and ensuring that rare syndromes are given the same name. The grouping of like with like has facilitated the ability to define the natural history, Introduction the genetic etiology, and pathophysiology of a dysplasia. It is an exciting time as pharmacological treatments are present The understanding of skeletal dysplasias has come a long way and emerging for a number of these conditions. since they were initially categorized into two groups: short limb (achondroplasia) and short trunk (Morquio). In 1970, Diagnosis

This article is part of the Topical Collection on Pediatrics There are many ways in which a skeletal dysplasia may present: it may be suspected in utero with the finding of * Sarah M. Nikkel short long bones or abnormal mineralization on prenatal [email protected] ultrasound, diagnosed in childhood due to disproportionate or fractures, or be detected when X-rays are 1 Provinical Program, BC Women’sHospitaland Health Centre, University of British Columbia, 4500 Oak Street, done for an unrelated reason. Regardless of the presenting Vancouver, BC V6H 3N1, Canada complaint, the next step is gathering a detailed medical Curr Osteoporos Rep history to obtain clues as to the potential etiology. The fam- can result in biochemical disturbances, thus the results may ily medical history may help determine if the condition is provide important clues for the diagnosis. X-linked likely to be de novo or inherited, and the possible pattern of hypophosphatemia is characterized by low serum inheritance. A parent who has or had the same clinical fea- levels, hypophosphatasia has low levels tures (including short stature—remember to measure both (sometimes with elevations in ), and Jansen type of parents!) can narrow the differential diagnosis as it is likely metaphyseal chondrodysplasia has elevations in calcium with to indicate an autosomal dominant condition. Knowing that low or low-normal PTH levels. the parents are consanguineous increases the likelihood that the condition could be recessive, but new dominant disor- Radiology ders in children of such parents are just as frequent as they are in the children of non-consanguineous parents. One may X-rays are still the most important diagnostic imaging tool also consider certain diagnoses based on the ethnicity of the when investigating dysplasias. One needs the right images at family. For example, hair hypoplasia (RMRP)is the appropriate age, as cardinal findings may only emerge more common in those of Finnish or Amish ancestry and with time or be present at a specific stage (i.e., the double Desbuquois (CANT1) is seen more frequently in the Korean patella sign in recessive multiple epiphyseal dysplasia is only population. present when the knee starts to ossify (ages 3–6years)until A complete review of systems may generate important bone maturation). However, what a skeletal dysplasia survey clues to aid in the diagnosis. Many dysplasias are associated entails from center to center can vary. Watson et al. [4]pro- with non-skeletal features, such as congenital heart in posed a standardization for imaging with the hope of facilitat- Ellis-van Creveld, ocular anomalies in the type II or type XI ing earlier diagnosis and reducing radiation exposure. Their -associated conditions, pancreatic insufficiency in list of standardized images include anteroposterior (AP) and Shwachman-Diamond syndrome, or Hirschsprung disease in lateral of the skull, lateral of the thoracolumbosacral spine, AP cartilage hair hypoplasia. Thus, one should ask about all body of the chest, AP the of , AP of one upper limb, AP of one systems. lower limb, and dorsopalmar of the left hand (this also allows Body proportions can provide important clues towards bone age to be done). Examples of abnormal bone morphol- making a diagnosis: is there or microcephaly, ogy obtained from such imaging are shown in Fig. 1.Unless is there rhizomelic or mesomelic shortening, or is there there is a clinical indication of asymmetry, only one limb ? When such a finding is present, the differential needs to be imaged. They also suggested that there be at least diagnosis can be narrowed. The Handbook of Physical a one-year interval between studies to allow time for the man- Measurements [3] is an excellent resource for normative ifestation of new findings. Outside of their protocol, they sug- values of all sorts of anthropometric measurements and de- gested other films may be needed but should be directed by scribes how to obtain such measurements correctly. At a min- the suspected differential diagnosis. imum, head circumference, height, and arm span should be measured. In the early years of life, arm span is typically less Skeletal Dysplasia Gene Panels than the height, and after the first decade of life it typically exceeds height. An arm span measurement that is much great- The advent of next-generation sequencing has greatly im- er than the height when plotted on a normative curve may proved our ability to molecularly diagnose genetic condi- suggest spine involvement/platyspondyly. A quick way to de- tions, and most laboratories, commercial and academic cen- termine upper limb proportions is looking at where the wrist ter affiliated, use this technology. A patient may present crease is in comparison to the shoulder when the elbow is fully with a non-specific dysplasia or be too young for some of flexed. If the crease is at or above the shoulder, this suggests the cardinal features to be present on radiographs. There rhizomelia. If it is midway along the humerus, this suggests may also be significant prognostic implications regarding mesomelic shortening of the limb. survival dependent upon the diagnosis, thus an urgency to There are a number of conditions that can mimic a skeletal get this information. In these instances, a skeletal dysplasia dysplasia in a growing child, such as hypothyroidism resulting gene panel can greatly reduce the time to diagnosis and can in epiphyseal changes or D deficiency causing be more cost- and time-efficient rather than testing gene by metaphyseal changes. Thus, doing some basic blood work gene. However, not all gene panels are created equally and may result in a diagnosis that can be resolved with treatment. different laboratories have different approaches to their Suggested investigations include thyroid stimulating hormone analyses. The American College of Medical Genetics (TSH), 25-hydroxy , 1,25-dihydroxyvitamin D, (ACMG) has a clinical practice guideline for clinical labo- (PTH), serum phosphate, calcium, cre- ratory standards for next-generation sequencing [5], which atinine, alkaline phosphatase, and urinary calcium, phosphate, the lab should follow. One should ensure that a panel con- and creatinine. As well, the pathogenesis of some dysplasias tains all the genes under consideration and there is Curr Osteoporos Rep a b c

e f

d

Fig. 1 Platyspondyly in a patient with a spondyloepiphseal dysplasia of the capital femoral epiphyses, and a patient with d (COL2A1) and in a patient with b brachyolmia (TRPV4)—note the (FGFR3) with an unremarkable pelvis but short difference in shape and proportions of the vertebral bodies. A patient femoral necks. Metaphyseal changes in a patient with e Schmid with c spondyloepiphyseal dysplasia congenita (COL2A1), (COL10A1) and in a patient with f recessive metaphyseal anadysplasia demonstrating short iliac bones, horizontal acetabular roofs, no (MMP9) appropriate deletion/duplication analysis when such patho- responsible for more than one phenotype. The results of a genic changes are noted to occur in the gene. A lab offering gene panel can also dictate the management of an individu- the largest gene panel is not always the best option, as cov- al. There are many genes associated with the infantile form erage (number of reads that include a given nucleotide in the of , and the genotype is important to know in reconstructed sequence), may not be as good as a lab who regards to treatment options. Those with CLCN7 mutations offers a more select group of genes. can respond well to hematopoietic stem cell transplantation, A patient with a non-specific spondyloepiphyseal dys- but those with TNFSF11 (RANKL) mutations do not [6]. plasia may be a good candidate for a gene panel, and one Thus, having the molecular results quickly aids in the care would want to confirm that the panel had good coverage of of the patient and the test is less invasive than doing a bone at least the COL2A1 and TRAPPC2 genes and that there marrow biopsy. were no exons deleted. The skeletal ciliopathies (i.e., However, a panel may not always be necessary. For a Jeune asphyxiating thoracic dystrophy, Ellis-van Creveld, classic presentation of achondroplasia, looking at the com- Sensenbrenner, short-rib thoracic dysplasia types) are an mon nucleotide change in the FGFR3 gene will detect ideal group for gene panel testing, as there are multiple > 99% of mutations (c.1138G > A (p.G380R) or candidate genes for a phenotype, with many genes c.1138G > C (p.G380R)). Curr Osteoporos Rep

One Size Does Not Fit All demonstrated a significant frequency of skeletal dysplasia of around 20% in this ISS and SGA group. These diagnoses were The management of skeletal dysplasias is complex and is very important to make as could be of dependent upon the underlying diagnosis. For achondroplasia, benefit for those with SHOX changes. Growth hormone is the American Academy of Pediatrics has developed health well recognized to improve growth in girls with Turner syn- supervision guidelines [7], with the latest update soon to be drome (45,X). As haploinsufficiency of SHOX underlies a published (personal communication). GeneReviews® significant component of the short stature seen, the use of [Internet] is an open access site, which contains a number of growth hormone has been expanded to those with isolated reviews on different conditions, with management guidelines SHOX deficiencies and has been of benefit in pre-pubertal included. These are typically written by experts on the condi- children [10]. Not all individuals with SHOX mutations will tion. However, for the majority of dysplasias, no such docu- have the Leri-Weill phenotype (mesomelic limb shortening ments exist and management must be based on the features with Madelung deformities) and may just present with ISS that are known to be associated with the condition and the or SGA. It is a difficult gene to analyze as non-coding se- presenting health concerns. This often means working as part quence anomalies distal from the gene may result in its dys- of a multidisciplinary team and being aware that different function. A gene panel using exome data may miss such issues may present at different stages of life. changes. In order to help identify those patients with SHOX One certainly does not want to miss cervical instability, gene aberrations, Hirschfeldova et al. [11] used a phenotype which is commonly seen in the type II collagenopathies (con- scoring form, with the higher scores correlating to an in- ditions due to changes in the COL2A1 gene) and Morquio creased likelihood finding a mutation. It is in those individuals syndrome. Thus if the child has spine involvement, the neck with higher scores where we need to ask for further analysis should be assessed as one of the initial investigations and than the routine screening of the SHOX gene. especially prior to any procedure that may involve neck ma- The majority of individuals with osteogenesis imperfect nipulations like a general anesthetic. This is also true for those (OI) have mutations in the COL1A1 or COL1A2 genes. with achondroplasia, where there is a risk of brainstem/cord However, a growing number of other genes have been de- compression due to a narrow foramen Magnum. scribedalsocausingOI.IntheabsenceofCOL1A1 or There are quite a number of health issues that can be very COL1A2 mutations, a decreased bone mineral density gene specific for a particular dysplasia, thus again emphasizing the panel can assist in making a diagnosis. Bisphosphonates are importance of having an accurate diagnosis. However, a com- frequently used as a treatment for OI. Although they are be- mon complication that often goes unrecognized is that of hear- lieved to be of benefit for the patient, a recent Cochrane re- ing loss. Tunkel et al. [8] assessed a number of individuals view [12] found there was no conclusive evidence that there with short-stature skeletal dysplasias and found that hearing was an improvement in clinical status in those treated. They loss was very common in both the adult and pediatric popu- did confirm the ability of the bisphosphonates, either oral or lations. This was true across a number of diagnoses, thus intravenous, to increase bone mineral density in children and recommending that hearing assessments be performed regu- adults, but suggested that further studies were necessary to larly throughout life. look at methods of therapy, long-term fracture reduction and improvements in quality of life indicators. It is likely that bisphosphonates will continue to be used and it behooves Pharmacological Management of Selected clinicians and researchers to collect the data to definitively Dysplasias answer these questions. One of the emerging therapies is for achondroplasia. The We have now entered an age where, as our understanding of mechanism of achondroplasia is due to gain of function of the pathophysiology of genetic conditions has improved, op- the fibroblast -3, resulting in tions regarding pharmacological management are emerging. sustained activation of the ERK/MAPK (extracellular But one does need to consider that a child with short stature signal-regulated kinase/mitogen-activated protein kinase) could have a dysplasia in the first place. Fletcher et al. [9•] pathway; the addition of c-type natriuretic peptide (CNP) looked at a series of patients referred to their center for idio- inhibits this. CNP was proposed as a potential therapy as it, pathic short stature (ISS) and small for gestational age (SGA). along with its preferential receptor [natriuretic peptide re- After excluding individuals with known specific diagnoses ceptor B (NPR-B)], are important as regulators of endo- (i.e., endocrine or genetic syndromes), the cohort had skeletal chondral bone growth. Biallelic loss-of-function mutations surveys. For those who had radiograph findings suggestive of in either of these genes in mouse models resulted in abnor- dyschondrosteosis or hypochondroplasia, they underwent ge- malities in bone growth [13, 14]. Yosado et al. [15] found in netic testing for SHOX and FGFR3. These were the two most mouse models of achondroplasia that there was improve- common conditions found and in total, these authors ment in bone growth with the use of CNP. Curr Osteoporos Rep

As CNP has a short half-life, a recombinant variant Support Groups (vosoritide) has been created that is resistant to degradation [16••]. This analog was shown in mouse models to increase Support groups provide an excellent service for families and axial and appendicular skeletal lengths and straighten the long individuals with skeletal dysplasias. There are Little People bones. Currently, Phase II and III trials are underway in pedi- (LP) Societies in many countries that organize social and atric patients with achondroplasia. It has been found to be well sporting events. For parents of a newly diagnosed child, there tolerated, with injection site reactions and mild, transient hy- is the opportunity to meet others who have gone through the potension being the most common adverse reactions. Outside same experience. For the individual who has been diagnosed of the improvement of linear growth, there is the potential of with a dysplasia, there is the opportunity to meet others who decreasing the incidence of as mean vertebral are the same, which is especially helpful when the diagnosis is foramen area increased when given to juvenile male cynomol- extremely rare. For clinicians and researchers, it is an oppor- gus monkeys [17]. Spinal stenosis is a cause of significant tunity to engage the LP population to identify needs and to morbidity in adults with achondroplasia, so treatment of CNP have a cohort of individuals who may be willing to participate in childhood while growing could have long-range benefits. in research. However, the likelihood that it will impact foramen magnum stenosis is lower as significant stenosis often presents in very early childhood/at diagnosis, prior to when treatment could Conclusions commence. Enzyme replacement therapy (ERT) has a role in the man- The advances in genetic technology have made it easier to agement of skeletal dyplasias with the treatment of determine the molecular diagnosis in someone with a skeletal hypophosphatasia. Hypophosphatasia is due to loss-of- dysplasia. However, the testing is not perfect and we still need function mutations in the tissue-nonspecific isoenzyme of alka- to be critical when reviewing laboratory results and interpret line phosphatase (TNSALP—ALPL gene), with residual activity the data in light of our detailed physical examination and use levels corresponding to severity of disease. Low activity levels of radiographs. It is the ability, however, to have clear diag- are associated with presentations prenatally/during infancy and noses that have advanced our understanding for a number of in childhood with , skeletal pain, and muscle weakness. conditions. This is the first step in developing appropriate There are high mortality rates in those with perinatal/infantile management tools for these individuals to improve their qual- forms due to the severity of the enzyme defect [18]. Asfotase ity of life. alfa was developed as a recombinant TNSALP targeted to bone. In individuals with infantile or childhood onset Acknowledgements I want to thank L.W. and E.I. for inviting me to hypophosphatasia, asfotase alfa has improved patient growth, write this article. I also want to express my appreciation to all the clini- strength, motor function, and quality of life with resolution of cians and families I have learned from over the years. pain. The treatment was well tolerated and safe [19••]. In the severe forms, it improved respiratory status and survival [20]. Compliance with Ethical Standards The use of asfotase alfa in those with milder phenotypes, such as Conflict of Interest Sarah Nikkel declares no conflicts of interest. odontohypophosphatasia where there is only the dental involve- ment, has yet to be evaluated. However, the costs of therapy may Human and Animal Rights and Informed Consent This article does limit its use in such scenarios. not contain any studies with human or animal subjects performed by the Not all enzyme replacement therapies have had such striking author. benefits to patients. Morquio syndrome (mucopolysaccharidosis (MPS) IVA) is a lysosomal storage disease that presents with a skeletal phenotype (dysostosis multiplex) with short stature, cor- References neal clouding, and preserved intelligence. Mutations in the galactosamine-6-sulfate sulfatase (GALNS) gene result in intra- Papers of particular interest, published recently, have been cellular accumulation of glycoaminoglycans (keratan sulfate and highlighted as: chondroitin-6-sulfate) in cartilage, heart valves, and corneal tis- • Of importance sues. It is difficult to deliver drugs to these avascular tissues, thus •• Of major importance these features are resistant to therapy. However, some modest response in the 6-min walk test has been demonstrated with the 1. International nomenclature of constitutional diseases of bones. Ann – use of elosulfase alfa as reported by a phase III trial, suggesting Radiol (Paris). 1970;13:455 64. improved cardiovascular endurance [21]. However, due to the 2. Bonafe L, Cormier-Daire V, Hall C, Lachman R, Mortier G, Mundlos S, et al. Nosology and classification of genetic skeletal pathophysiology of the condition, ERT, as it is used today, is disorders: 2015 revision. Am J Med Genet A. 2015;167A:2869–92. likely not to improve the skeletal phenotype. doi:10.1002/ajmg.a.37365. Curr Osteoporos Rep

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