Ovid: Pediatrics

Editors: Tornetta, Paul; Einhorn, Thomas A.; Cramer, Kathryn E.; Scherl, Susan A.
Title: Pediatrics, 1st Edition
> Table of Contents > Section III: – Specialty Clinics > 30 – Genetics

Sevan Hopyan
Benjamin A. Alman
The etiology of any biologic disorder is a combination
of genetic predisposition and environmental factors. As such, most
musculoskeletal conditions have, in whole or in part, a genetic basis.
This chapter reviews basic principles of inheritance and summarizes a
number of pediatric orthopaedic disorders with a genetic basis.
Patients with genetic disorders frequently present to
orthopaedists, and it is not uncommon for an orthopaedist to be the
first to entertain a genetic diagnosis for a given patient. For this
reason, it is necessary for the orthopaedists to have at least
background knowledge in genetics. When a patient is suspected to have a
genetic disorder, appropriate consultation with clinical genetics
should be made. In addition, information about genetic disorders is
moving at a rapid pace, making it difficult for traditional textbooks
to keep up with newest information. An excellent source for up- to-date
information is the Online Mendelian Inheritance in Man (OMIM), which is
maintained by the National Center for Biotechnology Information, and is
located at
A gene is a sequence of DNA
(deoxyribonucleic acid) that is required for the production of a
protein. Within the nuclei of human cells, there are about 30,000
genes, composed of just four nucleic acids (adenosine, cytosine,
thiamine, and guanine). Most cells are diploid, meaning they contain
two copies, or alleles, of every gene
contained within the autosomal and X chromosomes in females, and within
the autosomal chromosomes in males (males, of course, have one X and
one Y chromosome). Each gene has a region of DNA adjacent to it, which
regulates how the gene is activated. The gene itself is arranged into exon and intron
regions. The exons are transcribed and spliced together to form RNA
(ribonucleic acid), which then permits translation of the code for
amino acid assembly. Many proteins undergo extensive posttranslational
processing. A mutation is an irreversible change in DNA sequence, which
may be a deletion, an insertion or a substitution of DNA, and can vary
in length from a single nucleic acid to large portions of chromosomes.
Mutations may exist in all cells, and are termed germline mutations, or in only some cells, in which case they are termed somatic mutations.
Each time a cell divides, it makes a copy of its DNA, a process during
which new mutations can develop. Chromosomal abnormalities (trisomies
or translocations) occur when largescale changes occur, causing major
Patterns of Single-Gene Inheritance
A single-gene trait may be new or inherited, and inheritance may be Mendelian (classic) or non-Mendelian
(nonclassic). In Mendelian inheritance, single-gene traits segregate
within families, and usually occur in fixed proportions among children.
Autosomal and X-linked are terms used to note the chromosomal location of the involved gene, and dominant and recessive are terms that signify how a specific gene causes its phenotype.
Autosomal dominance is the most common pattern of
single-gene inheritance. With autosomal dominant inheritance, only one
of the two copies of the gene needs to be abnormal to cause disease,
and every affected individual has an affected parent. Children of
affected individuals have a 50% chance of inheriting an autosomal
dominant trait, and phenotypically normal family members do not
transmit the phenotype to their children. Males and females are equally
likely to transmit the phenotype to children of either sex.
Autosomal recessive inheritance requires both copies of
the gene to be abnormal to cause disease. The phenotype is seen in
children, but not in parents. The recurrence risk for each sibling of
an individual with a disease is 1 in 4. Because of the rarity in the
population of many alleles responsible for autosomal recessive
conditions, the parents of an affected child may in some cases be
consanguineous. Males and females are equally likely to be affected.

X-Linked Inheritance
Because males have one copy of the X chromosome, they
are more susceptible to recessive diseases inherited from a gene on
this chromosome than women, who have two copies. Most of one of the two
X chromosomes in every female cell is inactive. Inactivation (lyonization)
takes place within the first week of development, and is random in any
one cell. However, once established, all clonal descendants of a given
cell have the same inactive X chromosome. Females therefore have some
distribution of two cell populations and are thus mosaic
with regard to their X-linked alleles. The variability of this
mosaicism will affect the degree of manifestation of an X-linked
phenotype. Distinction of X-linked dominant and recessive patterns of
inheritance may be complicated by mosaicism.
X-linked recessive traits are much more common in males
than in females. A responsible allele is transmitted from an affected
father through all his daughters who become unaffected carriers. Any of
this man’s daughters’ sons has a 1 in 2 chance of inheriting that
allele. The allele is never transmitted from father to son, and
affected males in a kindred are related through females. Homozygosity
in females is rare, but will lead to an equal chance of being affected
or of being a carrier. Sometimes, due to unfavorable mosaicism,
heterozygous females may express an X-linked condition with variable
For a condition that is inherited in an X-linked
dominant fashion, affected males with non-affected mates will have no
affected sons and no unaffected daughters. Both female and male
offspring of female carriers have a 1 in 2 risk of inheriting the
phenotype, as is the case with an autosomal dominant phenotype. For
rare phenotypes, affected females are about twice as common as affected
males, but affected females typically have milder expression of the
Sometimes, the phenotype caused by a mutation may vary
with different individuals, even from within the same family. This may
be caused by factors altering gene expression, or by modifying genes. Penetrance
of a phenotype is reduced if it does not affect everyone who carries
the appropriate genotype in an all-or-none fashion. This phenomenon can
lead to apparent skipping of generations in autosomal dominant
conditions. Variable expressivity exists
when the manifestation of a phenotype differs in individuals with the
same genotype. Pedigrees of autosomal dominant conditions may show anticipation, the apparent worsening of a condition in successive generations due to variable expressivity.
In recent years it was discovered that diseases can be inherited in non-Mendelian manners. Examples of such mechanisms include unstable segments of DNA, uniparental disomy, imprinting, and mitochondrial DNA inheritance.
Mitochondria have their own circular chromosome. There
are several copies of this chromosome per mitochondrion, and thousands
per cell. Mitochondrial DNA (mtDNA) encodes for transfer RNAs and for
polypeptides that are subunits of enzymes of oxidative phosphorylation.
Some neuromuscular diseases are due to mutations in mtDNA. A unique
feature of these disorders is their maternal inheritance, due to the
abundance of mitochondria in ova and the lack of them in sperm. A
mother will transmit her mtDNA to all her offspring, but only her
daughters will transmit that mtDNA in their turn, whereas her sons will
Regions in DNA, usually composed of trinucleotide
repeats, can become unstable in length with subsequent generations.
When the length of a repeat reaches a certain critical threshold it
causes disease. Conditions such as fragile X syndrome are caused by
unstable DNA repeats.
Imprinting occurs when the
gene from one parent influences the expression of the gene from the
other parent. When this occurs, the affected individual inherits a
genetic abnormality from one parent, which does not cause disease in
the parent. However, in the affected individual, the same defect causes
disease, for instance by inactivating the normal gene from the other
Uniparental disomy refers to
the inheritance of two chromosomes of a given kind from only one
parent. This situation can result in the unusual clinical observations
of inheritance of an autosomal recessive disorder from only one
documented carrier parent, and transmission of an X-linked disorder
from father to son, or expression in homozygous form in females.
Mosaicism (a mutation occurring in only some cells of
the body) is responsible for some unusual observations. A mutation
occurring during embryonic development may be present in some fraction
of either somatic or germline cells, or both, depending on the stage of
development and the anatomic location in which the mutations occur.
Somatic mosaicism of a mutation may manifest as a segmental or patchy
abnormality. Germline mosaicism may result in the unusual finding of a new autosomal dominant phenotype in more than one member of a sibship.
The gene abnormalities responsible for many of the
conditions of interest to the orthopaedist are now known. Based on this
information, these disorders can be grouped broadly based on the
function of the causative gene into five categories:
  • Structural (e.g., collagen)
  • Tumor and cell regulatory (e.g., neurofibromatosis)
  • Developmental (e.g., fibroblast growth factor receptor in achondroplasia)
  • Important in nerve or muscle function
  • Protein processing (enzymes).

In addition, some disorders are caused by large
chromosomal abnormalities in which thousands of genes may be involved.
Disorders in each of these categories share similarities in their
clinical manifestations, treatment, prognosis, and inheritance pattern.
A few examples of disorders in these classes are outlined in the
remainder of this chapter.
Down Syndrome (Trisomy 21)
Down syndrome is the most common chromosomal disorder.
It occurs in about 1 in 5,000 births in women under 30, and 1 in 250
births in women over 35. Complete trisomies (due to chromosomal
nondisjunction) account for 95% of cases, while mosaicism,
translocations, and partial trisomies account for the remainder.
Individuals with Down syndrome have distinctive, easily recognizable physical findings:
  • Patients are short in stature.
  • They have a characteristic face, with
    upward slanting palpebral fissures, epicanthal folds, a flattened nasal
    bridge, low-set ears and a protruding, furrowed tongue.
  • The hands are short and broad, often with
    a single transverse palmar crease and clinodactyly. Other Down
    syndrome-associated findings:
  • It is the single most common cause of moderate mental retardation.
  • Congenital heart disease occurs in about
    one-third of patients, and other malformations such as duodenal atresia
    and tracheoesophageal fistula may also occur.
  • Auditory loss can occur.
  • There is a 15 times higher risk of developing leukemia.
  • The incidence of endocrinopathy, particularly, hypothyroidism, is high.
  • Infections are common, although the reason for this is unclear.
  • Individuals exhibit premature aging and an early development of mental deterioration similar to that in Alzheimer disease.
Nevertheless, with appropriate management of the
cardiac, endocrine, and gastrointestinal abnormalities, most affected
individuals live to adulthood.
One in five individuals with Down syndrome has a
musculoskeletal problem related primarily to joint instability. Changes
in joint shape and sites of ligament insertions may contribute to the
apparent instability. The results of surgery for joint instability are
not as good as for unaffected individuals.
An increased atlantoaxial distance on cervical spine
films is found in about 10% of individuals with Down syndrome. In most
cases, it is not associated with symptoms. Although the natural history
of the cervical spine in these individuals is not fully known, studies
following asymptomatic patients with an increased atlantoaxial distance
have not identified any acute episodes of spinal cord compromise. The
reported complication rate for atlantoaxial arthrodesis in Down
syndrome is high. For these reasons, the surgical management of the
atlantoaxial articulation focuses on symptoms rather than on
radiographic findings. Symptoms can be difficult to identify, and
patients may present with subtle findings, such as a change in gait
Scoliosis and spondylolisthesis can occur in Down syndrome, probably at a higher incidence than in the unaffected population.
Children with Down syndrome can develop hip dysplasia,
which often occurs after the first few years of life. Although it is
suggested that hip instability leads to functional problems later in
life, it is unclear whether operative intervention improves outcome.
Children may be habitual dislocators, and there is a high failure rate
when hip surgery is undertaken in these patients. Brace treatment for
children under 6 years has been advocated, although only small series
of children have been reported. Slipped capital femoral epiphysis
occurs in children with the syndrome and is associated with a high
incidence of avascular necrosis. Knee dislocations are often
asymptomatic, rarely requiring surgical intervention. The feet of Down
patients develop planovalgus and hallux valgus deformities, which can
be managed with shoe wear modification in most cases.
Turner Syndrome (45,XO)
This syndrome is caused by the absence of an X chromosome in females, and has an incidence of 1 in 2,500 births.
  • Affected girls have a webbed neck, low hairline, short stature, and sexual infantilism.
  • Because of a lack of sex steroid hormones, puberty does not occur and exogenous hormone replacement is usually administered.
  • Although its use remains controversial,
    growth hormone may be administered in these patients, resulting in a
    modest increase in height.
  • Scoliosis is common and patients must be
    monitored frequently if growth hormone is being used since it may
    accelerate curve progression.
  • Valgus of the elbow and of the knee are common, but rarely causes disability.
  • Most individuals have low bone density,
    probably related to the lack of sex steroid hormones and to altered
    renal vitamin D metabolism.
  • Intelligence and life expectancy are normal.
Neurofibromatosis type 1 (NF-1) is a common autosomal
dominant disorder, occurring in about 1 in 3,000 newborns. Penetrance
of the disorder is complete, though expressivity is highly variable.
Half of affected patients carry a new, rather than an inherited
mutation. Although


are several forms of neurofibromatosis, orthopaedic problems occur
primarily in NF-1. A diagnosis of NF-1 requires two or more of the

  • ≥6 café-au-lait spots whose greatest diameter is 5 mm in prepubertal and 15 mm in postpubertal patients
  • ≥2 neurofibromas of any type or one plexiform neurofibroma
  • Axillary freckles
  • Optic glioma
  • ≥2 Lisch nodules (hamartoma of the iris)
  • Distinctive osseous lesion
  • First-degree relative with NF-1
Most of these findings are absent in the newborn but
develop over time. NF-1 is caused by a mutation in the gene encoding
neurofibrillin (NF-1) which plays a role in the Ras signaling pathway.
Mutant neurofibrillin causes excessive Ras signaling, which leads to
increased cell division in patients. Patients have one mutant copy of NF1, but loss or mutation of the second copy of NF1
further dysregulates Ras signaling, and can give rise to malignancy.
Affected individuals may have a normal life span, but have a higher
risk of malignancy and hypertension (due to renal artery stenosis).
Scoliosis is common and occurs in two patterns. Most curves resemble an idiopathic pattern, and can be managed in a manner identical to curves in idiopathic scoliosis. Other curves have a dystrophic pattern, involving a short segment (four to six levels), with distortion of the vertebrae and ribs.
  • Curves that present in children under the age of 7 have a very high chance of being dystrophic.
  • The presence of rib penciling can aid in predicting which curves will become dystrophic.
  • Dystrophic curves are refractory to brace
    treatment, relentlessly progress, and, especially in cases associated
    with kyphosis, can lead to paralysis.
  • They are best managed with early anterior and posterior surgical stabilization.
  • Pseudoarthrosis of long bones is typical, with the tibia being the most common location.
    • □ An anterolateral bow in the tibia is a
      precursor to a pseudoarthrosis and should be managed with a total
      contact orthosis to prevent fracture.
    • □ Intramedullary fixation works well as the initial treatment for the established pseudoarthrosis.
    • □ Salvage procedures include vascularized bone grafting, distraction osteogenesis techniques, and amputation.
  • A variety of neoplastic processes can occur in neurofibromatosis.
    • □ Most are benign and do not require surgical intervention.
    • □ Plexiform neurofibromas are difficult to manage due to their vascularity and infiltrative nature.
    • □ It is difficult to distinguish neurofibromas from neurofibrosarcomas.
    • □ Lesions that rapidly change in size or become symptomatic should be managed as a potential sarcoma.
    • □ Children with neurofibromatosis have a propensity to develop other malignancies.
Multiple Hereditary Exostosis
This disorder is characterized by the presence of
multiple osteochondromas (exostoses). It is inherited in an autosomal
dominant manner, and is caused by a mutation in one of the three EXT
genes, whose protein products regulate how the hedgehog ligand, which
plays an important role in growth-plate function, diffuses through
extracellular matrix.
  • Clinical problems include pain or
    cosmetic problems from the bump, limb length inequality, angular bony
    deformity, dislocation of an adjacent joint, and malignant change.
  • Only symptomatic osteochondromas require excision.
  • Limb inequality and deformity can be managed using usual techniques.
  • Most deformities of the upper extremity do not cause symptoms, and the rarely require operative intervention.
  • Malignant change is a rare occurrence,
    but should be suspected in lesions that grow or become symptomatic
    after skeletal maturity.
Enchondromas are common benign cartilage tumors of bone.
They can occur as solitary lesions or as multiple lesions in
enchondromatosis (Ollier and Maffucci diseases). Maffucci disease is
also associated with soft tissue vascular malformations.
  • Clinical problems caused by enchondromas include skeletal deformity and the potential for malignant change to chondrosarcoma.
  • The extent of skeletal involvement is
    variable in enchondromatosis and may include dysplasia that is not
    directly attributable to enchondromas.
  • Standard techniques are used for the treatment of limb deformity and limb length inequality.
  • Changes in symptoms or size of a lesion,
    especially in skeletally mature individuals, raise the concern about
    malignant transformation, which occurs in a higher frequency in
    Maffucci disease.
  • Enchondromatosis can be caused by a
    mutation in the parathyroid hormone-related protein receptor, which
    dysregulates the same Hedgehog protein that is dysregulated in
Achondroplasia is an autosomal dominant disorder caused
by a mutation in fibroblast growth factor receptor type 3 (FGFR3).
Eighty percent of cases are due to new mutations with increased
paternal age as a risk factor. FGFr-3 influences chondrocyte maturation
in the growth plate, resulting in the chondroepiphysis developing
abnormally. There is a greater effect seen in regions of greater
endochondral growth, giving rise to the characteristic rhizomelic


pattern of shortening (worse shortening of proximal segments) seen in the disorder.

  • Children with achondroplasia are
    identified at birth by the presence of characteristic facial features
    (frontal bossing and mid-face hypoplasia) and short humerii and femurs.
  • The most severe problems in achondroplasia are related to the spine.
  • Kyphosis of the lumbar spine develops in
    infants, but usually resolves on its own in early childhood, when
    better trunk control develops.
  • The rare progressive case that persists past early childhood requires operative intervention.
  • In the lumbar spine, the distance between the pedicles narrows, rather than increases, as one proceeds caudally.
  • Patients may have more symptoms later in life when degenerative changes are superimposed on the congenital stenosis.
  • With respect to the lower extremities in achondroplasia, genu varum occurs but is usually mild.
  • Osteotomies can be performed in the patient with severe deformity and symptoms.
  • Distraction osteogenesis and the use of growth hormones to increase stature are controversial treatments for these individuals.
Cleidocranial Dysplasia
Cleidocranial dysplasia is an autosomal dominant condition caused by a mutation in the CBFA1 gene, which encodes a transcription factor that regulates osteoblast differentiation. Heterozygous loss of function of CBFA1 is sufficient to produce the disorder.
  • Characteristic features of cleidocranial
    dysplasia include midline and other bony defects, such as
    hypoplasia/aplasia of clavicles, patent fontanelles, supernumerary
    teeth, short stature, midline pelvic defects, and delayed skeletal
  • The absence of clavicles may allow patients to adduct their shoulders far enough to touch them together anteriorly.
  • Hips can develop coxa vara, which may require treatment with an osteotomy.




Stored Substance and Enzyme Defect




HS + DS; α-L-iduronidase




HS + DS; iduronidase-2-sulfatase




HS; four subtypes with different enzymes affected




KS, CS; three subtypes:








(formerly Scheie)




DS + CS; arylsulfatase B, N-acetylgalactosamine-4-sulfatase




CS + HS + DS; N-β-D-glucuronidase



CS + HS; glucuronate-2-sulphatase

autosomal recessive; CS, chondroitin sulfate; DS, dermatan sulfate; HS,
heparan sulfate; KS, keratan sulfate; XR, X-linked recessive.

The mucopolysaccharidoses
are a group of disorders each caused by abnormal function of a
particular lysosomal enzyme that degrades a sulfonated
glycosaminoglycan. Incomplete degradation products secondarily
accumulate in lysosomes. There are a variety of subtypes, most of which
are inherited in an autosomal recessive manner, as listed in Table 30-1.
  • Features common to these disorders
    include corneal clouding, organomegaly, epiphyseal deformation,
    contractures, cardiac disease, and deafness.
  • The diagnosis can be made using urine analysis for the specific glycosaminoglycan involved.
  • Hurler syndrome is the most common and one of the more severe forms of disease, as patients live only into their second decade.
  • Hunter syndrome is less severe, with patients having a normal life span.
    • □ Children with Hunter syndrome have
      upper cervical instability, kyphosis of any region of the spine, hip
      deformity, and malalignment of the lower limbs.
    • □ Bone marrow transplant has been used in severe cases to arrest progression.
Spondyloepiphyseal dysplasia is a short-trunk form of dwarfism with abnormalities of the physes and spine. It can broadly be classified into congenita and tarda forms.


The congenita form presents at birth, and is inherited in an autosomal
dominant fashion. It is caused by mutations in type II collagen. Type
II collagen is the major form of collagen present in cartilage. The
tarda form is milder, with most patients developing manifestations at
about 4 years of age, although some do not present until adolescence.
The tarda form is an X-linked condition, caused by a mutation in the SEDL gene, which plays a role in regulating intracellular protein trafficking. The exact mechanism by which the SEDL mutation causes abnormal chondroepiphyseal formation has yet to be elucidated.

  • Affected individuals have short limbs and a short trunk.
  • In the congenita form one finds coxa vara, valgus alignment of the knees, scoliosis, kyphosis, and increased lumbar lordosis.
    • □ The hands are normal.
    • □ Severe myopia, retinal detachment, and sensorineural hearing loss can occur.
  • The tarda form is less severe and often
    presents with hip pain or stiffness (generally in the second decade),
    flattened vertebrae (platyspondyly), and in many cases, scoliosis.
    • □ There is failure or delay of
      ossification of the proximal femoral physis, os pubis, distal femoral
      physis, talus, and calcaneus.
    • □ The hips show coxa valga and radiographic changes similar to Perthes disease.
  • Odontoid hypoplasia in spondyloepiphyseal dysplasia can predispose to upper cervical instability, and can cause myelopathy.
  • Flexion-extension views of the C-spine should be obtained before anesthesia is administered.
  • Scoliosis and kyphosis are treated using standard methods and principles for these spinal deformities.
  • Lower extremity malalignment may be treated with osteotomies.
Diagnostic confirmation of a genetic condition, although
not always necessary, is definitively ascertained by demonstration of a
causal mutation in the patient. In broad terms, mutations are either
alterations on a large chromosomal scale or on a small base-pair scale,
and a genetic test is chosen largely based on the resolution required
to identify the abnormality. A karyotype analysis will identify an
excess or absence of an entire chromosome, as in Down and Turner
syndromes, or of a large part thereof. Cytogenetic methods combining
karyotyping and labeling by hybridizing probes to DNA, as in
fluorescent in situ hybridization, allow
visualization of the presence and number of specific sequences as well
as their location in the genome. These methods are useful also in
identifying amplification or deletion of genes (e.g., in cancers).
When identification of a small-scale DNA alteration is
necessary, a number of tests are possible, depending on whether the
number of causal mutations in a given gene are limited and recurring.
For recurring mutations, resultant dysfunctional proteins or enzymes
can sometimes be identified by biochemical tests, without the need to
resort to genetic tests. The presence, absence, and relative abundance
of a single gene product can be identified by immunohistochemistry (for
protein) or by Northern blot or polymerase chain reaction (PCR) for
messenger RNA. Known DNA sequence alterations and translocations that
are recurring can be sought rather simply by attempting to amplify the
abnormal sequence by PCR, using mutationspecific primers. If the
mutations in a given gene vary significantly or have not all been
identified, then sequencing the gene either manually or using an
automated sequencer becomes necessary. Correlation of a newly
identified mutation with pathogenesis may then be required to establish
a causal relationship of the mutation.
Southern, Northern, and Western blotting are similar
techniques for the visualization, detection, and quantification of
genetic material. Southern blotting is used for DNA, Northern for RNA,
and Western for proteins. Basically, the technique consists of
denaturing the substance to be studied, “blotting” the fragments onto a
membrane, and then treating them with a specific labeled probe that
allows them to be visualized. Southern blotting was named for its
inventor, E.M. Southern. The names Northern and Western blotting were
chosen as a bit of a joke, when the technique proved useful for
substances other than DNA.
Polymerase Chain Reaction (PCR) is an automated
technique used to “amplify” a small amount of DNA into a larger one. It
utilizes a heat stable polymerase (the enzymes that replicate DNA) to
reproduce short segments of DNA, that are pre-heated to denature them.
The process, which is relatively quick and simple, is repeated 25-75
times to produce a useful quantity of DNA.
Alman BA. A classification for genetic disorders of interest to orthopaedists. Clin Orthop 2002;401:17-26.
Thompson MW, McInnes RR, Willard HF. Thompson & Thompson: genetics in medicine, 5th ed. Philadelphia: WB Saunders, 1991.

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