eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Genetics

Skeletal Dysplasia

Author: Harold Chen, MD, MS, FAAP, FACMG, Professor, Departments of Pediatrics, Obstetrics and Gynecology, Pathology, Director of Perinatal Genetics and Genetic Laboratory Services, Louisiana State University Medical Center; Laboratory Director, Hema-Con Cancer Cytogenetics Laboratory, Gainesville, Florida
Contributor Information and Disclosures

Updated: Nov 15, 2007

Introduction

Background

Dwarfism is a commonly used term for disproportionately short stature, although a more medically appropriate term for this disorder is skeletal dysplasia. Short stature is defined as height that is 3 or more standard deviations below the mean height for age. If short stature is proportional, the condition may be due to endocrine or metabolic disorders or chromosomal or nonskeletal dysplasia genetic defects.

In general, patients with disproportionately short stature have skeletal dysplasia (osteochondrodysplasia). Skeletal dysplasias are a heterogeneous group of more than 200 disorders characterized by abnormalities of cartilage and bone growth, resulting in abnormal shape and size of the skeleton and disproportion of the long bones, spine, and head.

Pathophysiology

Skeletal dysplasias differ in natural histories, prognoses, inheritance patterns, and etiopathogenetic mechanisms. During the 1950s and 1970s, many new bone dysplasias were identified based on clinical manifestations, radiographic findings, inheritance patterns, and morphology of the growth plate. In the 1980s, research focused on defining the natural history and variability of the disorders. In the 1990s, the focus shifted toward elucidating the responsible mutations and characterizing the pathogenetic mechanisms by which the mutations disrupt bone growth.

In 1997, the International Working Group on Bone Dysplasias proposed a newly revised "International Nomenclature and Classification of the Osteochondrodysplasias."¹ In the newly revised nomenclature, families of disorders were rearranged based on recent etiopathogenetic information concerning the gene and/or protein defect involved. Disorders for which the basic defect was well documented were regrouped into distinct families in which component disorders result from mutations of the identical gene. Several new groups of disorders were added, and other families were renamed. Despite this update, the basic defect remains unrecognized in many disorders. With increasing molecular discoveries, classification and nomenclature need to be constantly updated.

Frequency

United States

The overall incidence of skeletal dysplasias is approximately 1 case per 4000-5000 births. The true incidence may be twice as high because many skeletal dysplasias do not manifest until short stature, joint symptoms, or other complications arise during childhood. Lethal skeletal dysplasias are estimated to occur in 0.95 per 10,000 deliveries. The 4 most common skeletal dysplasias are thanatophoric dysplasia, achondroplasia, osteogenesis imperfecta, and achondrogenesis. Thanatophoric dysplasia and achondrogenesis account for 62% of all lethal skeletal dysplasias. Achondroplasia is the most common nonlethal skeletal dysplasia.

Mortality/Morbidity

Among infants with skeletal dysplasias detected at birth, approximately 13% are stillborn, and 44% die during the perinatal period. The overall frequency of skeletal dysplasias in infants who die perinatally is 9.1 per 1000.

Race

No racial predilections are described.

Sex

Males are primarily affected in X-linked recessive disorders. X-linked dominant disorders may be lethal in males. Otherwise, males and females are usually equally affected by skeletal dysplasias.

Age

Skeletal dysplasias are usually detected in the newborn period or during infancy. Some disorders may not manifest until later in childhood.

Clinical

History

• Family history
  • A complete and accurate family history is essential for evaluation of the nature and inheritance pattern of skeletal dysplasia.
  • Histories (including spontaneous abortions or stillbirths), medical records, photographs, and radiographs of affected individuals should be carefully studied for clues to the nature of skeletal dysplasia.
  • Parents, siblings, and other relatives should be carefully examined for mild manifestations of the disorder due to variable clinical penetrance and expressivity.
  • Multiple affected siblings, normal-appearing parents, and/or consanguinity favor an autosomal recessive mode of inheritance.
  • An affected parent (or advanced paternal age in a sporadic case) suggests autosomal dominant inheritance.
  • Multiple spontaneous abortions or stillbirths in a family with only female members affected suggest an X-dominant mode of inheritance.
  • Affected male siblings and maternal uncles suggest an X-recessive disorder.
• Pregnancy and birth histories
  • Maternal hydramnios is probably the most significant event associated with fetal skeletal dysplasia during pregnancy.
  • Fetal hydrops is frequently observed.
  • Fetal activity may be decreased in the lethal types of skeletal dysplasia.
  • Maternal usage of warfarin or phenytoin may induce stippling of the epiphyses, resembling the skeletal dysplasia chondrodysplasia punctata.
  • When an infant affected with skeletal dysplasia has died before or shortly after birth, lethal chondrodysplasias should be considered. Lethal types of congenital skeletal dysplasia include achondrogenesis, homozygous achondroplasia, chondrodysplasia punctata (recessive form), camptomelic dysplasia, congenital lethal hypophosphatasia, perinatal lethal type of osteogenesis imperfecta, thanatophoric dysplasia, and short-rib polydactyly syndromes.
• Clinical history
  • Disproportionately short stature (short limbs or short trunk), delayed motor milestone, and airway obstruction may be noted.
  • Pain, deformity, and minor or major neural deficits, such as paraparesis and quadriparesis, can be caused by spinal disorders.
  • Other skeletal anomalies and functional disturbances include large head with hydrocephalus and bowlegs with waddling gaits. Neurologic complications can be related to atlantoaxial instability, cervical kyphosis, or thoracolumbar kyphosis.

Physical

• Anthropometric parameters should be compared with the gestational age for the newborn or the chronologic age of the patient, considering appropriate racial, ethnic, socioeconomic, and perinatal factors. To detect disproportionately short stature, anthropometric measurements should include the upper-to-lower segment ratio and arm span.
• Diagnosis of short-limb skeletal dysplasia is based on the most severely affected segment of the long bone.
  • Rhizomelic shortening (short proximal segments [eg, humerus, femur]) is present in patients with achondroplasia, hypochondroplasia, the rhizomelic type of chondrodysplasia punctata, the Jansen type of metaphyseal dysplasia, spondyloepiphyseal dysplasia (SED) congenita, thanatophoric dysplasia, atelosteogenesis, diastrophic dysplasia, and congenital short femur.
  • Mesomelic shortening (short middle segments [eg, radius, ulna, tibia, fibula]) includes the Langer and Nievergelt types of mesomelic dysplasias, Robinow syndrome, and Reinhardt syndrome.
  • Acromelic shortening (short distal segments [eg, metacarpals, phalanges]) is present in patients with acrodysostosis and peripheral dysostosis.
  • Acromesomelic shortening (short middle and distal segments [eg, forearms, hands]) is present in patients with acromesomelic dysplasia.
  • Micromelia (shortening of extremities involving entire limb) is present in achondrogenesis, fibrochondrogenesis, Kniest dysplasia, dys-segmental dysplasia, and Roberts syndrome.
  • Diagnosis of the short trunk variety includes Morquio syndrome, Kniest syndrome, Dyggve-Melchior-Clausen disease, metatrophic dysplasia, SED, and spondyloepimetaphyseal dysplasia (SEMD).
• Certain clinical features may be of value as diagnostic indicators, although they may not be specific or consistent.
  • Skeletal dysplasias associated with mental retardation can be broadly categorized in the following terms according to etiology or pathogenesis:
    • CNS developmental anomalies - Orofaciodigital syndrome type 1 (hydrocephaly, porencephaly, hydranencephaly, agenesis of corpus callosum) and Rubinstein-Taybi syndrome (microcephaly, agenesis of corpus callosum)
    • Intracranial pathologic processes - Craniostenosis syndromes (pressure) and thrombocytopenia-radial aplasia syndrome (bleeding)
    • Neurologic impairment - Dysosteosclerosis (progressive cranial nerve involvement) and mandibulofacial dysostosis (deafness)
    • Chromosome aberrations - Autosomal trisomies
    • Primary metabolic abnormalities - Lysosomal storage diseases
    • Other disorders - Chondrodysplasia punctata, warfarin embryopathy (teratogen), and cerebrocostomandibular syndrome (hypoxia)
  • Skull
    • Disproportionately large head - Achondroplasia, achondrogenesis, and thanatophoric dysplasia
    • Cloverleaf skull - Thanatophoric dysplasia, Apert syndrome, Carpenter syndrome, Crouzon syndrome, and Pfeiffer syndrome
    • Caput membranaceum - Hypophosphatasia and osteogenesis imperfecta congenita
    • Multiple wormian bones - Cleidocranial dysplasia and osteogenesis imperfecta
    • Craniosynostosis - Apert syndrome, Crouzon syndrome, Carpenter syndrome, other craniosynostosis syndromes, and hypophosphatasia
  • Eyes
    • Congenital cataract - Chondrodysplasia punctata
    • Myopia - Kniest dysplasia and SED congenita
  • Mouth - Bifid uvula and high arched or cleft palate (as in Kniest dysplasia), SED congenita, diastrophic dysplasia, metatrophic dysplasia, and camptomelic dysplasia
  • Ears - Acute swelling of the pinnae (as in diastrophic dysplasia)
  • Radial ray defects - Trisomy 18; trisomy 13; vertebral, anal, cardiac, tracheal, esophageal, renal, limb (VACTERL) syndrome; Fanconi anemia; Cornelia de Lange syndrome; Holt-Oram syndrome; Townes-Brock syndrome; Okihiro syndrome, Aase syndrome; acrofacial dysostosis; Levy-Hollister syndrome; Tar syndrome, Roberts syndrome; and Baller-Gerold syndrome.
  • Polydactyly
    • Preaxial - Chondroectodermal dysplasia and short-rib polydactyly syndromes (frequently in Majewski syndrome, rarely in Saldino-Noonan syndrome)
    • Postaxial - Chondroectodermal dysplasia, lethal short-rib polydactyly syndromes, and Jeune syndrome
  • Hands and feet
    • Hitchhiker thumb - Diastrophic dysplasia
    • Clubfoot - Diastrophic dysplasia, Kniest dysplasia, and osteogenesis imperfecta
  • Nails
    • Hypoplastic nails - Chondroectodermal dysplasia
    • Short and broad nails - McKusick metaphyseal dysplasia
  • Joints - Multiple joint dislocations, as in Larsen syndrome and otopalatodigital syndrome
  • Long bone fractures (as in osteogenesis imperfecta syndromes, hypophosphatasia, osteopetrosis, and achondrogenesis type I)
  • Thorax/ribs
    • Long or narrow thorax - Asphyxiating thoracic dysplasia, chondroectodermal dysplasia, and metatrophic dysplasia
    • Pear-shaped chest - Thanatophoric dysplasia, short-rib polydactyly syndromes, and homozygous achondroplasia
  • Heart
    • Atrial septal defect or single atrium - Chondroectodermal dysplasia
    • Patent ductus arteriosus - Lethal short-limbed skeletal dysplasias
    • Transposition of the great vessels - Majewski syndrome

Causes

Skeletal dysplasia is a heterogeneous group of disorders characterized by abnormalities of cartilage and bone growth. Their modes of inheritance are heterogeneous (ie, autosomal recessive, autosomal dominant, X-linked recessive, or X-linked dominant. Skeletal dysplasias with known molecular bases are as follows:

• Achondroplasia group: Mutations in the fibroblast growth factor receptor 3 gene (FGFR3) cause achondroplasia, thanatophoric dysplasias, hypochondroplasia, and other FGFR3 disorders.
• Diastrophic dysplasia group: Mutations in the diastrophic dysplasia sulfate transporter gene (DTDST) cause diastrophic dysplasia, achondrogenesis type IB, and atelosteogenesis type II.
• Langer mesomelic dysplasia (LMD) and Leri-Weill dyschondrosteosis (LWDC): SHOX nullizygosity results in Langer mesomelic dysplasia, and SHOX haploinsufficiency leads to Leri-Weill dyschondrosteosis. Turner syndrome and idiopathic short stature are also associated with SHOX deficiency.
• Type II collagenopathies: Mutations in the procollagen II gene (COL2A1) cause achondrogenesis type II, hypochondrogenesis, Kniest dysplasia, SED congenita, SEMD Strudwick type, SED with brachydactyly, mild SED with premature onset arthrosis, and Stickler dysplasia.
• Type XI collagenopathies: Mutations in procollagen XI genes (COL11A1 and COL11A2) cause Stickler dysplasia and otospondylomegaepiphyseal dysplasia.
• Multiple epiphyseal dysplasias and pseudoachondroplasia: Mutations in the cartilage oligomatrix protein gene (COMP) cause multiple epiphyseal dysplasias and pseudoachondroplasia.
• Chondrodysplasia punctata (stippled epiphyses group): Genes that encode the peroxisomal biogenesis factors (PEX) are responsible for rhizomelic chondrodysplasia punctata and Zellweger syndrome. Mutations in the X-linked dominant chondrodysplasia punctata gene (CPXD) cause the Conradi-Hunermann type of chondrodysplasia punctata. Mutations in the X-linked recessive chondrodysplasia punctata gene (CPXR) cause the X-linked recessive type of chondrodysplasia punctata. Mutations in the arylsulfatase E gene (ARSE) cause the brachytelephalangic type of chondrodysplasia punctata.
• Metaphyseal dysplasias: A mutation in the gene encoding the parathyroid hormone/parathyroid hormone–related polypeptide receptor (PTHR) is responsible for the Jansen type of metaphyseal dysplasia. Mutations in the procollagen X gene (COL10A1) cause the Schmid type of metaphyseal dysplasia. Mutations in the adenosine deaminase gene (ADA) cause the adenosine deaminase type of metaphyseal dysplasia.
• Acromelic and acromesomelic dysplasias: Mutations in the gene encoding the cartilage-derived morphogenic protein-1 gene (CDMP1) cause Grebe dysplasia, Hunter-Thompson dysplasia, and brachydactyly type C. Mutations in the gene coding for the guanine nucleotide-binding protein of the adenylate cyclase a -subunit (GNAS1) cause pseudohypoparathyroidism (Albright hereditary osteodystrophy).
• Dysplasias with prominent membranous bone involvement: Mutations involving the transcription core binding factor a ₁ -subunit gene (CBFA1) cause cleidocranial dysplasia.
• Bent bone dysplasia group: Mutations in the gene coding for the SRY-box 9 protein (SOX9) cause camptomelic dysplasia.
• Dysostosis multiplex group: Specific gene mutations cause different types of mucopolysaccharidosis, fucosidosis, mannosidosis, aspartylglycosaminuria, G_M1 gangliosidosis, sialidosis, sialic acid storage disease, galactosialidosis, multiple sulfatase deficiency, and mucolipidosis types II and III.
• Dysplasias with decreased bone density: Mutations in the procollagen I genes (COL1A1, COL1A2) cause various types of osteogenesis imperfecta.
• Dysplasias with defective mineralization: Mutations in the liver alkaline phosphatase gene (ALPL) cause perinatal lethal and infantile forms of hypophosphatasia. Mutations in the X-linked hypophosphatemia gene (PHEX) cause hypophosphatemic rickets. Mutations in the parathyroid calcium-sensing receptor gene (CASR) cause neonatal hyperparathyroidism and transient neonatal hyperparathyroidism.
• Increased bone density without modification of bone shape: Mutations in the carbonic anhydrase II gene (CA2) cause osteopetrosis with renal tubular acidosis. Mutations in the gene encoding cathepsin K (CTSK) cause pyknodysostosis.
• Disorganized development of cartilaginous and fibrous components of the skeleton: Mutations in exostosis genes (EXT1, EXT2, EXT3) cause multiple cartilaginous exostoses. Mutations in the guanine nucleotide-binding protein a -subunit gene (CNAS1) cause fibrous dysplasia (McCune-Albright and others). The bone morphogenic protein 4 gene (BMP4) is overexpressed in fibrodysplasia ossificans progressiva.
• Skeletal dysplasias and disease genes associated with osteoarthritis: These mutations cause SED congenita (COL2A1), SED tarda (COL2A1, SEDL), Stickler dysplasia (COL2A1, COL11A1 -A2), pseudoachondroplasia (COMP), MED (COMP, COL9A1 -A3, MATN3, DTDST), and progressive pseudorheumatoid chondrodysplasia (WISP3).
• Mutations in osteopetrosis: These mutations cause type I (LRP5), type II (CLCN7), Van Buchem disease (SOST), sclerostenosis (SOST), autosomal recessive osteopetrosis (OSTM1, TCIRG1, CLCN7), and osteopetrosis with renal tubular acidosis (CA2).
• Mutations in osteoporosis: These mutations cause osteoporosis-pseudoglioma syndrome (LRP 5) and familial expansile osteolysis (RANK).
• Mutations in craniosynostosis: These include mutations in FGFR1 (osteoglophonic dysplasia, Pfeiffer syndrome), FGFR2 (Apert syndrome, Pfeiffer syndrome, Crouzon syndrome, Jackson-Weiss syndrome, Beare-Stevenson cutis gyrata syndrome, nonclassifiable and variable craniosynostosis), FGFR3 (thanatophoric dysplasia, type I and type II, crouzondermoskeletal syndrome, Muenke syndrome, hypochondroplasia), TWIST (Saethre-Chotzen syndrome), MSX2 (Boston type craniosynostosis), EFNB1 (craniofrontonasal syndrome), EFNA 4 (nonsyndromal coronal synostosis), POR (Antley-Bixler syndrome), and ALPL (hypophosphatasia, particularly infantile type).
• Mutations in IHH gene: These mutations cause brachydactyly type A1 and acrocapitofemoral dysplasia.
• Mutations in PTHR1: These mutations cause Jansen metaphyseal chondrodysplasia, Blomstrand chondrodysplasia, Eiken syndrome, and multiple enchondromatosis, Ollier type.
• Mutations in FLNA: These mutations cause otopalatodigital syndrome type I and II, frontometaphyseal dysplasia, and Melnick-Needle syndrome.

• Search for CME/CE on This Topic »

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