Curr Osteoporos Rep DOI 10.1007/s11914-017-0392-x PEDIATRICS (L WARD AND E IMEL, SECTION EDITORS) Skeletal Dysplasias: What Every Bone Health Clinician Needs to Know Sarah M. Nikkel1 # Springer Science+Business Media, LLC 2017 Abstract the first international nomenclature of constitutional diseases Purpose of Review This review highlights how skeletal dys- of bones 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 growth hormone 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 hypophosphatasia, 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 achondroplasia. 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 achondrogenesis ure has a skeletal dysplasia as options for management may be type 2, hypochondrogenesis, 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 short stature or fractures, or be detected when X-rays are 1 Provinical Medical Genetics 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 phosphate inheritance. A parent who has or had the same clinical fea- levels, hypophosphatasia has low alkaline phosphatase levels tures (including short stature—remember to measure both (sometimes with elevations in calcium), 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, cartilage 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 disease 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 collagen-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 pelvis, 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 macrocephaly 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 brachydactyly? 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 vitamin 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 vitamin D, 1,25-dihydroxyvitamin D, (ACMG) has a clinical practice guideline for clinical labo- parathyroid hormone (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 ossification of the capital femoral epiphyses, and a patient with d (COL2A1) and in a patient with b brachyolmia (TRPV4)—note the hypochondroplasia (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