Approach to skeletal dysplasia.

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MEDICAL GENETICS II

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APPROACH TO SKELETAL DYSPLASIA Bryan O. Hall, MO, FAAP

Skeletal dysplasia refers to a category of disorders affecting the epiphyses, metaphyses, or diaphyses in a generalized fashion that results in disproportionate shortness. Skeletal dysplasias are important because they are common as a group (1 in 3000 to 1 in 5000 births),l, 5 are not infrequently lethal, subject the affected person to chronic orthopedic and body image problems, and almost always have a genetic basis. Additionally, many of the more serious skeletal dysplasias can be diagnosed in utero by ultrasonography, biochemical tests, or molecular studies. Consequently, intervention, treatment, and accurate genetic counseling are potentially available to affected individuals and their families in a large percentage of cases. The following article presents a simplified approach to the diagnosis of skeletal dysplasias. The basis of its value is how to accurately categorize what is present clinically and radiologically.

SEQUENCE OF DIAGNOSTIC STEPS

Before applying the diagnostic steps outlined in Table I, certain information may be of value. Gestational observations such as polyhydramnios, increased or decreased uterine size, and decreased fetal activity are frequent gestational occurrences in skeletal dysplasias, particularly in the more severe or lethal forms. Polyhydramnios may or may not be accompanied by hydrops. Often, polyhydramnios is From the Division of Genetics and DysmorphoIogy, Department of Pediatrics, University of Kentucky, Lexington, Kentucky

PEDIATRIC CLINICS OF NORTH AMERICA VOLUME 39 • NUMBER 2 • APRIL 1992

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Table 1. IDEAL SEQUENCE OF DIAGNOSTIC STEPS IN DIAGNOSIS OF SKELETAL DYSPLASIAS Presence of reduced length/height noted Recognition of association with disproportion Determine body area(s) with greatest shortness long bones (limb) hands trunk (spine) Decide if the shortest body area has a relatively shorter portion long bones: proximal, middle segments hands: distal/middle/proximal phalanges, metacarpals, carpals trunk: thorax, neck, lumbar region Identify any secondary effects (deformations) (bowing, skin dimples, macrocephaly, craniotabes) Identify any primary defects (malformations) (polydactyly, cleft palate, heart defects) Roentgenographic examination of entire skeleton Categorize radiologic findings by areas of involvement physeal (epiphysis, metaphysis, diaphysis) spine (spondylo-) combination (spondyloepiphyseal dysplasia) other: hands (acro-), middle (meso-) Final categorization based on clinical and radiologic findings pure skeletal dysplasia (PSD) pure skeletal dysplasia with mental retardation (PSD/MR) malformation associated skeletal dysplasia (MSD) malformation/MR-associated skeletal dysplasia (MMRSD) Laboratory support/confirmation if available Diagnosis and genetic counseling

associated with excessive maternal weight gain and a paradoxically enlarged uterus in the presence of a small fetus. When polyhydramnios is absent, a small uterus with suspected decreased fetal growth may be observed. Decreased fetal activity can occur because of restricted movement secondary to a small uterus, joint contractures, dislocations, or fractures. The mother's drug history is potentially important because it is known that maternal warfarin (Coumadin) exposure can result in osseous findings identical to a group of genetic skeletal dysplasias categorized as chondrodysplasia punctata. A maternal or family history of stillbirths (malformed or otherwise) or late miscarriages should not be lightly passed over, even if the diagnoses seem entirely unrelated to the patient's problems. It is not uncommon for inexperienced physicians to confuse thanatophoric dysplasia with achondroplasia, hypophosphatasia with osteogenesis imperfecta, achondrogenesis with macerated fetus-hydrocephalus, and campomelic dysplasia with arthrogryposis-multiple congenital anomalies. Photographs, radiographs, and autopsy results, when available, should be reviewed, although these items may not be readily accessible or received in a timely fashion.

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The family history is most important; however, it may not be initially available, and critical relatives may not be present. Portions of the family history are often sketchy and misleading. Determine if the individual's parents are inbred (consanguineous), because many bone dysplasias are inherited in an autosomal recessive manner. During the history-taking session, one should scrutinize the parents, siblings, and close relatives because one of them may overtly have the disorder or be mildly manifesting signs that the affected child has more prominently. When any question exists, one should examine suspected relatives and review photographs of those not available. Knowing the age of onset (i.e., congenital, infantile, toddler, midchildhood), whether there were neonatal respiratory difficulties, and the ultimate height of "short relatives" can serve to include or exclude a number of skeletal dysplasias. Diagnostic Step One

The process of diagnosing a skeletal dysplasia (Table 1) first begins with the recognition of reduced length or height when compared with normal relatives and normal controls. This is no problem in severe congenital bone dysplasias; however, many individuals with mild, moderate, or late-onset bone dysplasias do not necessarily measure short at birth or early infancy. Sometimes, disproportion draws attention to a patient having, or potentially having, short stature. Diagnostic Step Two

Disproportion can best be appreciated in neonates, infants, or toddlers by standing back and comparing the anatomic and geographic relationships of various body parts. Normally, a young child's arms, when held down by the side of the body, fall between the iliac crest and upper one third of the thigh. When the fingertips of the hand fall above the iliac crest, one usually has clinical disproportion (Fig. 1). A short trunk sometimes allows the hands to fall further down on the thigh, however, giving a false normal placement. Again, very short limbs or hands are rarely missed, so there is no magic in recognizing limb disproportion in those instances. A short trunk is more difficult to identify clinically, but short trunks are wider along the lower costal margin, and the anterior chest appears fuller and sometimes prominent. A constricted or hypoplastic chest is usually associated with a short trunk, but even a relatively small chest can be obscured in an infant because of the camouflaging effect of

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Figure 1. Stillborn with osteogenesis imperiecta, type II. Note short arms that do not reach hip area, anteriorly bowed tibae, club feet, and small chest.

excess baby fat. Other clues to the presence of disproportion are a real or relative macrocephaly, bowing of the long bones, and asymmetry. Diagnostic Step Three

Once shortness or disproportion has been recognized, it is important to establish which body areas are the shortest. Only the limbs may be short, but more frequently the limbs and trunk have reduced length. It is unusual for the trunk or hands to be the only body areas that are short. Diagnostic Step Four

The long bones often have a predominately shorter segment. If the humerus or femur is relatively shorter, this proximal shortening is called rhizomelia. Disproportionate shortening of the middle bones such as the radius, ulna, tibia, and fibula is called mesomelia (Fig. 2). Certain


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bone dysplasias have a predictable pattern of geographic shortening. It is important to remember that some degree of shortening can usually be found in all segments of the long bones; however, our categorization scheme is based, in part, on which segment is relatively shorter. If the hands are the primary area of shortness, they are described as showing acromelia (distal shortness). There is some value in trying to clinically determine whether the carpal, metacarpal, or phalangeal bones are equally or individually short. This usually requires radiologic confirmation because the exterior hand examination does not always predict the osseous abnormalities underneath. Basic hand features are important to recognize and define. An architecturally normal hand in shape and size eliminates many skeletal dysplasias from diagnostic consideration. For instance, patients with spondyloepiphyseal dysplasia congenita (SED conge nita) and Langer

Figure 2. A, Young girl with Langer type mesomelia. Note short forearms in presence of normal hands. B, Radiograph of child's arm confirms mesomelic (radial and ulnar) shortening.

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mesomelic dysplasia (Fig. 2) have normal hands in the face of generalized (SED congenita) or localized (Langer) bone involvement. If the hand is small or wide or the digits are short (brachydactyly), then one must assume that some or all of the hand bones are abnormal (Fig. 3). Generalized shortening of the fingers is called brachydactyly, whereas shortening of primarily the metacarpals is called brachymetacarpy. Sometimes, only certain hand bones such as the middle phalanges or the fourth and fifth metacarpals are short. In other instances, certain segments within a grouping (i.e., second and fifth middle phalanges) may be primarily short. Brachydactyly has been classified into various patterns (types A-E), and some of these patterns can be found in specific skeletal dysplasias. 21 When the trunk is short, it usually means some section of the spine is short. This usually occurs because the vertebral bodies are flat (platyspondyly) or have segmentation defects (i.e., hemivertebra). The spine can be short in the cervical, thoracic, and lumbar regions; however, 'it is usual for all vertebrae to be involved with one area predominating. A short neck or cervical kyphosis might indicate more cervical spine involvement. Thoracic shortness, hypoplasia, asymmetry,

Figure 3. Photograph (A) and radiograph (B) of a 7-year-old girl with multiple epiphyseal dysplasia, type Fairbank. A, All fingers seem mildly short, but note relatively short distal phalanges, small nails, and lack of fifth finger knuckle dimple. B, Radiograph shows short distal phalanges, short fifth metacarpal, small carpal bones, and small distal radial and ulnar epiphyses.


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and rib gaps raise suspicions of more severe thoracic spine involvement. Lordosis or gibbus (lumbar kyphosis) likewise creates concern for more lumbar spine abnormalities. Diagnostic Step Five

Identifying the secondary effects or deformations caused by the osseous abnormalities can simplify the diagnostic process and may aid in more accurate categorization. Table 2 gives some of the more common examples of secondary effects. When such effects are present, they can both raise the diagnostic possibility of skeletal dysplasia and, when extreme, suggest specific diagnoses. Certain secondary effects merit more discussion. Bowing of the long bones signifies a curvature that is due to shortened long bones or bones that lack adequate bone density, which results in reduced strength and secondary bending. 7 No one knows for sure why abnormally short long bones tend to bow, but when bending does occur, skin dimples (Fig. 4) over the area of sharpest angulation, and medial semicircular skin creases often can be seen. Gentle bowing generally Table 2. SECONDARY EFFECTS (DEFORMATIONS) OFTEN RELATED TO OSSEOUS ABNORMALITIES FOUND IN SKELETAL DYSPLASIAS Feature Club feet Bowing Medial skin creases Skin dimples Dislocaiions Large joints Joint contractu res Joint hypermobility Prominent ends to long bones Spinal curvatures Short ribs/hypoplastic thorax Gibbus (lumbar protrusion) Macrocephaly Cranial contour abnormal Large anterior fontanel Craniotabes Craniosynostosis Flat nasal bridge Dentinogenesis imperfecta

Representative Example(s) Diastrophic dysplasia Numerous skeletal dysplasias Associated with moderate to severe bowing (common) Campomelia, diastrophic dysplasia Larsen syndrome Kniest syndrome Diastrophic dysplasia Morquio syndrome Many metaphyseal dysplasias Diastrophic dysplasia, metatrophic dysplasia Thoracic dystrophy, Majewski, Saldino-Noonan syndromes Hunter syndrome Achondroplasia, many lethal skeletal dysplasias Numerous dysplasias associated with osteopenia Cleidocranial dysplasia Osteogenesis imperfecta, hypophosphatasia (congenital) Hypophosphatasia (infantile), thanatophoric dysplasia Many skeletal dysplasias, dramatic in acrodysostosis Osteogenesis imperfecta

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Figure 4. Long-term survivor with campomelic dysplasia. Note pretibial skin dimple on left leg and bilateral bowed lower legs.

infers milder shortening, whereas marked angulation is frequently associated with severe shortening, decreased bone density, or fractures. Except in rare forms of mesomelia, the lower extremities tend to be more bowed than the upper extremities. The joints may be helpful in reaching a workable differential. Some bone dysplasias have generalized reduction in joint mobility, whereas others (e.g., achondroplasia) may have one joint (e.g., elbow) with reduced movement. Large joints (Fig. 5) are seen in relatively few disorders, and they sometimes look erroneously large because the metaphyses are widened. Diagnostic Step Six

Because a significant proportion of skeletal dysplasias have associated malformations, it is extremely useful to document these and use them in reaching a practical differential diagnosis. Sometimes the malformation or pattern of malformation is so specific that a diagnosis


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Figure 5. Young adult with Kniest dysplasia. A, Full-body view demonstrating large appearing knee joints. B, Hands of same individual with large finger joints. Most of enlargement is caused by widened metaphyses.

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can be made relatively easily. Good examples of this are the cystic ears in diastrophic dysplasia (Fig. 6) and the multiple gingival frenulae in Ellis-van Creveld syndrome (Fig. 7). Table 3 gives examples of associated malformations and some of the skeletal dysplasias in which they can be found. Occasionally, a malformation may actually represent a deformation, and one cannot be totally secure in the separation. A good example is craniosynostosis . Is it primarily a direct secondary effect of the generalized bone dysplasia or a localized malformative problem of the sutures? Another example is macrocephaly and achondroplasia. Is the macrocephaly caused by the intrinsic defect of the calvarial bone or skull base or is the cranium large simply because of the megaencephaly found in achondroplasia? When any doubts exist, one should include only clear-cut malformations (Table 3) or make note of potential exceptions. Diagnostic Step Seven

Categorizing radiologic findings by areas of involvement (Table 4) essentially results in defining a pattern that, hopefully, will be a match

Figure 6. Neonate with diastrophic dysplasia. Cystic ear was present at birth but can develop anytime up to 2 months after birth. This child also had a cleft palate. Note additional features of micrognathia and small thorax.


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Figure 7. Newborn with Ellis-van Creveld syndrome. This child displays the unusual feature of multiple gingival frenulae. He also had polydactyly (postaxial). small dysplastic nails. and congenital heart defects.

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Table 3. MALFORMATIONS THAT MAY BE PARTICULARLY USEFUL IN DIAGNOSING SPECIFIC SKELETAL DYSPLASIAS Representative Example(s)

Feature Encephalocele Sparse scalp hair Cystic ears Cataracts' Blue sclera' Hypertelorism Myopia/retinal detachment' Severe nasal bridge hypoplasia' Cleft palate/lip Multiple frenula Oligodontia/conical teeth Micrognathia" Clavicular agenesis/hypoplasia Polydactyly Camptodactyly' Nail agenesis/hypoplasia low-set (hitchhiker) thumb' Ichthyosis Tail Hypogenitalism Ambiguous genitalia Imperforate anus Intestinal atresia Renal cysts Heart defects

Dyssegmental dwarfism Cartilage·hair hypoplasia Diastrophic dwarfism Chondrodystrophica punctata Osteogenesis imperfecta Robinow syndrome Stickler syndrome Acrodysostosis Diastrophic dysplasia (CP), campomelia (CP), Majewski syndrome (Cl) Ellis-van Creveld syndrome Ellis-van Creveld syndrome, cranioectodermal dysplasia Campomelic dysplasia Cleidocranial dysplasia Ellis-van Creveld, Majewski, Saldino-Noonan syndromes Campomelic dysplasia Ellis-van Creveld syndrome Diastrophic dysplasia Chondrodysplasia punctata Metatropic dysplasia Robinow syndrome Majewski syndrome Saldino-Noonan syndrome Saldino-Noonan syndrome Majewski, Saldino-Noonan syndromes Ellis-van Creveld, Majewski, Saldino-Noonan syndromes

"May represent either malformations or deformations.

Table 4. EXAMPLES OF CATEGORICAL DIAGNOSES BASED ON RADIOLOGIC AREAS OF INVOLVEMENT Areas Involved

Categorical Diagnosis

Epiphyses only Metaphyses only Diaphyses only Spine only Spine plus epiphyses Spine plus metaphyses Spine plus diaphyses Spine/epiphyses/metaphyses Hands only (or primarily) Hands plus other areas Proximal limb segment Middle limb segment Cranium and diaphyses Cranium and metaphyses

Multiple epiphyseal dysplasia Multiple metaphyseal dysplasia Diaphyseal dysplasia Spondylo [brachyolmia] Spondyloepiphyseal dysplasia Spondylometaphyseal dysplasia Spondylodiaphyseal dysplasia Spondyloepimetaphyseal dysplasia Acro-(dysostosis, peripheral dysostosis) Acro-(acromicric, acromesomelic dysplasia) Rhizomelia (rhizomelic dwarf) Mesomelia (mesomelic dwarfism) Craniodiaphyseal dysplasia Craniometaphyseal dysplasia


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with a known skeletal dysplasia. 18 The groundwork is laid by careful review of a full skeletal series. In radiologic terms, the major interest lies in the physeal regions (epiphyseal, metaphyseal, and diaphyseal), spine, hands, or any combination thereof. It is fortunate that most disorders involving skeletal dysplasias have predictable adverse effects on the epiphyses (Fig. 8), metaphyses, and diaphyses. The epiphyseal involvement can include delayed ossification, irregular ossification, flattened or small epiphyses, or stippled epiphyses. Metaphyseal involvement (Fig. 9) includes wide metaphyses, cupped metaphyses, irregular metaphyses, spiculed lateral metaphyseal borders, and growths on or off the metaphyses, such as enchondromas or exostoses. Generally, diaphyseal involvement as the only long bone finding is rare and found primarily in disorders of hyperostosis and hypo-ostosis. Bone density (i.e., sclerosis, osteopenia, osteoporosis), however, should always be evaluated because it can be of distinct value in reaching a diagnosis. Terms such as overtubulation, undertubulation, undermodeled, and overmodeled are confusing and rarely aid in reaching a diagnosis. Radiologically, the spine is represented almost exclusively by vertebral size, contour, and basic anatomy. Of particular interest is the height of the vertebrae. Most skeletal dysplasias that have spine involvement have reduced height or platyspondyly (Fig. 10). The degree of reduced height (flatness) is extremely variable and sometimes age related among various skeletal dysplasias. For a specific bone dysplasia, the reduction is fairly uniform. In instances in which the degree of platyspondyly is mild, it can be detected quicker by observing, on a lateral film, the increased distance between adjacent vertebrae. The vertebral body architecture can be abnormal in numerous ways, including anterior beaking (inferior, superior, or mid) (Fig. 11), posterior concavity, coronal clefts, and superior and inferior border irregularities (depressed, midportion, piled up). Anatomic defects (Fig. 12) can include hemivertebra (sometimes called dyssegmented when multiple vertebra are involved), hypoplastic vertebra, and coronal clefts. Nonvertebral body abnormalities, such as widened or narrow interpedicular distances and spina bifida, also can be seen in some skeletal dysplasias. Many of the above-mentioned spinal abnormalities can result in shortened spinal heights (i.e., short trunk, short neck), scoliosis, lordosis, kyphosis, kyphoscoliosis, gibbus, or a combination of these findings. The most important radiologic features of the chest involve size, both of the entire rib cage and of the ribs. Many bone dysplasias are associated with a small chest, and some of the lethal varieties are associated with an extremely hypoplastic thorax (Fig. 13).22 It is usually not difficult to determine radiologically that a chest is small. Most small

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Figure 8. Seven-year-old girl with multiple epiphyseal dysplasia, Fairbank type. A, Note relative normality of knee metaphyses, whereas epiphyses look mottled and irregular. B, Hip radiograph of same girl with small proximal femoral epiphyses and irregular acetabulae .


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Figure 9. Pediatric patient with Schmid type of metaphyseal dysplasia. At the knees the metaphyses are widened and irregular, whereas the epiphyses are normal. Also, note rather severe metaphyseal involvement of proximal femoral metaphyses, which are associated with short femoral necks.

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Figure 10. Adult with metatrophic dysplasia showing very flat (platyspondylous) vertebral bodies, with anterior wedging of the twelfth thoracic and first lumbar vertebrae.


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Figure 11. The spine of a 6-year-old girl with pseudoachondroplasia demonstrating platyspondyly and anterior beaking of the midportion of vertebrae.

chests have short ribs that are either thick or thin. Those with thick ribs tend to have horizontally placed ribs with cupped ends. Normal width or narrow ribs tend to form a triangular rib cage, with the superior portion being more narrow. Rib fractures are seen in various forms of osteogenesis imperfecta. Multiple prenatal fractures can reduce the size of the thorax and cause almost any chest contour (Fig. 14). If vertebral body defects such as hemivertebrae are present, ribs can be absent, bifid, hypoplastic, or duplicated. One should always look at the clavicles and scapulae because absent-hypoplastic clavicles (cleidocranial dysplasia) and hypoplastic scapulae (campomelic dysplasia) can be seen in certain skeletal dysplasias. . The skull is of primary value in disorders involving reduced calvarial bone density, such as is seen in osteogenesis imperfecta (Fig. 15) and hypophosphatasia. The major radiologic findings of reduced

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Figure 12. Stillborn with probable dyssegmental dysplasia. The vertebral bodies are flat, irregular, and poorly segmented. Note very short long bones, with wide metaphyses and small thorax.


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Figure 13. Newborn with thanatophoric dysplasia who died at 12 hours of age. Note small thorax, thin horizontal ribs, platyspondyly, square hypoplastic ilial bones, drum-stick proximal femoral heads, and generalized long bone shortening with metaphyseal spicules.

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Figure 14. Stillborn neonate with osteogenesis imperfecta, type II (particular subtype not yet established). Prenatal healing rib and long bone fractures are obvious. Secondary bowing, shortening, and widening can be seen in the long bones.


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Figure 15. Same infant noted in Figure 14 with osteogenesis imperfecta, type II. Note poorly ossified skull with islands of calvarial bone.

calvarial bone density are wormian bones, which are irregular, linear areas of translucency found primarily in the occipital and parietal regions. In severe instances, islands of poorly ossified bone can be seen among an otherwise nonossified calvarium. These features often are associated with large fontanels, prominent forehead, and a relatively large (macrocephalic) head. A large anterior fontanel associated with mild to moderate reduction in calvarial bone density is typical for cleidocranial dysplasia (Fig. 16). The pelvic abnormalities noted in radiographs of skeletal dysplasias rarely enter into the categorization or classification of these disorders. The findings are very important, however, and sometimes are strongly supportive of certain diagnoses. The most common iliac abnormalities include hypoplastic iliac bones, excessive iliac wing flare, reduced iliac

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Figure 16. Neonate with cleidocranial dysplasia. Note large anterior fontanel and markedly widened sutures. Some wormian bone formation is obvious in oCcipital region. Right hypoplastic clavicle can be observed.

wing flare, squared ilia, short ilial base, and narrow ilial base. Sometimes, the presence of iliac horns (bony protuberances off the lateral border of the lower iliac wing) and lacey ilial borders can be specific for disorders such as nail-patella syndrome and Dyggve-MelchiorClausen syndrome, respectively. Also, some bone dysplasias have one or two medial spurs or projections off the lower ilial base. It is also useful to determine the status of the acetabulum. Is the angle appropriate and is the surface smooth, irregular, or widened? Radiologically, the hands are more complex to interpret than any other body area. If they are normal, which they definitely are in some bone dysplasias, the differential diagnosis can be reduced substantially. The diagnostic focus of hand radiographs can be divided into carpal, metacarpal, and phalangeal bones in order of increasing importance. The carpal bones play an insignificant role in the diagnosis of most bone dysplasias except for the occasional bone dysplasia, which displays delayed carpal ossification, carpal fusion, or stippled carpal bones. The main contribution of the metacarpal bones lies in their being abnormally short, particularly in fourth and fifth metacarpal hypoplasia, like that seen in pseudopseudohypoparathyroidism or some of the brachydactyly conditions to be discussed. In diastrophic dysplasia, the first metacarpal bone is invariably short. This causes the low-set thumb


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(hitchhiker thumb). Sometimes the distal ends of the metacarpal bones are cupped or widened in association with metaphyseal disorders. The phalanges form useful but potentially confusing patterns of abnormalities. In the least confusing situation, isolated (i.e., not otherwise associated with a bone dysplasia) brachydactyly can be found when various phalangeal bones are short and wide. Here the pattern of phalangeal shortening (i.e., generalized, distal, middle, proximal, or a mixture) must be identified and matched with previously recognized patterns (Fig. 17). This can be done easily, in most cases, because almost all brachydactyly conditions are genetic and usually dominantly or recessively inherited. Consequently, classifiable patterns and their variations have been previously documented. If the patient has bone abnormalities elsewhere in the body, the hand-phalangeal pattern can be potentially matched to the other findings of that particular bone dysplasia. Certain phalangeal features in addition to or in place of the finding of brachydactyly can be important to recognize. Distal phalangeal bone hypoplasia or absence can be found in a small number of bone dysplasias. It is usually associated with small or absent fingernails. Other phalanges (i.e., fifth middle, second middle) can be missing and have specificity toward diagnosis. The phalangeal epiphyses can have a conical configuration rather than a rectangular shape. Here the

Figure 17. Hands of a young child with type C brachydactyly, which involves only the hands and is autosomally dominantly inherited. The pattern of involvement shows shortness of second and third middle phalanges, proximal third phalanx, and first metacarpal.

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triangular epiphysis invaginates into the metaphysis rather than fusing in a flush fashion. This often causes the involved phalanx or phalanges to deviate off the midline, causing clinodactyly clinically and metaphyseal spurs radiologically. Fusion of phalanges (symphalangism), bifid phalanges (with or without polydactyly), and extra phalanges are a partial list of other phalangeal abnormalities that can be found in bone dysplasias. Other bony abnormalities that do not fit into the neat scheme noted earlier also may be useful. Such findings as short femoral neck, long distal fibula, short distal ulna, bifid distal humerus, and medial slant and constriction of the distal radial epiphyses (Madelung deformity) are just a few examples that can be found in certain bone dysplasias. These types of findings carry various degrees of importance relative to the ultimate diagnosis. Diagnostic Step Eight

The final categorization (Table 5) is based on the clinical and radiologic findings. The radiologic distribution is identified (i.e., spondyloepiphyseal dysplasia) as well as the characteristics of the spine, physis, or hand abnormalities. If the patient has any malformations or is mentally retarded, this is now put into the equation. The decision can now be made if the patient has a pure skeletal dysplasia (PSD), which means no associated malformations are present; a multiple congenital Table 5. REPRESENTATIVE EXAMPLES OF SKELETAL DYSPLASIAS CATEGORIZED AS PURE, MALFORMATION ASSOCIATED, AND MALFORMATION/MENTAL RETARDATION ASSOCIATED Pure Skeletal Dysplasia Achondroplasia Hypochondroplasia* Spondyloepiphyseal dysplasia congenital Achondrogenesist Thanatophoric dysplasiat Osteogenesis imperfecta Hypophosphatasia

Malformation Associated

Malformation/Mental Retardation Associated

Diastrophic dysplasia Ellis-van Creveld syndrome Thoracic dystrophy (Jeune)

Campomelic dysplasia Chondrodysplasia punctata Acrodysostosis

Cleidocranial dysplasia Stickler syndrome . Majewski syndromet Saldino-Noonan syndromet

Pseudohypoparathyroidism:j: Kneist syndrome:j:

'Can be associated with mental retardation and could be basis of a fourth category, Pure Skeletal dysplasia/Mental Retardation. trotal lethality precludes judgment as to presence or absence of mental retardation. :j:Some cases have no malformations and would then fit into Pure Skeletal Dysplasia Category with mental retardation.


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anomaly-skeletal dysplasia (MCA/SD); or a multiple congenital anoll1alymental retardation-skeletal dysplasia (MCA/MRlSD). When malformations are present, it is necessary, and often advantageous, to match the combined pattern of malformations and osseous involvement with other potentially similar cases. A good example is Stickler syndrome, which causes a mild spondyloepiphyseal dysplasia, but can present with cleft palate, micrognathia, flat face, myopia, and retinal detachment. 20 Some pure skeletal dysplasias are associated with mental retardation, but they are not common. 3 Obviously, there are important historical facts and measured parameters that influence one's judgment in the inclusion or exclusion of certain skeletal dysplasias. A patient with achondroplasia without a large head, a 6-foot-tall diastrophic dwarf, a patient with hypochondroplasia with a heart defect and cleft palate, a patient with Morquio syndrome who was noted to be disproportionate at birth, and a patient with thanatophoric dysplasia with no neonatal respiratory distress are unlikely cases with probable erroneous diagnoses. Diagnostic Step Nine

The laboratory can be of help in diagnosing some skeletal dysplasias by electron microscopy of bone samples and molecular diagnosis utilizing DNA studies for disorders of collagen (i.e., osteogenesis imperfecta). Some skeletal disorders show abnormalities of calcium, phosphorous, and alkaline phosphatase. Chromosome studies are remarkably normal in skeletal dysplasias, except for campomelic dysplasia, in which sex reversal (external XX female, genotypic XY male) is common. Immune studies are definitely indicated when recurrent infections are documented, mild nonspecific multiple metaphyseal dysplasia is present (ADA deficiency), or the clinical diagnosis includes cartilage-hair hypoplasia. 17 Autopsy studies, particularly of severe, lethal, neonatal skeletal dysplasias, are strongly recommended because the internal anomalies, when present, may raise an entirely different diagnostic possibility or help establish a new previously unknown disorder. As mentioned previously, a full skeletal survey is always indicated in any patient who is disproportionately short. Repeat films over time in instances of questionable diagnosis or in unknown types of skeletal dysplasia show important changes with the potential of contributing to the ultimate diagnosis. Clinical photographs are also extremely important because clinical descriptions are often inaccurate, incomplete, or misleading.

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Diagnostic Step Ten

The final and most difficult step is that of reaching a secure and specific diagnosis. If Steps One to Ten are followed, chances are optimized. The remaining efforts should be directed at textbooks on multiple congenital anomaly syndromes that include skeletal dysplasias 2, 6, 9, 19,23 and books dealing primarily with skeletal dysplasia or disorders.4, 8,10,12,13,15,16,19,24 Computer diagnostic programs may be of some benefit, particularly when the skeletal dysplasia is associated with multiple congenital anomalies (i.e., POSSUM, London Dysmorphology Database). Recently, a computer diagnostic laser disk program called OSSUM became available specifically for skeletal dysplasias. All cases of skeletal dysplasia that do not have a secure diagnosis should be reviewed and confirmed by specialists in skeletal dysplasias, whether such experts are experienced radiologists, geneticists, or dysmorphologists. Most of these experts offer the service free of charge and can give valuable advice over the telephone as to what to do and how to prepare any materials sent to them. The hardest part of diagnosing a skeletal dysplasia is feeling confident about the interpretation of what the radiographs show versus what the radiographs show in literature cases. Only experience helps with this, but comparisons are easier to achieve currently because of the relative increase in written and visual information. SUMMARY

The mystique of skeletal dysplasias is gradually vanishing. Many more physicians are being taught about disorders of disproportionate shortness. The classification system is more practical, and the genetics of these individually uncommon disorders is better established. Metabolic studies will continue to identify the basic defect in these previously hard to get at disorders, allowing for prenatal diagnosis, carrier detection, and treatment. Advances such as bone marrow transplant, bone lengthening, and the encouraging positive effects- of growth hormone therapy are exciting new interventions to aid the disproportionately short statured person. The scenario is set for clinicians to become effective participants in the realm of skeletal dysplasias, but it all starts with an accurate diagnosis. References 1. Andersen PE: Prevalence of lethal osteochondrodysplasias in Denmark. Am J Med Genet 32:484, 1989 2. Buyse ML: Birth Defects Encyclopedia. Cambridge, Blackwell Scientific Publications, 1990, p 1892


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3. Chen H: Skeletal dysplasias and mental retardation. In Papadatos C}, Bartsocas CS (eds): Skeletal Dysplasias (Progress in Clinical and Biological Research, Vol. 104). New York, Alan R. Liss, 1982, P 451 4. Cremin BJ, Beighton P: Bone Dysplasias of Infancy. New York, Springer-Verlag, 1978, p 107 5. Erik PA Jr, Hauge M: Congenital generalized bone dysplasias: A clinical, radiological, and epidemiological survey. J Med Genet 27:37, 1989 6. Gorlin RJ, Cohen MM Jr, Levin LS: Syndromes of the Head and Neck, ed 3. Oxford, Oxford University Press, 1990, p 977 7. Hall BD, Spranger J: Congenital bowing of the long bones. Eur J Pediatr 133:131, 1980 8. Houston CS, Awen CF, Kent HP: Fatal neonatal dwarfism. Journal of the Canadian Association of Radiologists 23:45, 1972

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Address reprint requests to Bryan D. Hall, MD, FAAP Department of Pediatrics University of Kentucky 800 Rose Street Lexington, KY 40536-0084

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