Skeletal dysplasias: Approach to evaluation

INTRODUCTION — The skeletal dysplasias are an extremely heterogeneous group of conditions that affect bone development. They encompass over 400 disorders [1]. Most are the result of genetic defects. Skeletal dysplasias can present any time from the prenatal period to adult life. Forms with an early presentation may result in perinatal/neonatal death due to lung hypoplasia and respiratory complications. The estimated incidence of skeletal dysplasias is approximately 15.7 in 100,000 births.

The classification of these disorders and the understanding of their pathophysiology have improved over time due to the advent of molecular studies and gene discoveries. This knowledge has contributed to the development of treatment options for specific skeletal dysplasias, such as achondroplasia, hypophosphatasia, X-linked hypophosphatemic rickets, and osteogenesis imperfecta.

The evaluation of nonlethal skeletal dysplasias is discussed in this topic review. An overview of specific nonlethal skeletal dysplasias is reviewed separately (see "Skeletal dysplasias: Specific disorders"). Prenatal diagnosis of the lethal skeletal dysplasias is covered in detail separately. (See "Approach to prenatal diagnosis of the lethal (life-limiting) skeletal dysplasias".)

OVERVIEW OF SKELETAL DEVELOPMENT — Embryologically, bone development arises from two different processes [2]:

●Membranous ossification

●Endochondral ossification

Membranous ossification is a direct mechanism of bone development by which mesenchymal cells condense and directly develop into bone. Most flat bones of the skull, pelvis, and the terminal aspects of the clavicles develop through this process of membranous ossification.

Endochondral ossification is an indirect process of bone formation. It starts with proliferation of chondrocytes that become hypertrophic and subsequently undergo cell death. This creates cavities that are later invaded by progenitor bone cell-forming osteoblasts. The osteoblasts elaborate matrix material that becomes calcified (osteoid formation), furthering trabecular formation of the bone. The area is later populated by osteoclasts, which allow bone resorption and remodeling. Endochondral ossification is a complex process that depends upon multiple ligands, signaling molecules, and receptors (hedgehog proteins, bone morphogenic proteins, fibroblast growth factors, Wnt signaling molecules, insulin growth factors, and retinoids) [3]. It is the most common process for bone formation in mammals.

CLASSIFICATION OF SKELETAL DYSPLASIAS — The approach to the classification of skeletal dysplasias has evolved over the years. Initially, the approach was based upon clinical and radiologic observations. This was subsequently complemented by the molecular discoveries that helped to understand them as part of gene disorder groups or pathways. A nosology and classification system for genetic skeletal disorders designed to facilitate diagnosis includes over 400 disorders categorized into 42 groups of skeletal dysplasias [1].

These groups include disorders that lead to short stature such as achondroplasia, disorders with decreased bone density such as osteogenesis imperfecta, disorders with increased bone density like osteopetrosis, and lysosomal storage diseases with skeletal involvement such as many of the mucopolysaccharidoses and mucolipidoses.

WHEN TO SUSPECT A SKELETAL DYSPLASIA — There are essentially two distinctive forms of skeletal dysplasia: those with prenatal onset (including lethal forms and many more nonlethal forms) and those with postnatal onset. The prenatal lethal forms are discussed in greater detail separately. (See "Approach to prenatal diagnosis of the lethal (life-limiting) skeletal dysplasias".)

The prenatal cases are often suspected from findings on fetal ultrasound [4], including (see "Approach to prenatal diagnosis of the lethal (life-limiting) skeletal dysplasias"):

●Growth deficiency

●Bowing or shortening of the long bones

●Vertebral defects

●Rib abnormalities

●Fractures

●Abnormal calvaria ossification

However, prenatal detection of skeletal dysplasias can be elusive. Many of the skeletal dysplasias are the result of abnormalities of the endochondral ossification, which is the process mainly involved in the growth and development of the long bones. This process is most active during the last trimester. Some skeletal findings therefore may not be obvious until the end of the second trimester or the beginning of the third trimester. Thus, an early routine ultrasound may miss many bone dysplasias. Prenatal diagnosis of skeletal dysplasias is discussed in greater detail separately. (See "Approach to prenatal diagnosis of the lethal (life-limiting) skeletal dysplasias", section on 'Establishing a diagnosis'.)

Most skeletal dysplasias present during childhood and are suspected because of obvious clinical manifestations including:

●Short stature

●Bone deformities

●Recurrent fractures

●Abnormal findings on radiographs obtained because of the above listed findings or discovered incidentally (ie, presence of enchondromas, vertebral segmentation defects, rickets changes)

Poor or delayed linear growth is one of the most common clinical presentations postnatally. It is important for the clinician to determine if the growth deficiency began prenatally or postnatally. The diagnosis of short stature is given when linear growth is beyond two standard deviations below the mean. The workup for short stature often precedes evaluation for a skeletal dysplasia and is frequently conducted by a pediatric endocrinologist, with radiographs to determine bone age among the most common investigations. The evaluation of short stature in children is discussed in greater detail separately. (See "Diagnostic approach to children and adolescents with short stature".)

INITIAL EVALUATION — Patients with a suspected bone dysplasia require a thorough clinical history, family history, a clinical exam including performance of measurements, and radiographic studies.

Medical history — The medical history is key to understanding onset and progression. One important question is whether the growth restriction, when present, is the result of a pre- or postnatal growth deficiency. As an example, achondroplasia is easily recognized at birth. However, other conditions such as pseudoachondroplasia may not be suspected until two to three years of age, when the patient presents with growth failure and knee deformities.

Patients with skeletal dysplasias may have delays achieving their motor milestones (eg, holding head, sitting up, walking) that can be due to discrepancy of body parts (eg, macrocephaly), presence of joint laxity or instability, bone deformities, or other factors. Common examples include:

●Delays in holding the head up, sitting, and standing in patients with achondroplasia due to their relative larger head. In some of these patients, their joint laxity can further interfere with reaching other milestones like walking.

●Delays in sitting and walking in patients with cleidocranial dysplasia due to hypoplasia of pubic bones.

Family history — A careful family history may help identify other similarly affected family members and may suggest specific diagnoses. Important information to obtain includes whether there is short stature in the immediate relatives, particularly parents (although actual measurement of parental height is more accurate than historical report), or a history of recurrent fractures, limb bowing, retinal detachment, polydactyly, and kidney disease. This may identify a number of genetic disorders, such as history of leg bowing in first-degree relatives of patients with suspected X-linked hypophosphatemic rickets, retinal detachment in relatives of patients with a type II collagenopathy such as Stickler syndrome, and kidney disease in family members of patients with a ciliopathy. Family history may also help to distinguish those individuals with familial short stature or constitutional delay of growth and puberty (an autosomal-dominant genetic trait in which a child achieves normal growth after puberty) (table 1). Lastly, consanguinity may raise concerns for rare recessive bone disorders. (See "Diagnostic approach to children and adolescents with short stature" and "Causes of short stature".)

Physical examination — Height and specific measurements of body segments may give clues that help determine the type of skeletal dysplasia. Besides measuring height, measuring arm span and the length of the lower and upper segments of the body are important for the workup to determine body disproportion. The physical exam is also an important tool to determine extremity bowing, scoliosis, kyphosis, chest size abnormalities, rib flaring, widening of the metaphysis (wrists and knees), and joint laxity.

The physical examination should include evaluation of the following:

●Height or length

●Body segments including arm span, lower segment length, and upper segment length or alternatively sitting height to calculate upper segment versus lower segment ratio

●Limb length, to look for limb shortening

●Finger length, to look for obvious brachydactyly

●Fingernails, which are absent in some skeletal disorders such as nail-patella syndrome

●Joint movements or limitations, including radioulnar synostosis, abnormalities that impede pronation-supination or extension, or joint laxity

●Chest deformities

●Scoliosis

●Neck shortening

●Midface hypoplasia

●Palate exam, to look for cleft palate that is associated with type II collagenopathies

●Head size, to look for macrocephaly, which is associated with a number of bone dysplasias

●Dysmorphic features of the face and other organ involvement (hepatomegaly, bone deformities) associated with mucopolysaccharidoses and oligosaccharidoses

The arm span is obtained by measuring the span of both arms outstretched perpendicular to the body axis. The measurement encompasses the longest span, which is from the tip of one middle finger to the tip of the middle finger of the contralateral arm. It is best to position the subject flat against the wall and place marks on the wall at equal height on either side. The distance between the marks is measured after the patient has moved. Performing the measurement directly on the subject may result in an incorrect measurement. If the measuring tape goes over the shoulders, for example, the measurement will be longer than the actual distance. The arm span should be always equal to or greater than the height in children as well as adults and never exceed the height by 10 cm in adults. Children tend to have an arm span that is equal to their height, whereas arm span in adults is usually a few centimeters longer than their height. Decrease in the arm span may indicate shortening of the upper extremities (rhizomelic, mesomelic, or acromelic bone shortening), as is the case in achondroplasia or other skeletal dysplasias that affect the length of the long bones.

The segment lengths are usually obtained by performing the sitting height in children and adults or by performing crown-to-rump measurements in infants and young children that are not yet ambulating. This measurement provides the upper segment length, and subtracting that from the height will yield the lower segment length. Another option for measuring the lower segment length in older children and adults is to palpate the lower aspect of the symphysis pubis while standing and measure the length from this point to the ground. Subtracting the lower segment length from the height will provide the upper segment length.

The upper segment measurement is divided over the lower segment to obtain the upper to lower segment ratio (US/LS). The ratio is normally higher in young children (eg, 1.2 to 1.3) but decreases after puberty to 1 or just below 1. A low US/LS ratio can indicate that the extremities are longer or the trunk is short and is useful in determining the nature of the disproportion. A higher number may indicate that the extremities are short. As an example, a child with achondroplasia will show a US/LS ratio ranging from 2 to 1.6 from infancy to adulthood [5]. Specific US/LS ratio curves are available for plotting [6]. A quick way to determine if the upper limbs are short is by extending the arms of the child next to their body. The tips of the fingers should come down past the hips and reach up to the mid-upper segment of the leg in older children.

Imaging — Radiologic evaluations can contribute significant information to aid with the diagnosis. This evaluation may include:

●Skeletal survey

●Bone-age estimation

●Computed tomography (CT) scan

●Magnetic resonance imaging (MRI)

●Ultrasonography

The skeletal survey should be comprehensive and include hands and feet. Visualization of the bony structures is best if the growth centers have not yet fused or closed. Once this has occurred, many of the anatomical details are lost or difficult to interpret.

A bone age is important to obtain for most patients presenting with short stature. Typically, wrist and hand radiographs are obtained for bone age and read using the standards provided by Greulich and Pyle [7]. Bone age is usually normal in patients with skeletal dysplasias. However, bone age could appear delayed due to an epiphyseal dysplasia. Thus, it is always prudent to glance at other bone centers for anomalies and irregularities of the growth centers. (See "Diagnostic approach to children and adolescents with short stature", section on 'Bone age determination'.)

CT scans and MRI studies are usually reserved for certain skeletal disorders and to answer specific questions. An example is performing a spine-brain MRI or CT scan of the skull base and foramen magnum in children with achondroplasia if and when their head circumference is growing over the expected curve or when they manifest neurologic symptoms suggestive of spine compression. Other cases in which imaging studies are indicated include bone dysplasias associated with spine narrowing in older individuals, as is seen in achondroplasia and hypochondroplasia. These imaging evaluations are typically requested by the orthopedics specialist, geneticist, or neurosurgeon.

Ultrasonography is typically reserved for prenatal evaluations and is a very useful tool in pregnancies with suspected skeletal dysplasias. A good ultrasound can assess bone density prenatally; determine overall growth, bone length, rib and chest size; and detect many other skeletal abnormalities.

REFERRAL — The pediatrician and the pediatric endocrinologist are the most frequent source of referral to the genetic/metabolic disease specialist for suspected skeletal dysplasia, usually after an extensive workup has been conducted for short stature. In some cases, referral comes from the pediatric orthopedist after clinical and radiologic clues may have shown concerns for a bone dysplasia.

Indications for referral include:

●Poor linear growth since birth, below two standard deviations

●Disproportionate short stature (ie, short trunk or short limbs)

●Severe brachydactyly

●Decreased growth (height) velocity in childhood

●Obvious bone deformities with or without short stature, including bowing of the bones, pectus deformities, polydactyly, scoliosis, bone growths (exostosis)

●Radiographic findings concerning for a bone disorder, including density abnormalities (osteoporosis or osteopetrosis), fractures, bone deformities

●Family history of a bone dysplasia in a first-degree relative in association with clinical or radiologic concerns

●Dysmorphic features associated with neurologic problems, failure to thrive, corneal clouding, or developmental delay

DETERMINING THE SPECIFIC SKELETAL DYSPLASIA — There are a number of approaches to determine the specific type of skeletal dysplasia once one is suspected, including clinical exam, radiologic evaluation, biochemical testing in some instances, and molecular testing.

The clinical exam is useful to establish general parameters, such as head circumference, length/height, proportions, arm span, trunk length, presence of scoliosis or back/chest deformities, and brachydactyly. In addition, other malformations such as clefting, facial abnormalities, and polydactyly may suggest specific diagnoses. A Madelung deformity (picture 1 and image 1) may point to conditions such as Turner syndrome, short stature homeobox (SHOX) gene deletions/mutations, or syndromes including Leri-Weil dysostosis. (See "Overview: Causes of chronic wrist pain in children and adolescents", section on 'Madelung deformity' and "Clinical manifestations and diagnosis of Turner syndrome" and "Causes of short stature", section on 'SHOX gene variants' and "Skeletal dysplasias: Specific disorders", section on 'Leri-Weill dyschondrosteosis'.)

One of the most popular ways to determine the specific type of skeletal dysplasia is the radiologic approach. Determining which areas of the bone are affected (eg, spine, long bones [diaphysis, epiphysis, metaphysis]) can lead to a general grouping of disorders. Anatomically, the long bones regions are formed by the diaphysis (main tubular bone), metaphysis (distal bone regions), and epiphyses (growth centers). If any of those areas are affected, the dysplasias are then known as diaphyseal, metaphyseal, and/or epiphyseal [1].

Delayed, small, or irregular epiphyses may suggest a form of epiphyseal dysplasia such as multiple epiphyseal dysplasias, pseudoachondroplasia, or spondyloepiphyseal dysplasia (SED), while widening or irregular metaphyses (eg, as seen in rickets) may suggest a metaphyseal dysplasia. Flattening, shortening, or deformation of the vertebral bodies may be the manifestation of a spondylar dysplasia (osteogenesis imperfecta due to compression fractures, X-linked SED tarda, pseudoachondroplasia, spondylometaphyseal dysplasias). Lastly, deformation or widening across the length of a long bone may represent a diaphyseal dysplasia (ie, Camurati-Engelmann, craniodiaphyseal dysplasia, craniometaphyseal dysplasia).

Oftentimes, the disorders may involve more than one region. When both the epiphyses and metaphyses are involved, for example, this is termed epi-metaphyseal dysplasia. When the vertebral bodies are also affected in combination with other regions such as the metaphyses or epiphyses, the terms spondylometaphyseal dysplasia or spondyloepiphyseal dysplasia (SED; congenital, Kniest dysplasia) are used.

Dysmorphic features in mucopolysaccharidoses or oligosaccharidoses may not be present at birth but may develop with age at varying rates. Although skeletal abnormalities may or may not be obvious at the time of evaluation, biochemical investigations for urine glycosaminoglycans (mucopolysaccharides), oligosaccharides, and plasma I-cell screen (elevated plasma lysosomal enzymes such as hexosaminidase) are recommended. The suspicion for a mucopolysaccharidosis may be raised by the presence of radiologic (dysostosis multiplex) or pertinent clinical findings (corneal clouding, short trunk, pectus deformity, joint restriction or laxity). Oftentimes, the diagnosis may be suggested by the interpreting radiologist.

Some rare skeletal dysplasias can be secondary to biochemical disorders and are associated with stippling located in the epiphyses and spine. One such example is rhizomelic chondrodysplasia punctate. This rare disorder is associated with severe micromelia and short stature and accompanied by elevation of very long chain fatty acids (VLCFA) and phytanic acid in plasma [8]. (See "Skeletal dysplasias: Specific disorders", section on 'Chondrodysplasia punctata'.)

Once the suspicion for a skeletal dysplasia is established, the clinician may opt for molecular testing including specific gene testing, the use of gene panels, and, in some instances, exome sequencing. At this point, it is appropriate to involve a genetics or bone dysplasia specialist, if available. Whole-exome sequencing (WES) is reserved for those children in whom the clinical information is equivocal and specific gene testing is negative [9].

Even after molecular testing, a definitive diagnosis may be elusive. Regular clinical follow-up, with a skeletal survey performed every two to three years, is key to determining the type of bone dysplasia in these cases. It is challenging to make a radiologic diagnosis once the growth plates start to close in adolescence because the metaphyses and epiphyses are fused and much of the valuable anatomical detail is lost.

Once the diagnosis is established, proper follow-up for the condition should be arranged to establish appropriate anticipatory guidance. Handling complications and comorbidities is important in many of these disorders. One example is the care of children with type II collagen disorder (ie, Stickler syndrome), who are at a high risk for retinal detachment.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of skeletal dysplasias is broad and is determined in large part by the type of skeletal dysplasia suspected. The evaluation and causes of short femur in fetuses and short stature in children are discussed in greater detail separately. (See "Approach to prenatal diagnosis of the lethal (life-limiting) skeletal dysplasias" and "Diagnostic approach to children and adolescents with short stature" and "Causes of short stature".)

It is important that other organic causes (endocrine, gastrointestinal, kidney, cardiac) are investigated before these children are referred to a bone specialist. It is key for the primary care clinician to rule out possible endocrine causes such as hypothyroidism or growth hormone deficiency. Consultation with a pediatric endocrinologist may be valuable to help rule out these disorders. Malabsorption disorders such as celiac disease can cause growth deficiency. Thus, evaluation of a child with growth deficiency should include determination of transglutaminase levels in serum. In the presence of chronic pulmonary infections, conditions such as cystic fibrosis must be considered. There are a number of genetic conditions that are associated with short stature, although they are not necessarily true skeletal dysplasias. A geneticist can help with evaluation if any of these are suspected. A chromosome study and/or a chromosome microarray study can determine the presence of abnormalities that can explain short stature (eg, monosomy X, also known as Turner syndrome or Xp deletions in females, as well many other chromosome microdeletions).

SUMMARY

●Overview – The skeletal dysplasias are an extremely heterogeneous group of over 400 conditions that affect bone development. Most are the result of genetic defects. They can present any time from the prenatal period to adult life. The estimated incidence of skeletal dysplasias is approximately 15.7 in 100,000 births. (See 'Introduction' above.)

●Pre- and postnatal onset – There are essentially two distinctive forms of skeletal dysplasia: those with prenatal onset (including lethal forms and many more nonlethal forms) and those with postnatal onset. The prenatal cases are often suspected from findings on fetal ultrasound. However, most skeletal dysplasias present during childhood and are suspected because of obvious clinical manifestations including short stature, bone deformities, recurrent fractures, or abnormal radiographic findings. (See 'When to suspect a skeletal dysplasia' above and "Approach to prenatal diagnosis of the lethal (life-limiting) skeletal dysplasias".)

●Initial evaluation – Patients with a suspected bone dysplasia require a thorough clinical history, family history, a clinical exam including performance of measurements, and radiographic studies. (See 'Initial evaluation' above.)

•Medical history – The medical history is key to understanding onset and progression. One important question is whether the growth restriction, when present, is the result of a pre- or postnatal growth deficiency. (See 'Medical history' above.)

•Family history – A careful family history may help identify other similarly affected family members and may suggest specific diagnoses. Family history may also help to distinguish those individuals with familial short stature or constitutional delay of growth and puberty. (See 'Family history' above.)

•Physical examination – Height, arm span, and measurements of upper and lower body segments may give clues that help determine the type of skeletal dysplasia. The physical exam is also an important tool to determine extremity bowing, scoliosis, kyphosis, chest size abnormalities, rib flaring, widening of the metaphysis (wrists and knees), and joint laxity. (See 'Physical examination' above.)

•Imaging – Radiologic evaluation typically includes skeletal surveys and bone-age estimation. Computed tomography (CT) scans, magnetic resonance imaging (MRI), and ultrasonography are usually reserved for evaluation of specific suspected disorders. (See 'Imaging' above.)

●When to refer – Indications for referral to a genetic/metabolic disease specialist include poor linear growth since birth, disproportionate short stature, severe brachydactyly, decreased height velocity in childhood, obvious bone deformities with or without short stature, radiographic findings concerning for a bone disorder, and family history of a bone dysplasia in a first-degree relative in association with clinical or radiologic concerns, dysmorphic features associated with skeletal dysplasia, and neurologic abnormalities. (See 'Referral' above.)

●Determining specific type of skeletal dysplasia – There are a number of approaches to determine the specific type of skeletal dysplasia once one is suspected, including clinical exam, radiologic evaluation, biochemical testing in some instances, and molecular testing. (See 'Determining the specific skeletal dysplasia' above.)

•The clinical exam is useful to establish general parameters, such as head circumference, length/height, proportions, arm span, trunk length, presence of scoliosis or back/chest deformities, and brachydactyly. In addition, other malformations such as clefting, facial abnormalities, and polydactyly may suggest specific diagnoses.

•Determining which areas of the bone are affected (eg, spine, long bones [diaphysis, epiphysis, metaphysis]) using a radiologic approach can lead to a general grouping of disorders.

•Biochemical evaluations for urine glycosaminoglycans (mucopolysaccharides), oligosaccharides, and plasma I-cell screening are recommended for any patients with skeletal dysplasia associated with dysmorphic features.

•Once the suspicion for a skeletal dysplasia is established, the clinician may opt for molecular testing including specific gene testing, the use of gene panels, and, in some instances, exome sequencing.

●Differential diagnosis – The differential diagnosis of skeletal dysplasias is broad and is determined in large part by the type of skeletal dysplasia suspected. It is important that other organic causes (endocrine, gastrointestinal, kidney, cardiac) are ruled out. The evaluation and causes of short femur in fetuses and short stature in children are discussed in greater detail separately. (See 'Differential diagnosis' above and "Approach to prenatal diagnosis of the lethal (life-limiting) skeletal dysplasias" and "Diagnostic approach to children and adolescents with short stature" and "Causes of short stature".)