Causes of growth delay
Benign causes of short stature include constitutional delay of growth and
development and genetic short stature. If these normal variants of growth are
deemed unlikely, however, it is important to investigate further, in order to
identify and treat a potentially serious condition initially manifesting as
delayed growth.
A pattern of growth deceleration may indicate:
- Inflammatory bowel disease or other gastroenterologic
or inflammatory processes
- Craniopharyngioma or other causes of acquired
pituitary insufficiency
- Inadequate assimilation of nutrients
- Renal insufficiency or abnormal renal handling of
transported substances such as potassium, phosphorus, or acid
- Heart failure
- Liver dysfunction
- Neoplastic processes
- Hormone abnormalities
- Growth plate abnormalities
- Psychosocial deprivation
Prenatal growth delay
In order to assess growth patterns, pediatricians should first explore
whether slow growth began prenatally. Conditions associated with prenatal growth
delay include maternal undernutrition, placental insufficiency (such as vascular
disease), teratogenic substances (including pharmaceuticals, ethanol, smoke, and
cocaine), intrauterine infections, chromosome abnormalities, various syndromes
and idiopathic intrauterine growth retardation.[1,2]
A history of maternal nutrition, maternal illness, and maternal
treatments and ingestions may give important clues. Physical findings such as
jaundice, petechiae, hepatosplenomegaly, cataracts, chorioretinitis,
microcephaly, and hydrocephalus, suggest intrauterine infection. Appropriate
cultures (especially of urine), antibody studies, bone radiographs, head
computerized tomography, and ophthalmology evaluation allow detection of most
intrauterine infections.
Careful measurement of lower body segment (upper border of pubic bone to
feet), arm span, and head circumference allows detection of disproportion, which
may suggest chromosomal or syndromal problems. Skeletal survey, karyotype and
genetic consultation may help in identifying these conditions.
Conditions which need not be considered in patients whose growth
retardation began in utero include constitutional delay of growth and
development, genetic short stature, growth hormone deficiency, and
hypothyroidism.
Patterns of growth delay in infancy
Poor weight gain prior to poor growth in length:
A common cause of infantile growth delay is inadequate assimilation of
nutrients. This problem manifests as poor weight gain occurring prior to
appearance of poor growth in length.[3] Additionally, the weight gain deficit is
often more marked than the deficit in growth in length.
Inadequate assimilation of nutrients may occur because of undernutrition,
inadequate digestion, or malabsorption. While diet history may point to
undernutrition, this determination is more challenging in breastfed infants. The
family may give a history of emesis, diarrhea or steatorrhea.
The possibility of maldigestion or
malabsorption may be reflected in excessive stool fat (quantitative and
qualitative). Also, the quantity and quality of stool fat can suggest the cause of
steatorrhea. If there is mild steatorrhea (7% to 10% of ingested fat) and if the fat is
in the form of fatty acid crystals, then intestinal malabsorption is
likely. Ifthereisseveresteatorrhea(>15%) and if the fat is in the form of fat globules, then
maldigestion is more likely.
Pediatricians are keenly aware that undernutrition may result from
parental neglect. For this reason, investigation of undernutrition should
include thorough examination of the social milieu.
Normal weight gain with decelerated growth in length:
With this growth pattern, deficiencies in secretion of growth hormone or
thyroid hormone are the major hormonal abnormalities to be considered. Excessive
cortisol secretion is another potential cause. Also, a number of skeletal
dysplasias and, occasionally, inflammatory conditions,[4] as well as illnesses
in various organ systems can produce this pattern of growth.
Parallel decrease in weight gain and in growth in length:
Individuals with this growth pattern could have growth hormone deficiency
or other conditions noted in the discussion of normal weight gain with
decelerated growth in length. Parallel decreases in weight gain and in growth in
length may suggest systemic illness, such as heart failure, inflammation (eg,
inflammatory bowel disease or arthritis), renal insufficiency, or hepatic
insufficiency.
However, this may also be a characteristic pattern for infants with
variants of normal growth – genetic short stature and constitutional delay in
growth and development. According to a common guideline, infants who have
crossed 2 major growth percentiles warrant investigation. This guideline has
recently been questioned, since approximately one-third of infants up to 6
months of age may fall within the group requiring further study. Between 6
months and 24 months, approximately 10% of infants cross 2 major
percentiles.[5]
Both genetic short stature and constitutional delay of growth and
development are characterized by normal birth size. In both conditions, growth
velocity becomes normal by 2 to 3 years of age. After 2 to 3 years of age,
growth proceeds at a normal velocity along a percentile line within the normal
range or parallel to (but below) the normal curve. In genetic short stature, the
bone age is close to the chronological age, and puberty occurs at the normal
time. In constitutional delay of growth and development, the bone age is
delayed, and puberty occurs later than in most children. Since closure of the
growth centers is hastened by sex steroids (especially estrogen) and since
closure of the growth centers is the cause of post-pubertal growth cessation,
children with constitutional delay of growth and development are able to grow
for a longer period of time than are other children. This prolonged time of
growth allows individuals with constitutional delay to enjoy catch-up growth in
the latter part of puberty. In both constitutional delay and genetic short
stature, family history is frequently positive.
Patterns of growth delay after infancy
A major difference between normal growth in infancy and in the juvenile
period is that during the juvenile period, growth must maintain expected
constant velocity to be regarded as normal. Thus, height percentiles should
remain the same during this period of growth. Changes in height percentiles
warrant evaluation.
Declining weight gain prior to declining growth in height:
In children as in infants, poor weight gain preceding and being more
prominent than decelerated growth in height suggests failure to assimilate
nutrients. The evaluation should begin with assessment of caloric intake. If
intake is normal, then stool studies are indicated to examine possible
malabsorption or maldigestion. Also, systemic illnesses may produce a decline in
weight gain preceding a decline in height growth.
Concurrent slowing of weight gain and growth in height:
Systemic illnesses also may manifest as concurrent slowing of weight gain
and growth in height. Illnesses which might produce this pattern include heart
failure, renal insufficiency, acidosis, inflammatory conditions such as
inflammatory bowel disease and arthritis, and hepatic insufficiency. This
pattern may also be seen in some individuals with skeletal dysplasias. Children
with this growth pattern also may have deficiencies of growth hormone or thyroid
hormone, or excess glucocorticoids (Cushing syndrome).
Continued weight gain with decelerated growth in height:
This pattern suggests possible growth hormone or thyroid hormone
deficiency. Another possibility is cortisol excess. It may also occur in
individuals with skeletal dysplasias.
Another important cause of this pattern in post-infancy children is
psychosocial deprivation. These patients often present with a characteristic
pattern of behavior that includes a ravenous appetite (including ingestion of
abnormal amounts of usual foods, large amounts of condiments, and ingestion of
abnormal foods such as pet food.) Additionally, these patients often manifest
nocturnal roaming. They are unable to secrete growth hormone in response to
standard provocative tests, but do not have catch-up growth when treated with
exogenous growth hormone.[6–9]
Growth deceleration in peripubertal period:
Some individuals with constitutional delay of growth and development
manifest putatively worrisome growth in the peripubertal period. They grow at a
normal velocity after the infancy period until 10 to 12 years of age when growth
slows. If constitutional delay is the cause of this growth deceleration, there
is spontaneous growth acceleration in association with the pubertal growth
spurt. Unfortunately, the same growth deceleration may characterize pathologic
growth delay. Craniopharyngioma may present with this pattern. Thus, this
pattern of growth may be benign, but merits careful and complete
investigation.
See Table 1 for a summary of conditions that may present as specific
growth delay patterns.
Radiologic and laboratory evaluation of growth delay
One of the most important studies is determination of bone age. In older
children, this is usually accomplished by obtaining a radiograph of the left
hand and wrist. The film is taken with the palm facing downward and in contact
with the film cassette. The upper arm and forearm must be on the same plane as
the hand. In infants younger than 18 months of age, X-ray of the left hand and
wrist may be supplemented with one of the left knee and foot. Alternatively, a
radiograph of the left hemiskeleton may be utilized.
This study can help divide causes of short stature into those that result
from the endocrine and metabolic milieu of the growth centers (most commonly
manifested as delayed bone age) and those that reflect an intrinsic abnormality
of the bone or its growth centers (when bone age is the same as chronologic
age). In some children, growth is abnormally rapid during childhood and then
stops prematurely. Most commonly, this pattern results from early exposure to
sex steroids and is manifested by early sexual development and advanced bone
age.
Skeletal dysplasias should be considered if the bone age is not delayed
and/or if physical examination reveals disproportion in length of arms, legs,
trunk or in head size.[10] Skeletal dysplasias can be evaluated by performing a
radiologic skeletal survey and by a genetics consultation.
Inflammatory conditions can be studied by measuring erythrocyte
sedimentation rate, C-reactive protein, and complete blood count with
differential white blood cell count. Abnormalities in other organ systems can be
sought by measuring liver function, creatinine, blood urea nitrogen,
electrolytes, calcium, and phosphorus.
A preliminary set of studies to consider growth hormone deficiency
includes measures of insulinlike growth factor 1 (IGF-1) and IGF-binding protein
3 (IGF-BP3). The possibility of excessive cortisol secretion (Cushing syndrome)
can be studied by measuring free cortisol in a 24-hour collection of urine.
Another study that can indicate Cushing syndrome is midnight salivary
cortisol.
Children with low levels of IGF-1 may
have growth hormone deficiency or may be resistant to growth hormone. The most
common cause of growth hormone resistance is undernutrition. Intercurrent illness
may also cause growth hormone resistance. Less commonly, children have a
genetic abnormality in the growth hormone response mechanisms. In order
to distinguish growth hormone deficiency from growth hormone resistance, growth hormone
measurements are made. If the basal growth hormonelevelisquitehigh(>10ng/ml), then growth hormone
resistance is likely. However, lower basal levels of growth hormone may not
distinguish growth hormone resistance from deficiency. Under these
circumstances, provocative tests of growth hormone secretion are performed using
clonidine, insulin, arginine, levodopa, or glucagon.
All patients found to be growth hormone deficient must undergo magnetic
resonance imaging of the brain and pituitary gland. In order to adequately study
these structures, the neuroradiologist should take images of thin sections
through the pituitary and hypothalamus in axial, sagittal, and coronal planes
and should image with and without infusion of gadolinium. The need for dynamic
studies, comprising rapid sequences following gadolinium infusion, is not well
established in this setting.
Girls with short stature should have a karyotype to consider Turner
syndrome. This study is indicated even if a patient does not manifest typical
Turner syndrome features, such as webbed neck, cubitus valgum, short fourth and
fifth metacarpals, narrow palate, or cardiovascular abnormalities, such as
bicuspid aortic valve (with or without aortic stenosis) or coarctation of the
aorta.
Treatment of short stature
The principal reason to study abnormal growth in infants and children is
to identify conditions that may threaten health and life. Correction of many of
the pathologic conditions will result in normalization of growth. Renal tubular
acidosis, for example, results in growth deceleration; its correction with
bicarbonate or citrate produces catch-up growth. Effective treatment of
hypophosphatemia, zinc deficiency, undernutrition, malabsorption, maldigestion,
and inflammatory illnesses also corrects growth deficiency.
Treatment of hormonal abnormalities producing short stature is typically
associated with other benefits. Children with hypothyroidism enjoy improved
energy and bowel function following treatment. Children with growth hormone
deficiency often are more energetic and experience improved muscle function and
bone density after treatment.
Growth hormone is an approved indication for individuals with renal
insufficiency, Turner syndrome, persistent postnatal short stature following
intrauterine growth retardation, Prader-Willi syndrome, and idiopathic short
stature. Results of studies of the psychosocial benefits of these treatments are
mixed.[11] For this reason, the potential stress associated with injection of
growth hormone must be taken into account when deciding upon this treatment.
Potential side effects, such as insulin resistance, increased intracranial
pressure, sleep apnea, and possible increased risk of neoplasia, must also be
considered.[12–17]
Children with poor growth may have conditions that are not effectively
treated with growth hormone. This treatment also is not appropriate for children
with altered growth hormone response mechanisms, such as abnormal receptors or
abnormal signaling molecules downstream from the growth hormone receptor.[18,19]
Recently, some of these individuals have been treated with IGF-1. This
medication is now approved by the Food and Drug Administration for such
treatment.
Finally, the pediatrician should be vigilant for psychosocial stress. On
occasion, stress is produced by short stature (even if it is produced by a
normal variant of growth), and treatment of short stature can be extremely
salutary. On other occasions, stress is the cause of short stature, particularly
in psychosocial deprivation syndrome. Under these circumstances, correction of
psychosocial conditions produces rapid catch-up growth.
REFERENCES
[1.] Chernausek SD. Mendelian genetic causes of the short child born
small for gestational age Journal of Endocrinological Investigation 2006;29(1
Suppl):16-20.
[2.] Ergaz Z, Avgil M, Ornoy A. Intrauterine growth restriction-etiology
and consequences: What do we know about the human situation and experimental
animal models? Reproductive Toxicology 2005;20(3):301-322.
[3.] Krugman SD, Dubowitz H. Failure to thrive. American Family Physician
2003 Sep 1;68(5):879-884.
[4.]Wong SC,
Macrae VE, McGrogan P, Ahmed SF. The role of pro-inflammatory cytokines in
inflammatory bowel disease growth retardation. Journal of Pediatric
Gastroenterology & Nutrition 2006;43(2):144-155.
[5.] Mei Z, Grummer-Strawn LM, Thompson D, Dietz WH. Shifts in
percentiles of growth during early childhood: Analysis of longitudinal data from
the California
child health and development study. Pediatrics 2004
Jun;113:e617-e627.
[6.] Powell GF, Brasel JA, Blizzard RM. Emotional deprivation and growth
retardation simulating idiopathic hypopituitarism. I. Clinical evaluation of the
syndrome. New England Journal of Medicine 1967
Jun 8;276(23):1271-1278.
[7.] Powell GF, Brasel JA, Raiti S, Blizzard RM. Emotional deprivation
and growth retardation simulating idiopathic hypopituitarism. II. Endocrinologic
evaluation of the syndrome. New England Journal
of Medicine 1967 Jun 8;276(23):1279-1283.
[8.] Gohlke BC, Frazer FL, Stanhope R. Growth hormone secretion and
long-term growth data in children with psychosocial short stature treated by
different changes in environment. Journal of Pediatric Endocrinology 2004
Apr;17(4):637-643.
[9.] Gohlke BC, Khadilkar VV, Skuse D, Stanhope R. Recognition of
children with psychosocial short stature: A spectrum of presentation. Journal of
Pediatric Endocrinology 1998 Jul-Aug;11(4):509-517.
[10.] Halac I. Zimmerman D. Evaluating short stature in children.
Pediatric Annals 2004
Mar;33(3):170-176.
[11.] Radcliffe DJ, Pliskin JS, Silvers JB, Cuttler L. Growth hormone
therapy and quality of life in adults and children. Pharmacoeconomics
2004;22(8):499-524.
[12.] Swerdlow AJ. Does growth hormone therapy increase the risk of
cancer? Nature Clinical Practice Endocrinology & Metabolism 2006
Oct;2(10):530-531.
[13.] Sheppard MC. Growth hormone therapy does not induce cancer. Nature
Clinical Practice Endocrinology & Metabolism 2006
Oct;2(10):532-533.
[14.] Ergun-Longmire B, Mertens AC, Mitby P, et al. Growth hormone
treatment and risk of second neoplasms in the childhood cancer survivor. Journal
of Clinical Endocrinology & Metabolism 2006 Sep;91(9):3494-3498.
[15.] Dunger DB, Ong KK. Babies born small for gestational age: Insulin
sensitivity and growth hormone treatment. Hormone Research 2005;64(Suppl
3):58-65.
[16.] Wilson SS, Cotterill AM, Harris MA. Growth
hormone and respiratory compromise in Prader-Willi Syndrome. Archives of Disease
in Childhood 2006 Apr;91(4):349-350. [17.] Gerard JM, Garibaldi L, Myers SE, et
al. Sleep apnea in patients receiving growth hormone. Clinical Pediatrics 1997
Jun;36(6):321-326.
[18.] Laron Z. Prismatic cases: Laron syndrome (primary growth hormone
resistance) from patient to laboratory to patient. Journal of Clinical
Endocrinology & Metabolism 1995 May;80(5):1526-1531.
[19.] Rosenfeld RG. Molecular mechanisms of IGF-I deficiency. Hormone
Research 2006;65(Suppl 1):15-20. | 
