Version July 2025
INTRODUCTION —
The skeletal dysplasias are an extremely heterogeneous group of conditions that affect bone development. They encompass over 771 disorders [1]. Most are the result of genetic defects. 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 including 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 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 mechanism for bone formation in mammals.
CLASSIFICATION OF SKELETAL DYSPLASIAS —
Skeletal dysplasias encompass over 771 disorders associated with abnormalities in 552 genes [1]. 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 classification system for genetic skeletal disorders designed to facilitate diagnosis categorizes these disorders into 42 groups [1].
These groups include disorders that may lead to short stature due to abnormalities of bone development as in achondroplasia, decreased bone density as in osteogenesis imperfecta, increased bone density as in osteopetrosis, or a number of lysosomal storage diseases that cause significant skeletal involvement as in 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 nonlethal forms) and those with postnatal onset, which can present throughout life. Lethal forms with an early onset often result in perinatal/neonatal death due to lung hypoplasia and respiratory complications.
Prenatal onset — Skeletal dysplasias with prenatal onset are often suspected from findings on fetal ultrasound [4], including:
●Growth deficiency and IUGR
●Bowing or shortening of the long bones
●Vertebral defects
●Rib abnormalities (eg, shortening)
●Fractures and decreased bone density
●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. Thus, some skeletal findings may not be obvious until the end of the second trimester or the beginning of the third trimester, and an early routine ultrasound may miss many bone dysplasias. Prenatal diagnosis of skeletal dysplasias, including ultrasound evaluation, is discussed in greater detail separately. (See "Approach to prenatal diagnosis of life-limiting skeletal dysplasias".)
Postnatal onset — 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 findings listed above or discovered incidentally (ie, presence of enchondromas, vertebral segmentation defects, scoliosis, rickets-like changes in the metaphyses)
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 made when linear growth is beyond two standard deviations below the mean, which may be obvious after birth or later in childhood. 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 OF SUSPECTED DISEASE —
Patients with suspected skeletal dysplasia require a thorough medical history, family history, physical examination (including extremity and other measurements), and radiographic studies.
Medical history — The medical history is key to understanding onset and progression. It is important to determine whether the presenting growth restriction 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 child 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 discrepancies in size of body parts (eg, macrocephaly), the 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 relatively larger head. In some of these patients, joint laxity can further interfere with acquiring other milestones such as the initiation of ambulation.
●Delays in sitting and walking in patients with cleidocranial dysplasia due to hypoplasia of the pubic bones.
Family history — A careful family history may help to identify other similarly affected family members and may suggest specific diagnoses. Important information to obtain includes whether there is a history of:
●Short stature in the immediate relatives, particularly parents (although actual measurement of parental height is more accurate than historical report)
●Fractures
●Limb bowing
●Retinal detachment
●Polydactyly
●Kidney disease
●Consanguinity
This may identify a number of genetic disorders. For example, a history of leg bowing may be present in first-degree relatives of patients with suspected X-linked hypophosphatemic rickets, retinal detachment may be found in relatives of patients with a type II collagenopathy such as Stickler syndrome, or kidney disease and polydactyly may be present 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 — Measurements of height and specific body segments may provide clues to help determine the type of skeletal dysplasia. In addition to height, measurement of arm span and the length of the lower and upper segments of the body are important to determine body disproportion. It is also important to assess for bone and joint deformities.
Specifically, the physical examination should include evaluation of the following:
●Height (or length for infants and children who are unable to stand).
●Arm span, and both upper and lower body segment lengths to calculate the upper to lower segment ratio. Measurement of the sitting height can be used to calculate the upper segment length, which can be subtracted from the standing height to provide the lower segment length (as discussed below).
●Limb length, to assess for limb shortening, including finger length (to assess for brachydactyly).
●Head size to assess for macrocephaly, which is associated with a number of bone dysplasias.
●Neck shortening.
●Fingernails, which may be absent or hypoplastic in some skeletal disorders such as nail-patella syndrome, or Ellis-Van Creveld syndrome.
●Joint movements or limitations, including radioulnar synostosis, abnormalities that impede pronation-supination or extension, or joint laxity.
●Extremity deformities (eg, extremity bowing, widening of metaphyses of the wrist and knees).
●Chest deformities (eg, chest size abnormalities, rib flaring).
●Spinal deformities (eg, scoliosis, kyphosis).
●Dysmorphic features of the face (eg, midface hypoplasia).
●Cleft palate, which is often associated with type II collagenopathies.
●Other organ involvement (hepatomegaly, bone deformities) associated with mucopolysaccharidoses and oligosaccharidosis.
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 patient flat against the wall and place marks on the wall at equal height on either side. Care should be taken to place both arms at the same height and to avoid errors. The distance between the marks is measured after the patient has moved away. Performing the measurement directly on the patient may result in incorrect measurements. For example, if the measuring tape goes over the shoulders, the measurement will be longer than the actual distance.
In children and adults, the arm span should be always equal to or greater than the height in children and can exceed the height by up to 10 cm in adults. For example, an individual whose height is 155 cm could have an arm span of up to 165 cm. Children tend to have an arm span that is equal to their height, whereas the arm span in adults is usually a few centimeters longer than their height. A shortened arm span may indicate shortening of the upper extremity bones (rhizomelic, mesomelic, or acromelic bones), as is the case in achondroplasia or other skeletal dysplasias which affect the length of the long bones.
Body segment lengths are usually obtained by measuring the sitting height in children and adults or by performing crown-to-rump measurements in infants and young children who are not yet ambulating. This measurement provides the upper segment length, which can be subtracted from the standing height to 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 pubic symphysis while they are standing and measure the length from this point to the ground, although this can be subject to errors. Subtracting the lower segment length from the standing 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 measurements [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 the mid-upper segment of the leg in older children.
Imaging — Radiologic evaluations can provide 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 the 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. Radiologic evaluation for the diagnosis of specific skeletal dysplasias is discussed separately. (See 'Radiologic evaluation' below.)
It is important to obtain a bone age for most patients presenting with short stature. Typically, this involves obtaining wrist and hand radiographs to assess for bone age using the standards provided by Greulich and Pyle [7], although other methods may also be used. Bone age is usually normal in patients with skeletal dysplasias. However, bone age can appear to be delayed due to an epiphyseal dysplasia, and some rare dysplasias caused by abnormalities of aggrecan can present with advanced bone age. Thus, it is always prudent to assess other bone growth centers for anomalies and irregularities. (See "Diagnostic approach to children and adolescents with short stature", section on 'Bone age determination'.)
CT scans and MRI studies are usually reserved to assess findings associated with a skeletal disorder and to answer specific questions. For example, an MRI of the brain and spine or CT scan of the skull base and foramen magnum is indicated in children with achondroplasia when their head circumference is growing beyond the expected curve or when they manifest neurologic symptoms suggestive of spinal compression. Other cases in which imaging studies are indicated include bone dysplasias associated with spinal 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 the assessment of suspected skeletal dysplasias in pregnancy. A high quality ultrasound can assess the fetus's bone density; determine overall growth, bone length, rib and chest size; and detect many other skeletal abnormalities. The use of ultrasound in the prenatal diagnosis of skeletal dysplasias is discussed in more detail separately. (See "Approach to prenatal diagnosis of life-limiting skeletal dysplasias", section on 'Diagnostic evaluation of suspected skeletal dysplasia'.)
REFERRAL —
The pediatrician and the pediatric endocrinologist are the most frequent sources 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 (ie, 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 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
DIAGNOSIS OF A SPECIFIC SKELETAL DYSPLASIA —
Once a skeletal dysplasia is suspected, the specific type of dysplasia can be determined by performing a clinical assessment, radiologic evaluation, biochemical testing (in some instances), and molecular testing.
Clinical assessment — As discussed above, the clinical assessment is useful to establish general parameters such as head circumference, length/height, body segment proportions, arm span, trunk length, presence of scoliosis or other spinal/chest deformities, and brachydactyly (see 'Physical examination' above). In addition, other malformations such as clefting, facial abnormalities, and polydactyly may suggest specific diagnoses. For example, a Madelung deformity (picture 1 and image 1) may point to conditions such as Turner syndrome, short stature homeobox (SHOX) gene deletions/pathogenic variants, or Leri-Weil dysostosis. (See "Overview: Causes of chronic wrist pain in children and adolescents", section on 'Madelung deformity' and "Turner syndrome: Clinical manifestations and diagnosis" and "Causes of short stature", section on 'SHOX gene variants' and "Skeletal dysplasias: Specific disorders", section on 'Leri-Weill dyschondrosteosis'.)
Radiologic evaluation — One of the most common ways to determine the specific type of skeletal dysplasia is the radiologic approach. As discussed above, different imaging modalities (eg, bone age, skeletal radiographs, ultrasound) may be useful depending on the presenting features and timing of evaluation (see 'Imaging' above). 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 bone 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].
Often, the disorders may involve more than one region. For example, when both the epiphyses and metaphyses are involved, 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 (ie, SED congenita, Kniest dysplasia) are used.
Examples of radiologic findings and associated conditions include:
●Delayed, small, or irregular epiphyses may suggest a form of epiphyseal dysplasia (eg, multiple epiphyseal dysplasias, pseudoachondroplasia, or spondyloepiphyseal dysplasia [SED]).
●Widening or irregular metaphyses (as seen in rickets) may suggest a metaphyseal dysplasia (eg, cartilage-hair-hypoplasia, Schwachman-Diamond Syndrome, Jensen syndrome).
●Flattening, shortening, or deformation of the vertebral bodies may be the manifestation of a spondylar dysplasia (eg, osteogenesis imperfecta due to compression fractures, X-linked SED tarda, pseudoachondroplasia, spondylometaphyseal dysplasias).
●Deformation or widening across the length of a long bone may represent a diaphyseal dysplasia (ie, Camurati-Engelmann, craniodiaphyseal dysplasia, craniometaphyseal dysplasia).
Biochemical testing — Biochemical testing may be useful in the diagnostic evaluation of some skeletal dysplasias. 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 testing for urine glycosaminoglycans (mucopolysaccharides), oligosaccharides, and plasma I-cell screen (elevated plasma lysosomal enzymes such as hexosaminidase) are warranted when these conditions are suspected. The suspicion for a mucopolysaccharidosis may be raised by the presence of radiologic (dysostosis multiplex) or pertinent clinical findings (eg, corneal clouding, short trunk, pectus deformity, joint restriction or laxity). Oftentimes, the diagnosis may be suggested by the radiologist.
In addition, some rare skeletal dysplasias can be secondary to biochemical disorders and are associated with stippling located in the epiphyses and spine (as seen on radiographs). One such example is rhizomelic chondrodysplasia punctate. This rare disorder is associated with severe micromelia and short stature, and are also accompanied by elevated plasma levels of very long chain fatty acids (VLCFA) and phytanic acid [8]. (See "Skeletal dysplasias: Specific disorders", section on 'Chondrodysplasia punctata'.)
Molecular (genetic) testing — 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 in consultation with 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. However, 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.
Follow-up after diagnosis — Once the diagnosis is established, proper follow-up for the condition should be arranged to establish appropriate anticipatory guidance. Management of complications and comorbidities is important in many of these disorders. For example, children with type II collagen disorder (ie, Stickler syndrome) are at high risk for retinal detachment.
The evaluation and management of specific skeletal dysplasias is discussed in more detail separately. (See "Skeletal dysplasias: Specific disorders".)
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 life-limiting skeletal dysplasias" and "Diagnostic approach to children and adolescents with short stature" and "Causes of short stature".)
It is important for the primary care clinician to evaluate for other organic causes of disease (eg, endocrine, gastrointestinal, kidney, cardiac) before these children are referred to a bone specialist. For example, it is key 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 measurement of serum transglutaminase levels. In the presence of chronic pulmonary infections, conditions such as cystic fibrosis must be considered.
In addition, there are a number of genetic conditions that are associated with short stature, although they are not necessarily true skeletal dysplasias. Consultation with a geneticist can help with evaluation if any of these conditions are suspected. A chromosome study and/or a chromosome microarray study can determine the presence of abnormalities that can explain short stature such as monosomy X, also known as Turner syndrome or Xp deletions in females, and many other chromosome microdeletions.
SUMMARY AND RECOMMENDATIONS
●Overview – The skeletal dysplasias are an extremely heterogeneous group of over 771 conditions that affect bone development. Most are the result of genetic defects. They can present at 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 life-limiting skeletal dysplasias".)
●Initial evaluation – Patients with suspected skeletal dysplasia require a thorough history, physical examination, and radiographic studies (see 'Initial evaluation of suspected disease' 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 (table 1). (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. It is also important to evaluate for extremity bowing, scoliosis, kyphosis, chest size abnormalities, rib flaring, widening of the metaphysis (wrists and knees), and joint laxity. (See 'Physical examination' above.)
•Imaging – Initial radiologic evaluation typically includes skeletal surveys and bone-age estimation. CT scans, MRI, and ultrasonography are usually reserved for evaluation of specific suspected disorders or for prenatal evaluation. (See 'Imaging' above.)
●When to refer – Indications for referral to a genetic/metabolic disease specialist include poor linear growth since birth, disproportionate short stature, decreased height velocity in childhood, severe brachydactyly, obvious bone deformities with or without short stature, dysmorphic features or 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. (See 'Referral' above.)
●Diagnosis of a specific skeletal dysplasia – The following assessments can aid in the diagnosis of a specific skeletal dysplasia once it is suspected (see 'Diagnosis of a specific skeletal dysplasia' above):
•Clinical evaluation is useful to assess for physical findings associated with specific diagnoses (eg, head circumference, length/height, arm span, scoliosis, cleft palate, brachydactyly).
•Radiologic evaluation can determine the specific area of the affected bone (eg, spine; long bone diaphysis, metaphysis, or epiphysis).
•Biochemical testing for urine glycosaminoglycans (mucopolysaccharides), oligosaccharides, and plasma I-cell screen are warranted to evaluate for mucopolysaccharidoses or oligosaccharidosis in patients who present with dysmorphic features.
•Molecular testing may assist with the diagnosis of specific genetic disorders in consultation with a genetics or bone dysplasia specialist, if available.
●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 for the clinician to evaluate for other causes (eg, endocrine, gastrointestinal, kidney, cardiac) of disease. 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 life-limiting skeletal dysplasias" and "Diagnostic approach to children and adolescents with short stature" and "Causes of short stature".)
