General Considerations

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Chapter 685 General Considerations

The genetically and clinically heterogeneous group of disorders of skeletal development and growth are referred to as skeletal dysplasias, bone dysplasias, and osteochondrodysplasias. Their prevalence is estimated to be about 1/4,000 births. They can be divided into the osteodysplasias typified by osteogenesis imperfecta (Chapter 692) and the chondrodysplasias. The latter result from mutations of genes that are essential for skeletal development and growth. The clinical picture is dominated by skeletal abnormalities. The manifestations may be restricted to the skeleton, but in most cases nonskeletal tissues are also involved. The disorders may be lethal in utero or mild with features that go undetected.

The chondrodysplasias are distinguished from other forms of short stature by a disproportionality of skeletal manifestations. The importance of cartilage in bone formation is noted in Figure 685-1. There are two basic categories: predominantly with short limbs and predominantly with short trunks. Efforts to define the extent of clinical heterogeneity resulted in the delineation of >100 distinct entities. Many of these disorders result from mutations of a relatively small group of genes, the “chondrodysplasia genes.” An International Working Group on Bone Dysplasias has named and classified these disorders into groups based on genetic cause if known or on similarities of clinical and radiographic manifestations, which often imply a common pathogenesis and a common genetic basis, if the cause is unknown (Table 685-1). The better-defined chondrodysplasia groups, such as the achondroplasia and type II collagenopathy groups, contain graded series of disorders that range from very severe to very mild. This may be true for other groups as more mutations are found and the full spectrum of clinical phenotypes associated with mutations of a given gene is defined. These disorders are clinical phenotypes distributed along spectra of phenotypic abnormality associated with mutations of particular genes. For mutations of some genes such as COL2A1, the distribution is fairly continuous, with clinical phenotypes merging into one another across a broad range. There is much less clinical overlap for mutations of some other genes, such as FGFR3, in which the distribution is discontinuous. Because most clinicians and most reference materials refer to the disorders as distinct entities, this vernacular continues to be used.

Figure 685-1 The importance of cartilage in bone formation.

(From Horton WA: Skeletal development: Insights from targeting the mouse genome, Lancet 362:560, 2005.)

Table 685-1 GENETICS OF SKELETAL DYSPLASIAS

Most chondrodysplasias require the analysis of information from the history, physical examination, skeletal radiographs, family history, and laboratory testing to make a diagnosis. The process involves recognizing complex patterns that are characteristic of the different disorders (Tables 685-2, 685-3, 685-4, and 685-5). Comprehensive descriptions of disorders and references are at the Online Mendelian Inheritance in Man (OMIM) Internet site (see the references).

Table 685-2 MAJOR PROBLEMS ASSOCIATED WITH SKELETAL DYSPLASIAS

PROBLEM	EXAMPLE
Lethality*	Thanatophoric dysplasia
Associated anomalies^†	Ellis-van Creveld syndrome
Short stature	Common to almost all
Cervical spine dislocations	Larsen syndrome
Severe limb bowing	Metaphyseal dysplasia, Schmid type
Spine curvatures	Metatropic dysplasia
Clubfeet	Diastrophic dysplasia
Fractures	Osteogenesis imperfecta
Pneumonias, aspirations	Campomelic dysplasia
Spinal cord compression	Achondroplasia
Joint problems (hips, knees)	Most skeletal dysplasias
Hearing loss	Common (greatest with cleft palate)
Myopia/cataracts	Stickler syndrome
Immunodeficiency^‡	Cartilage-hair hypoplasia, Schimke immuno-osseous dysplasia
Poor body image	Variable, but common to all
Sex reversal	Campomelic dysplasia

* Mostly due to severely reduced size of thorax.

^† See Table 685-3.

^‡ At least four additional disorders, all involving the metaphyses, can have immunodeficiency.

Table 685-3 ASSOCIATED ANOMALIES IN SKELETAL DYSPLASIAS

ANOMALY	EXAMPLE
Heart defects	Ellis-van Creveld syndrome, Jeune syndrome
Polydactyly	Short rib polydactyly, Majewski type
Cleft palate	Diastrophic dysplasia
Ear cysts	Diastrophic dysplasia
Spinal cord compression	Achondroplasia
Encephalocele	Dyssegmental dysplasia
Hemivertebrae	Dyssegmental dysplasia
Micrognathia	Campomelic dysplasia
Nail dysplasia	Ellis-van Creveld syndrome
Conical teeth, oligodontia	Ellis-van Creveld syndrome
Multiple oral frenulae	Ellis-van Creveld syndrome
Dentinogenesis imperfecta	Osteogenesis imperfecta
Pretibial skin dimples	Campomelic dysplasia
Cataracts, retinal detachment	Stickler syndrome
Intestinal atresia	Saldino-Noonan
Renal cysts	Saldino-Noonan
Campodactyly	Diastrophic dysplasia
Craniosynostosis	Thanatophoric dysplasia
Ichthyosis	Chondrodystrophica punctata
Hitchhiker thumb	Diastrophic dysplasia
Sparse scalp hair	Cartilage-hair hypoplasia
Hypertelorism	Robinow syndrome
Hypoplastic nasal bridge	Acrodysostosis
Clavicular agenesis	Cleidocranial dysplasia
Genital hypoplasia	Robinow syndrome
Tail	Metatropic dysplasia
Omphalocele	Beemer-Langer syndrome
Blue sclera	Osteogenesis imperfecta

Clinical Manifestations

There may also be disproportionate shortening of different segments of the limbs; the particular pattern can provide clues for specific diagnoses. Shortening is greatest in the proximal segments (upper arms and legs) in achondroplasia; this is termed rhizomelic shortening. Disproportionate shortening of the middle segments (forearms and lower legs) is called mesomelic shortening; acromelic shortening involves the hands and feet.

With some exceptions, there is a strong correlation between the age at onset and the clinical severity. Many of the lethal neonatal chondrodysplasias are evident during routine fetal ultrasound examinations performed at the end of the 1st trimester of gestation (see Table 685-4). Gestational standards exist for long-bone lengths; discrepancies are often detected between biparietal diameter of the skull and long-bone lengths. Many disorders become apparent around the time of birth; others manifest during the 1st yr of life. A number of disorders manifest in early childhood and a few in late childhood or later.

Non–Growth Related

Most patients also have problems unrelated to growth. Skeletal deformities, such as abnormal joint mobility, protuberances at and around joints, and angular deformities, are common and usually symmetric. Skeletal abnormalities can adversely affect nonskeletal tissues. Impaired growth at the base of the skull and of vertebral pedicles reduces the size of the spinal canal in achondroplasia and can contribute to spinal cord compression. Short ribs reduce thoracic volume, which can compromise breathing in patients with short trunk chondrodysplasias. Cleft palate is common to many disorders, presumably reflecting defective palatal growth.

Manifestations may be unrelated to the skeleton; they reflect expression of mutant genes in nonskeletal tissues. Examples include retinal detachment in spondyloepiphyseal dysplasia congenita, sex reversal in campomelic dysplasia, congenital heart malformations in Ellis-van Creveld syndrome, immunodeficiency in cartilage-hair hypoplasia, and renal dysfunction in asphyxiating thoracic dystrophy. These nonskeletal problems provide valuable clues to specific diagnoses and must be managed clinically (see Table 685-3).

Family and Reproductive History

A family history might identify relatives with the condition; a mendelian inheritance pattern may be elicited. Because the presentation can vary in some disorders, features that might be related to the disorder should be identified. Special attention should be given to mild degrees of short stature, disproportion, deformities, and other manifestations such as precocious osteoarthritis because they may be overlooked. Physical examination of relatives may be useful, as may the review of their photographs, radiographs, and medical records.

A reproductive history might reveal previous stillbirths, fetal losses, and other abnormal pregnancy outcomes resulting from a skeletal dysplasia. Pregnancy complications, such as polyhydramnios or reduced fetal movement, are common in bone dysplasias, especially neonatal lethal variants.

Even though most of the skeletal dysplasias are genetic, it is common to have no family history of the disorder. New mutations are common for autosomal dominant disorders, especially lethal disorders in the perinatal period (thanatophoric dysplasia, osteogenesis imperfecta). Most cases of achondroplasia result from new mutations. Germ cell mosaicism, in which a parent has clones of mutant germ cells, has been observed in osteogenesis imperfecta and in other dominant disorders. A negative family history is usually seen in recessive disorders. Prenatal diagnosis is available for disorders that have a genetic locus identified. Appropriateness of the testing depends on many factors, and genetic counseling is warranted for these families.

Radiographic Features

Radiographic evaluation for a chondrodysplasia should include plain films of the entire skeleton. Efforts should be made to identify which bones and which parts of bones (epiphyses, metaphyses, diaphyses) are most affected. If possible, films taken at different ages should be examined because the radiographic changes evolve with time. Films taken before puberty are generally more informative because pubertal closure of the epiphyses obliterates many of the signs needed for a radiographic diagnosis. Prenatal diagnosis may also be possible with fetal ultrasound.

Diagnosis

If an infant or child is short with disproportionate features, a diagnosis is established by matching the observed clinical picture (defined primarily from clinical, family, and gestational histories; physical examination; and radiographic evaluation) with clinical phenotypes of well-documented disorders. Pediatricians should be able to gather most of this information and, in consultation with a radiologist, diagnose the common chondrodysplasias. A number of reference texts and online databases provide information about the disorders and comprehensive lists of current references. For less common disorders and for infants and children whose phenotypes do not closely match well-established clinical phenotypes, consultation with experts in the bone dysplasia field is warranted.

Laboratory testing has not been useful in diagnosing chondrodysplasias except in osteogenesis imperfecta, in which analysis of collagen synthesis by skin fibroblasts or genes whose products are involved in collagen biosynthesis, has helped establish a diagnosis. Osteogenesis imperfecta is not a chondrodysplasia, but it is often in the differential diagnosis, especially for newborns with severe skeletal deformities (Chapter 692). Reduced plasma levels of COMP (cartilage oligomeric matrix protein) have been detected in patients with pseudoachondroplasia and multiple epiphyseal dysplasias in which COMP mutations have been found.

Molecular genetic testing for chondrodysplasias is very useful, especially for disorders in which recurrent mutations occur (typical achondroplasia has the same FGFR3 mutation). Mutation testing for achondroplasia is available, although the diagnosis is usually made clinically. The greatest utility for testing may be for prenatal diagnosis for couples where both parents have typical (heterozygous) achondroplasia. Their children are at a 25% risk of the much more severe homozygous achondroplasia, which can be detected by mutation analysis. Another example is in disorders resulting from mutations of DTDST. These disorders are inherited in an autosomal recessive manner, and a limited number of mutant alleles have been found. If the mutations are identified in the patient, they should be detectable in the parents and potentially used for prenatal diagnosis. Mutational analysis is now commercially available for many of the skeletal dysplasias and is increasingly used to confirm clinical diagnosis and for future pregnancy planning.

Many of the chondrodysplasias have distinct histologic changes of the skeletal growth plate. Sometimes such tissues obtained at biopsy or discarded from a surgical procedure are helpful diagnostically. It is uncommon to make a diagnosis histologically if it was not already suspected on clinical grounds. An exception is for the lethal neonatal chondrodysplasias, in which an aborted fetus is macerated, thus making a clinical and radiographic assessment difficult.

Molecular Genetics

A number of chondrodysplasia genes have been identified (see Table 685-1). They encode several categories of proteins, including cartilage matrix proteins, transmembrane receptors, ion transporters, and transcription factors. The number of identified gene loci is smaller than anticipated from the number of recognized clinical phenotypes. The majority of patients have disorders that map to <10 loci; mutations at 2 loci (COL2A1 and FGFR3) account for more than half of all cases. There may be a limited number of genes whose function is critical to skeletal development, especially linear bone growth; mutations in these genes give rise to a wide range of chondrodysplasia clinical phenotypes. However, new genes harboring mutations that cause chondrodysplasias continue to be identified with advances in detection technology.

Mutations at the COL2A1 and FGFR3 loci illustrate different genetic characteristics. COL2A1 mutations are distributed throughout the gene, with few instances of recurrence in unrelated persons. In contrast, FGFR3 mutations are restricted to a few locations within the gene, and occurrence of new mutations at these sites in unrelated persons is the rule. There is a strong correlation between clinical phenotype and mutation site for FGFR3, but not COL2A1, mutations.