Congenital and Developmental Disorders

Classification

Although hereditary disorders of the skeleton are relatively rare, they attract a great deal of interest. Many of these disorders are associated with short stature, or dwarfism. Dwarfism can be either proportionate or disproportionate. Symmetric shortness of the trunk and limbs is common with proportionate dwarfism. Disproportionate dwarfism, in which either the trunk or limbs are more affected than the other, is common with skeletal dysplasias such as Kniest syndrome, spondyloepiphyseal dysplasia, achondroplasia, and so on.

Skeletal dysplasias, or chondrodystrophies, are a heterogeneous group of disorders resulting in short-limb or short-trunk types of disproportionate short stature. In the types of dwarfism that primarily affect the limbs, the shortening may predominate in the proximal segments (rhizomelia), the middle segments (mesomelia), or the distal segments (acromelia). The term dwarf has traditionally been applied to persons of disproportionate short stature, whereas the term midget referred to those of proportionate short stature.

Disproportionate dwarfism is caused by a hereditary intrinsic skeletal dysplasia, whereas proportionate dwarfism results from chromosomal, endocrine, nutritional, or nonosseous abnormalities. Over the past several years, we have gained further understanding regarding the mode of inheritance, the genetic defect, and the fundamental biochemical and/or molecular fault that causes the dysplasia. Many cases of dwarfism are the result of a rare genetic event, the spontaneous mutation. Unaffected parents of a child with a mutation are essentially at no risk of having another affected child, and unaffected siblings are not at risk of having children with the disorder. Affected parents may pass the trait on to their children, depending on the mode of inheritance—autosomal dominant, autosomal recessive, or X-linked.

Genetic counseling must be based on an accurate diagnosis and on familiarity with the natural history, range of manifestations, severity, and associated findings of the specific disorder.

Diagnosis

Prenatal Testing. Prenatal diagnosis of certain skeletal dysplasias without biochemical markers can be established by radiography (less commonly used), ultrasonography (most widely used), fetoscopy, amniography, three-dimensional ultrasonography, fetal magnetic resonance imaging (MRI), and intrauterine computed tomography (CT). Knowledge of the natural history of intrauterine growth in dwarfing conditions is incomplete. Ossification of the fetal skeleton is not well established until 16 weeks, and it is not known when limb-length discrepancy becomes apparent in the fetus. Serial sonograms are necessary to recognize the decreased growth rate of the femur or to monitor the fetal biparietal diameter, polydactyly, clubfoot, and other skeletal abnormalities.

History. A thorough family history is a particularly important factor in reaching the correct diagnosis. Because disorders with clinically indistinguishable features may have different patterns of inheritance, evaluation of other family members can be very helpful. Genetic testing can also be helpful because clinically some disorders can appear similar to one another. Genetic testing can help to define the disorder and also help with expectations for future generations.

Physical Examination. Measurements of head circumference, height, weight, and arm span are taken, and body proportions are evaluated. A careful examination should be done for nonosseous signs such as cleft palate, cataracts, or congenital heart disease that may contribute to the diagnosis. Ophthalmologic examination and evaluation of speech and hearing may also be needed.

Intelligence is normal in nearly all types of dwarfism. Exceptions include, but are not limited to, hypochondroplasia (see Plate 4-5 ), the rare Dyggve-Melchior-Clausen dysplasia (see Plate 4-16 ), pycnodysostosis (see Plate 4-13 ), and Hurler and Hunter syndromes (see Plate 4-18 ). The need for specific intellectual evaluation or treatment is dictated by the diagnosis and the patient's past performance.

Radiographic Findings. Radiographs must be taken of the entire skeleton (skeletal survey) because diagnosis of most bone dysplasias cannot be made on the basis of one or two radiographs of selected body parts. It is particularly important to look for atlantoaxial instability of the cervical spine. Abnormal vertebral movements occur in many bone dysplasias and, unless detected, may lead to acute compressive myelopathy. Because the radiographic characteristics of many dysplasias change with time, review of earlier radiographs is often necessary (e.g., in the epiphyseal dysplasias, the growth plates fuse with age and all evidence of disturbed epiphyseal development is obliterated).

Laboratory Tests. Initial symptoms or the preliminary diagnosis may suggest the need for specific laboratory tests. For example, if Schmid-type metaphyseal chondrodysplasia (see Plate 4-3 ) is suggested, a complete blood analysis is needed to differentiate this disorder from vitamin D–resistant rickets; and if the mucopolysaccharidoses, a group of biomechanical storage disorders, are suggested, testing for specific enzymes is required.

Achondroplasia

Achondroplasia, which occurs in about 1 in 40,000 persons, is the most common and best-known type of disproportionate short-limb dwarfism (see Plates 4-1 to 4-3 ). It is transmitted by a single autosomal dominant gene. Infants with homozygous achondroplasia generally do not survive for more than a few weeks or months. About 80% of cases result from a spontaneous mutation. The mutation occurs in the fibroblast growth factor receptor 3 (FGFR-3), which affects endochondral bone formation specifically in the proliferative zone of the physis. Achondroplasia is a quantitative, not qualitative, cartilage defect. The parents are usually average size, and no other family member is affected. Statistical evidence suggests that elevated paternal age (>37 years) may be linked to this type of mutation.

Clinical Manifestations. The characteristic signs of achondroplasia—disproportionate short stature, a comparatively long trunk, and rhizomelic shortening of the limbs—are evident at birth (see Plates 4-1 and 4-2 ). The head is both relatively and absolutely large with a prominent, or bulging, forehead (frontal bossing); parietal bossing and flattening of the occiput may also be evident. In infancy, the head increases rapidly in size and hydrocephalus can occur. It can be recognized early by using established norms for head size in patients with achondroplasia, and appropriate treatment can be instituted.

Midfacial hypoplasia of variable degree is manifested by a flat or depressed nasal bridge, narrow nasal passages, and malar hypoplasia (see Plate 4-2 ). The nose has a fleshy tip and upturned nostrils. These features result from restricted development of the chondrocranium and the middle third of the face.

Recurrent and chronic middle ear infections (otitis media) are common in infancy and early childhood and, if untreated, may lead to significant hearing loss. Generally, these infections become less frequent by the time the patient is 8 to 10 years of age.

A relative protrusion of the jaw is often mislabeled as prognathism. Dental development is normal, but underdevelopment of the maxilla may cause dental crowding and malocclusion. About 70% of patients have tongue thrust or other speech defects that seem to be related to the dysplastic bone structure. These problems usually subside spontaneously by school age.

The root portions of the limbs are shorter than the middle or distal segments. Soft tissues may appear excessive with redundant, partially encircling folds and grooves on the limbs. Because the long bones are shortened, the muscle mass looks bunched up, creating the appearance of great strength.

Initially, the legs appear straight but with ambulation may develop a varus position, resulting in bowleg (genu varum) with or without back knee (genu recurvatum).

The hands and feet may appear large in relation to the limbs, but the digits are short, broad, and stubby (brachydactyly). The so-called trident hand (see Plate 4-2 ) is common but becomes less apparent in late childhood and adulthood. The fingertips may reach only to the level of the trochanters or even the iliac crests. Elbow extension is restricted (30 to 45 degrees), but this has little functional significance. In some instances, this may be due to radial head subluxation.

Although the trunk is relatively long, deformities contribute to the overall height reduction. The chest tends to be flat and broad and the abdomen and buttocks protuberant. Excessive lumbar lordosis and a tilted pelvis cause a waddling gait, and fixed flexion contractures of the hip appear early.

In a sitting position, infants commonly exhibit thoracolumbar kyphosis (see Plate 4-1 ). A hump, or gibbus, seen in some infants, may be associated with anterior wedging of the first or second lumbar vertebra. The kyphosis is related to a variety of factors, including ligamentous laxity, hypotonia, and immature strength and motor skills. Although it requires monitoring, the kyphosis usually disappears when the child begins to walk.

Neurologic complications are common. Respiratory abnormalities suggest stenosis of the foramen magnum and compression of the normal-sized medulla oblongata and/or cervical spinal cord. This quite frequent complication results in hypoventilation or apnea, paralysis of voluntary respiration, and compressive myelopathy at the level of the foramen magnum (see Plate 4-4 ). (Therefore, hyperextension of the neck and sudden, whiplash-like movement should be avoided.) Sudden infant death syndrome has also been reported. Somatosensory evoked potential (SSEP) and polysomnography coupled with CT and MRI can provide valuable information to help avert both short-term and long-term complications.

Stenosis of the lumbar spine, prolapse of intervertebral discs, osteophytes, and deformed vertebral bodies may compress the spinal cord and/or nerve roots, frequently causing neurologic manifestations. Pressure on blood vessels impairs the regional blood supply, producing focal areas of ischemia. The pedicles tend to be short and the interpedicular distance tends to decrease (instead of the normal increase) caudally in the spine.

In the teenage period, slowly progressive symptoms such as paresthesias, weakness, pain, and paraplegia develop and may be aggravated by obesity and prolonged standing or walking. Initially, the patient can quickly relieve these symptoms by flexing the spine and hips forward, squatting, or assuming a non–weight-bearing position. As the condition progresses, pain develops and may be localized to the low back or, more commonly, may radiate into the buttocks, posterior thigh, and calf. Muscle weakness and foot drop may also develop. Although these symptoms are more common in the legs, the arms may also be affected.

Patients with symptomatic spinal stenosis require a physical examination with attention to sensory levels, and a careful neurologic history should also be obtained. Specific tests such as somatosensory evoked responses, CT, MRI, and myelography all have a diagnostic function.

Growth rate is normal in the first year of life and then drops to about the third percentile, where it remains for the first decade; it may increase during puberty. Obesity is a common problem. Adult height ranges from 42 to 56 inches.

Children with achondroplasia should not be evaluated against normal developmental milestones but rather against standards developed for children with the condition. Motor skills are often delayed because of the physical difficulties posed by short limbs and hypotonia (which tends to abate by age 2); cognitive skills are usually attained at the expected ages.

Radiographic Findings. The characteristic features are present at birth and change little throughout life. Although virtually all bones of the body are affected, the abnormal configuration of the skull, lumbar spine, and pelvis are hallmarks of the disease. Typical are a shortened skull base, large cranium with prominent frontal and occipital areas, and superimposition of the spheno-occipital synchondrosis over the mastoid. The angle of the base of the skull is 85 to 120 degrees (110 to 145 degrees is normal), and the foramen magnum is small.

The radial heads may be partially or completely dislocated and dysplastic. The phalanges in the hands are short, broad, and conic. The femoral necks are short and the long bones relatively thick and short. Distinctive rectangular or oval radiolucencies in the proximal humerus and femur that are apparent in infancy disappear by age 2. The inverted- V –shaped (chevron) growth plate of the distal femur is characteristic. The fibulas tend to be longer than the tibias, especially at the knees.

A diagnostic feature is a decrease of the interpedicular distance in a caudal direction, primarily in the lumbar spine (in the normal spine, the interpedicular distance increases in the caudal direction). Spinal stenosis, most evident in the lumbosacral region, is more pronounced in adulthood. Lateral radiographs reveal posterior scalloping of the vertebral bodies. Dorsolumbar kyphosis, commonly seen in infancy, disappears with ambulation and is replaced by an exaggerated lumbar lordosis. As the lordosis increases, the plane of the sacrum becomes more horizontal. The pelvis is short and broad with relatively wide, nonflaring iliac wings, small and deep greater sciatic notches, and horizontal superior margins of the acetabulum (champagne glass shape).

Conradi-Hünermann Type

Chondrodysplasia punctata has been known by a bewildering array of names including chondrodystrophia calcificans congenita, Conradi-Hünermann disease, and dysplasia epiphysealis punctata. Although it is commonly considered a discrete entity characterized by radiographic evidence of punctate epiphyseal and extraepiphyseal calcifications (stippling) in childhood, this form of intrinsic bone dysplasia actually has nonosseous manifestations. To complicate the diagnosis further, epiphyseal stippling is seen in a number of unrelated disorders, including cerebrohepatorenal syndrome, generalized gangliosidosis, cretinism, Smith-Lemli-Opitz syndrome, Down syndrome (trisomy 21), and anencephaly.

In genetic counseling, it is important to distinguish this autosomal dominant type from the clinically similar X-linked dominant type, which is fatal in hemizygous males. Severely affected infants are either stillborn or die soon after birth. Prognosis for survival is relatively good for those less severely affected. The Conradi-Hünermann type is X-linked recessive affecting Xp22 and the arylsulfatase E (ARSE) gene.

Clinical Manifestations. The major signs are usually evident at birth: a head of average circumference with a distinctive flat facies, mildly flattened nasal bridge, relatively short neck, and asymmetric shortening of the limbs. By early childhood, the characteristic facies largely disappears but the limb asymmetry may need surgical correction. Congenital cataracts are seen in about 18% of cases. Scoliosis is common after age 1; joint contractures occur later. The skin is often dry, scaly, and atrophic. The ichthyosiform skin changes and alopecia usually persist into adulthood. Adult height is 51 to 63 inches.

Radiographic Findings. Early signs consist of punctate calcifications in the vertebral column and the epiphyses of the long bones and the carpal, tarsal, and pelvic bones, usually in asymmetric distribution. The metaphyses are intact, but the epiphyses frequently become dysplastic (flattened, small, or irregularly shaped).

Rhizomelic Type

Rhizomelic-type chondrodysplasia punctata has an autosomal recessive inheritance and is more severe than the Conradi-Hünermann or X-linked dominant type. The PEX7 gene is affected, which encodes the protein peroxin 7. Recurrent infections usually cause death in the first year of life. Survivors have a high incidence of profound psychomotor retardation and other neurologic abnormalities, such as spastic quadriparesis.

Clinical Manifestations. The features of rhizomelic-type chondrodysplasia punctata are the same as those of the Conradi-Hünermann type, but the rhizomelic shortening of the limbs is more severe and congenital cataracts are extremely common. Microcephaly, contractures, and postnatal failure to thrive are also typical.

Radiographic Findings. The epiphyseal and extraepiphyseal calcifications are usually severe, with a symmetric distribution sparing the vertebral column. Lateral radiographs reveal vertical coronal clefts of the vertebral bodies. In the humerus and/or femur, severe shortening, splaying, and metaphyseal cupping are characteristic.

X-Linked Dominant Type

Approximately 25% of reported cases of chondrodysplasia punctata are probably transmitted as an X-linked dominant trait. This results in a mutation in the emopamil-binding protein and alters the effects on the cholesterol biosynthesis pathway. Most patients are female, and the disorder is usually fatal in males.

Clinical Manifestations. This disorder shares many features with the Conradi-Hünermann type, with hypoplasia of the distal phalanges a distinctive trait. Pathognomonic cutaneous findings in the first months of life include erythematous skin changes and striated ichthyosiform hyperkeratosis. Patterned ichthyosis, coarse and lusterless hair, and cicatricial alopecia become evident later. A variable severity, marked asymmetry of long bones, and cataracts are thought to be consistent with functional X-chromosome mosaicism in females.

Chondroectodermal Dysplasia (Ellis-Van Creveld Syndrome)

This very rare type of short-limb dwarfism has an autosomal recessive mode of inheritance with a link to chromosome 4p16.1. It is characterized by chondrodysplasia; polydactyly; ectodermal dysplasia of hair, teeth, and nails; and congenital heart defects.

Clinical Manifestations. At birth, the head and face are normal but oral and dental abnormalities are common, including natal teeth, multiple frenula that obliterate the buccolabial sulcus, and partial or pseudocleft in the midline of the upper lip. Precocious exfoliation and missing or peg-shaped teeth are evident later. Mesomelic and acromelic limb shortening is greater in the lower limbs and, with growth, knock-knee becomes serious enough to require surgical treatment. The hands are short and stubby with postaxial polydactyly, which also occurs in the feet in 10% of patients. The fingernails and toenails are hypoplastic or dysplastic. The trunk is not affected. Adult height varies from 42 to 60 inches. Congenital heart disease, typically an atrial septal defect, is seen in more than 50% of patients.

Radiographic Findings. The long bones show a progressive distal shortening with broadened metaphyses. In the hands, the capitate and hamate are fused or deformed. Delayed ossification of the lateral portions of the epiphyses and metaphyses of the proximal tibias results in knock-knee. The pelvis has short iliac crests and, in infancy, spurlike inferior projections from the medial and lateral margins of the acetabula. The configuration of the pelvis becomes normal by late childhood.

Grebe Chondrodysplasia

The rare Grebe chondrodysplasia is transmitted as an autosomal recessive trait. Mild shortness of the hands and feet may be an indicator of the carrier state (heterozygosity). Although stillbirth is frequent and neonatal mortality high, after infancy the prognosis for survival is good.

Clinical Manifestations. Marked shortening of both upper and lower limbs is apparent at birth. The legs are more affected than the arms, and length reduction of the long bones increases progressively from the proximal to the distal segments. The fingers are extremely short and toelike. In the short, valgus feet, the toes may be rudimentary, ball-like structures. Polydactyly occurs in 50% of patients. Adult height is only 39 to 41 inches.

Radiographic Findings. The skull and axial skeleton appear essentially normal. The limbs, however, show severe dysplasia or aplasia of all bony elements.

Acromesomelic Dysplasia

Transmitted as an autosomal recessive trait, acromesomelic dysplasia results in severely restricted growth.

Clinical Manifestations. This short-limb form of dwarfism is usually apparent in the first few weeks or months of life. Head size is normal, but the frontal bones may be prominent and the midface mildly hypoplastic and flattened. Limb shortening is greatest in the middle or distal segments. Range of motion of the elbow joints is limited by partial dislocation of the radial heads. The forearms are often bowed. Fingers, toes, and nails are very short. The thorax is small with mild anterior flaring of the lower ribs. Exaggerated lumbar lordosis makes the buttocks prominent; lower thoracic kyphosis is also common. Adult height ranges from 38 to 48 inches.

Radiographic Findings. Radiographs reveal a progressive shortening of the long bones, bowing of the radii, and often subluxation of the radial head. The epiphyses are relatively normal in infancy and become cone shaped later. The hands are unusually squat, and the phalanges appear square or sugarloaf shaped. The height of the vertebral bodies is minimally reduced, primarily in the posterior portions.

Spondyloepiphyseal Dysplasia Tarda

This group of intrinsic bone dysplasias is characterized by progressive abnormalities of spinal and epiphyseal development. The disorders must be differentiated from spondylometaphyseal and spondyloepimetaphyseal dysplasias, which primarily involve the metaphyses instead of, or in addition to, the epiphyses.

Although most cases of spondyloepiphyseal dysplasia tarda have an X-linked recessive mode of inheritance, both autosomal dominant and autosomal recessive forms are also known. This has been mapped to the SEDL gene in the Xp22 chromosome affecting the protein sedlin, which plays an important role in endoplasmic reticulum/Golgi vesicular transport.

Clinical Manifestations. Growth failure does not become evident until 5 to 10 years of age. The height reduction, which is primarily due to trunk shortening, becomes quite obvious by adolescence. At this time, patients complain of pain and stiffness in the back or hips. Secondary osteoarthritis of the hip is common and may become disabling. The chest is broad or barrel shaped. Adult height ranges from 52 to 61 inches.

Radiographic Findings. The distinctive configuration of the vertebral bodies is most evident in the adult lumbar spine. Initially, the vertebral bodies are mildly flattened (platyspondyly) with a hump-shaped accumulation of bone in the posterior and central portions of the cartilage ring apophysis; the disc space appears narrowed. The thoracic cage is broad, while the pelvis is small and deep. The epiphyses of the long bones show variable dysplastic changes, and osteoarthritis of the hips is evident.

Spondyloepiphyseal Dysplasia Congenita

Spondyloepiphyseal dysplasia congenita is the more severe form affecting the spine and epiphyses of long bones. Most cases of spondyloepiphyseal dysplasia congenita are a result of spontaneous mutation. This type of short-trunk dwarfism is typically transmitted as an autosomal dominant trait, although cases of autosomal recessive inheritance are known. Mutations to COL2A1 locus on chromosome 12 lead to abnormal type II collagen.

Clinical Manifestations. In the newborn, a broad or barrel chest, deep Harrison's grooves, and pigeon chest suggest the diagnosis. Flat, dishlike facies, cleft palate, and wide-set eyes are other early signs. In older children, the short neck makes the normal-sized head appear to rest directly on the shoulders. Myopia and retinal detachment or degeneration is occasionally seen.

The limbs show mild rhizomelic shortening but are long in comparison with the trunk; the hands and feet are essentially normal. Ligamentous laxity is excessive. Marked lumbar lordosis and moderate kyphoscoliosis occur in late childhood or early adulthood. Adults reach a height of only 33 to 52 inches.

Motor development is often delayed. In 50% of patients, hypotonia, ligamentous laxity, and odontoid hypoplasia result in atlantoaxial instability leading to spinal cord compression, which first manifests as overwhelming fatigue and decreased endurance.

Radiographic Findings. Retarded ossification of the pubic bones, femoral heads, and epiphyses of the knees, calcanei, and tali is the major feature in young children. Early in life, the vertebral bodies are ovoid or pear shaped but become flattened and irregular with time, resulting in kyphoscoliosis. Careful radiographic evaluation of the cervical spine is important because of the hazards associated with odontoid hypoplasia. Coxa vara is common, and rhizomelic shortening of the long bones with minimal dysplastic changes in the hands and feet may also be seen.

Spondylocostal Dysostosis

Syndromes that comprise vertebral and thoracic abnormalities have been called by many designations, and more data are needed for a complete understanding of this group of disorders. However, evidence suggests genetic heterogeneity in spondylocostal dysostosis with at least three phenotypes: (I) autosomal recessive with high mortality in the first 2 years; (II) autosomal recessive with good prognosis for survival; and (III) autosomal dominant with mild-to-moderate clinical manifestations.

Clinical Manifestations. Posterior shortening of the thorax and thoracolumbar lordosis are the major causes of short stature. The neck is short and often nearly immobile, and the head appears to rest on the shoulders. The limbs are long in relation to the trunk. The barrel chest bulges anteriorly, the lower anterior ribs may infringe on the iliac crests, and the abdomen protrudes. Recurrent respiratory infections are common and may be related to the chest deformity, pulmonary hypoplasia, or cor pulmonale. Laryngotracheomalacia is an uncommon feature.

Radiographic Findings. Severe vertebral abnormalities—hemivertebrae, fused (block) vertebrae, absent and butterfly vertebrae—characterize this disorder. The ribs are reduced in number, and the posterior costovertebral articulations may be bizarrely approximated, producing a fanlike radiation of ribs. The posterior shortening of the spine causes anterior flaring of the chest and deformity of the rib cage. No significant abnormalities are seen in the appendicular skeleton or skull.

Dyggve-Melchior-Clausen Dysplasia

Dyggve-Melchior-Clausen dysplasia is a rare and unusual disorder with an autosomal recessive inheritance.

Clinical Manifestations. Recognizable as early as 6 to 12 months of age, this disorder results in short-trunk dwarfism with a short neck, exaggerated lumbar lordosis, scoliosis, and prominent interphalangeal joints of the fingers with mild contractures and claw hand. Mental retardation and speech delay are common but not invariable. Adult height is about 52 inches.

Radiographic Findings. Radiographs reveal a generalized platyspondyly that usually persists into adulthood. In childhood, lateral views show anterior pointing of the vertebral bodies, with broad notches in the superior and inferior epiphyseal plates. The dens of the axis (odontoid process) may be hypoplastic. Irregular ossification of the iliac crests creates a characteristic lacelike appearance on radiographs. The ilia are short and broad.

In young children, the growth plates of the proximal femurs are horizontal, with prominent spurlike projections on the medial side of the femoral necks. Ossification of the femoral epiphyses is delayed, and the long bones are short with irregular epiphyseal and metaphyseal ossification.

Differential Diagnosis. Patients with this condition bear some resemblance to persons with Morquio syndrome (see Plate 4-18 ). However, there is no corneal clouding and the urine contains no keratan sulfate. In fact, studies of lysosomal enzymes and histologic examination refute the hypothesis that Dyggve-Melchior-Clausen dysplasia is due to an abnormality of mucopolysaccharide metabolism.