Prenatal Development and Common Genetic Disorders
Infants and children are frequently evaluated and treated by
physical therapists for motor deficits and chronic illnesses. There are multiple
reference texts, resources, and documents related to physical therapy intervention
for children from the neonatal level up to adulthood. This text is designed to give
a broad brush to the developmental sequence of growth and maturity for the normal
while discussing the many variances from normal along with potential causes that may
create deficits and thus require intervention by therapy. The importance of
understanding the abnormal will be in the evaluation and treatment process to design
effective treatment regimes to allow the infant/child to progress to the highest
practicable level possible. This course may be used as a general reference in the
treatment and understanding of physical therapy in the pediatric population.
Chapter 1 will investigate prenatal development and common
genetic disorders that may give rise to infants and children who may require
rehabilitation intervention. It is important that clinicians understand the role of
gestation and influencing factors on the gestational process that may result in
abnormal findings or development. The purpose of Chapter 1 is to lay the groundwork
from which the next chapters will build on to allow the therapist to understand the
developmental processes required in setting treatment parameters and interventions.
Chapter 1 will be information based only.
Prenatal development begins at the cellular level through a process referred to as
fusion when the male germ cell, the sperm, unites with the female germ cell, the ovum
to create a new cell referred to as a zygote. The zygote contains the base genetic
prototype from which all the remaining cells will develop.
The developing cellular process is divided into two processes:
- Meiosis - cellular divisions occurring prior to fertilization. This process provides
for random combinations of genetic materials from each parent through production of
haploid germ cells. Haploid germ cells contain half the number of chromosomes found in
other body cells.
- Mitosis - cellular divisions occurring after fertilization that create the ongoing
growth and development of the organism. This process creates the diploid cells containing
a complete chromosome number. The diploid cells are the result of a combination of one
maternal X chromosome with one paternal X or Y chromosome to create either an a) XX female
or a B) XY male.
Genetic disorders may occur in association with either cellular process resulting in the most
common cause of birth defects. Genetic disorders are responsible for one third of all birth
defects and about 85% of those with identified causes.
Genetic disorders may be grouped within three groups:
Chromosome Number Abnormalities
- Chromosome number abnormalities
- Chromosome structure abnormalities
- Gene mutations
Chromosome number abnormalities are the result in nondisjunction errors during cellular
divisions in the meiosis process prior to fertilization. Thus, there are unequal distributions
of chromosomal material. There are four main types of chromosomal number abnormalities:
Monosomy is the result of only one of the chromosome pair present at a specific cell site.
This is the most common cytogenetic abnormality causing spontaneous abortions. 99% of
infants born do not survive. The most common monosomy is Turner Syndrome, 45 XO, is found in
1 in 3000 to 1 in 10,000 newborn females. Characteristics may include transient congenital
lymphadema, small stature at birth with web-like appearance of the lateral neck, gonadal
underdevelopment, hearing impairment, bone trabecular abnormalities.
47 XYY Syndrome
47 XXY Syndrome
Trisomy 21 Down Syndrome
Trisomy 18 Edward’s Syndrome
Trisomy is the result of 3 of a particular chromosome present at a specific site. Zygotes
with 47 chromosomes are produced when a germ cell with 24 chromosomes fuses with one that
has 23. Trisomies of sex chromosomes are common and often undetected until later life.
Tetrasomies (48 XXYY, 48 XXXY) and pentasomies (49 XXXYY, 49 XXXXX) are characterized by short
stature, hypogenitalism, moderate to severe cognitive delay and hypotonia.
- 47XYY Syndrome characterized by tall stature, shoulder girdle weakness, and generalized
incoordination particularly fine motor.
- 47 XXY or Klinefelter Syndrome that is present in 1 in 500 males and is the most common
cause of infertility in adult males. Characteristics include hypogonadism, long limbs, and slim
stature though obesity may be problematic in adults.
- Autosomal trisomies with only 21, 18, and 13 recognized as surviving postnatally. These are
associated with growth abnormalities and cognitive delays.
Chromosome Structure Abnormalities
Chromosome structure abnormalities may result from mosaicism, translocation, chromosome deletion,
Mosaicism typically results from a nondisjunction error during mitotic cell division and may occur
in sec chromosomes or as autosomes.
Translocation results from a breakage and transfer of chromosomal material to unrelated, intact
chromosome pairs. May be caused by environmental influences such as drugs, radiation, viruses, or
chemical teratogens rather than inheritance. This condition may or may not result in abnormal
Chromosomal deletion is induced by chromosome breakage and the broken potion is lost rather than
attached. Similar to translocation, may be caused by environmental influences. Most noted of
chromosomal deletions is Cri-du-chat syndrome with results in abnormal laryngeal development that
produces a weak and high-pitched cry. Cognitive deficits, mircrocephaly are always present. Also,
hypotonia, hypertelorism, scoliosis, and congenital heart abnormalities are often present.
Microdeletions may span several contiguous genes and produce Prader-Willi syndrome and Angelman
Prader-Willi syndrome characteristics include mild cognitive delay, hypotonia during infancy,
short stature, and hyperphagia.
Angleman (Happy Puppet syndrome) is associated with severe cognitive delay, microcephaly,
seizures, ataxia contributing to a "puppet-like" gait, and frequent laughter.
Specific gene mutations account for 7-8% of all congenital anomalies. Mutations can occur randomly
and besides an inheritance factor may be cause by environmental agents such as radiation and
ENVIRONMENTAL INFLUENCE ON PRENATAL DEVELOPMENT
- Autosomal dominant inheritance - indicates that the mutant gene was contributed by one parent.
Achondroplacia - the most frequent cause of short stature caused by disturbance to the
endochondral ossification resulting in bilateral shortness of the humerus, femur, and macrocephaly
associated with hydrocephalus.
Ectrodactly - cleft hand or cleft foot in which two or more digits are fused
Polydactyly - Extra digits present on the hand or foot
Osteogenesis Imperfecta - error in collagen development resulting in multiple bone fractures
generally categorized in four types with varying degrees of mortality and fragile bony structure.
- Autosomal recessive inheritance - the gene mutation is transmitted by both parents.
Cystic fibrosis - progressive disorder of the exocrine glands with progressive digestive and
pulmonary problems most often fatal though life spans have been lengthening with appropriate
Childhood spinal muscular atrophy resulting in progressive flaccid paralysis. Defined in
three types with decreasing severity of the disease and improved life span with weaknesses
noted occurring in later childhood for Types II and III. Type 1, is usually fatal before
3 years of age.
- X-linked inheritance - transmitted on the X-chromosome primarily affecting males while
females may be minimally affects or may be unaffected carriers.
Rett Syndrome - lethal in males before birth, females with syndrome have a normal development
up to the age of 6 months followed by gradual cognitive and motor losses, deceleration of head
growth, onset of hypotonia, ataxia and may be associated with autism.
Hemophilia - clotting disorder of the blood resulting in excessive bleeding or hemorrhage.
Duchenne’s muscular dystrophy - muscle wasting disease
Fragile X Syndrome - most common cause of mental retardation in males after Down syndrome.
It is associated with older paternal age with characteristics of increased head circumference,
prominent forehead, generalized hypotonia, torticollis, and scoliosis.
Lesch-Nyan syndrome - x-linked recessive causing excessive production of uric acid with
deleterious effects on the brain and liver. Associated with spasticity beginning at 6-8 months
of age, choreoathetosis, growth deficiency, autism, and tendency to self mutilate.
Environmental Agents - environmental agents such as radiation, heavy metals, infectious or
chemical teratogens may cause chromosomal abnormalities, especially deletion and translocation,
and increase the rate of gene mutations. When in the pregnancy the mother came into contact
with a teratogenic agent also determines the outcome of the fetus.
First two weeks of gestation - typical outcome is embryonic death
Weeks 3-8 of gestation - most susceptible for multi-system congenital abnormalities.
Weeks 9- 38 - most tissues have differentiated; the brain is the most susceptible
Toxoplasmosis - maternal infection resulting from ingestion of uncooked meat, eggs,
unpasterurized milk, soil, or cat feces infected. Causes hydrocephaly, microcephaly, and cerebral palsy.
Cytomegalovirus (CMV), herpes simplex virus (HSV), varicella (chicken pox), human immunodeficiency
virus (HIV), and syphilis - all may result in microcephaly and/or cognitive delay.
Rubella - infection after the first trimester carries a lower risk of anomalies. Infection with
this virus cases visual, auditory, and CNS dysfunction.
Thalidomide - fetal results are highly dependent on timing. Complete absence of a limb is associated
with 24-36 days gestational age.
MATERNAL SUBSTANCE ABUSE
Alcohol Ingestion and Fetal Alcohol Syndrome (FAS)
First described in the 1960s, however the full impact of maternal alcohol ingestion on
fetal development and frequency of occurrence was not recognized until the 1990s.
Children with FAS may have multiple, sometime subtle, developmental problems including
hypotonia, gross motor delays and fine motor limitations. In addition, they may present
with flattened nasal and bridge appearance, with microcephaly, learning disorders,
hyperactivity, and joint and cardiac abnormalities.
Maternal Drug Use
It is difficult to determine effects of specific drugs on the fetus because maternal
substance abuse often includes multiple drugs. Research studies report a range of outcomes
from no specific developmental sequelae to CNS impairment.
GROWTH: INFLEUNCES AND PROGRESSION
The regulation of growth is highly complex and is dependent upon the interaction of nutrition,
genetic, hormonal, mechanical, and environmental factors. There are many normative charts
available that give growth parameters considered to be normal. Fetal growth depends upon the
physical size of the mother’s uterus under normal conditions.
Average birth weight is between 5.5 (2500g) and 9 lbs.
Failure to Thrive (FTT) - is a growth deficiency occurring during infancy and early childhood.
It is attributable to psychosocial and/or biological factors. Generally, length, weight, and height
are below the 3rd percentile for age. There may be environmental factors contributing to the disorder
including inadequate nutrition, inconsistent parenting, and environmental neglect. Organic disease is
present in less than 50% of children typically diagnosed with FTT.
- AGA - appropriate/average for gestational age - birth weight between 10 and 90th percentiles
- LGA- large for gestational age - birth weight above the 90th percentile
- SGA - small for gestational age - birth weight below the 10th percentile
- LBW - low birth weight - less than 2500 g
- full-term infant weight less than 5.5 lb. is consider SGA and LBW
- preterm infant weighing less than 5.5 lb. is considered LW not necessarily SGA
- VLBW - very low birth weight - birth weight is less than 1500 g
- ELBW - extremely low birth weight - birth weight is less than 1000 g
- Micropreemie - birth weight is less than 750 g
BIOMECHANICAL ASPECTS OF GROWTH
Mechanical forces, mediated by genetic and chemical factors, influence the child’s growth from the
earliest weeks of development.
Examples of joint and bone malalignment:
- Plasticity of adjacent tissues leads to complex series of motions that either constrain or allow growth.
- Movement is an essential factor to complete joint development during the second and third prenatal months.
Fetal akinesia sequence - results in multiple congenital contractures
Spina bifida infant may demonstrate less movement
- Muscle cells align developmentally according to the direction of pull placed upon them. Muscles appear more
compliant than bone to force and thus respond to stretch by lengthening.
- Bone appears to be noncompliant as compared to muscle. Wolff’s law describes the association between bone
structure and mechanical demands placed on it.
- Deforming forces appear to have much greater impact on the lower extremity than the upper extremity in
- Scoliosis and kyphoscoliosis - may develop prenatally due to the development of wedge-shaped vertebral bodies
or fused vertebrae. The most common reasons appear to be related to asymmetrical muscle pull or lack of support of
the trunk related to paralysis. Cerebral palsy, spina bifida, spinal muscle atrophy, poliomyelitis, osteogenesis
imperfecta, and muscular dystrophies are all contributing conditions to joint or bone malignment.
- Coxa valga- increased angle of inclination of the femoral neck relative to the femoral shaft when viewed in the
frontal plane. Abnormal stresses may negatively influence acetabulum develop and contribute to an increased risk of
- Coxa vara - decreased angle of inclination of the femoral neck relative to the femoral shaft when viewed in the
frontal plane. Decreased pressure on the acetabulum and increased bending stress on the femoral neck leads to
predisposition for femoral neck fractures and slipped capital femoral epiphysis.
- Femoral anteversion - anterior rotation (version or torsion) in the transverse plane of the upper femur.
Infantile anteversion is present in cerebral palsy children with in toeing gait patterns.
- Femoral retroversion - posterior rotation in the transverse plane of the upper femur. Generally not seen as a
drawback to the normal person, and is an advantage for ballet dancers desiring hip external rotation.
- Genu valgus, varus - increased lateral (valgus), or medial (varus) knee angulation in the frontal plane. It may
be due to hamstring, quadriceps, hip adductor, or hip abductor weakness or spasticity.
- Medial, lateral tibial rotation - tibia rotates in relation to femur at the knee joint. It is very common in
neonates and is often due to ligamentous laxity.
- Medial, lateral tibial torsion - rotation within the tibial shaft leading to spiral development of the bone
associated with muscle imbalance of the knee-ankle and ankle-foot muscles especially in children with spastic
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