Introduction to Short Stature

Disturbances of growth are the most common presenting complaints in the pediatric endocrine clinic.

Fetal growth is dependent on maternal factors (placental sufficiency, maternal nutrition, etc.), insulin-like growth factor-2 (IGF-2) and insulin.

Growth in late infancy and childhood is dependent on growth hormone/IGF-1 axis and thyroid hormone. Growth is more rapid during infancy—up to 20 cm per year. It is common to see shifts in the growth curve in the first 18 months when children are adjusting to their genetic potential growth isopleth. During childhood, growth rate is fairly constant at approximately 2 inches (approximately 5 cm) per year.
Pubertal growth is dependent on sex hormones as well as growth hormone/IGF-1 axis and the thyroid gland. There is a mild deceleration in growth velocity before initiation of pubertal growth spurt.

Abnormal growth and stature: criteria

• Child’s growth curve is crossing percentiles.
• Child’s growth rate is <2 inches or 5 cm per year.
• Height is >2 standard deviations (SDs) (4 inches/10 cm) below from midparental height.
• If poor weight gain and lack of nutrition is the problem without affecting height velocity, it is unlikely to be an endocrine cause and patient may warrant a gastrointestinal evaluation instead.

Etiology
Normal growth patterns that can look like a growth disorder

Genetic (familial) short stature. Children have normal growth velocity, normal timing of development and puberty, and bones fuse at the appropriate age. Height is short because of a short mother and/or a short father. Bone age (BA) = chronologic age (CA).

Constitutional delay of growth and puberty. Children have normal growth velocity, delayed timing of puberty, and delayed BA. There is a family history of late bloomers. Anticipate a less robust growth spurt.

Primary growth failure

• Chromosomal disorders such as Turner syndrome, Down syndrome, Noonan syndrome, Russell-Silver syndrome, Prader-Willi syndrome, and pseudohypoparathyroidism
• Skeletal dysplasias such as hypochondroplasias, achondroplasias, osteogenesis imperfecta, and Albright hereditary osteodystrophy

Secondary growth failure

• Prenatal onset
• Maternal hypertension, fetal alcohol syndrome, and congenital infections
• Small for gestational age (SGA). Infants are born with weights below the 10th percentile for their gestational age. Russell-Silver syndrome is one of the many syndromes that includes SGA in the features.
• Postnatal onset
• Endocrine, such as hypothyroidism, growth hormone deficiency, growth hormone resistance (Laron dwarfism), and glucocorticoid excess
• Nonendocrine, such as renal failure, renal tubular acidosis, malabsorption, cystic fibrosis, celiac disease, and Crohn disease

History

Physical history

• History of changes in growth pattern and onset of puberty
• History of chronic illnesses
• Prenatal exposures to toxins, drugs, or alcohol; use of other medications (e.g., steroids, psychostimulants)
• History of prematurity; weight for gestational age and catch-up growth

Social history

• History of adoption and ethnic background
• History of child abuse or neglect, which may give information supportive of psychosocial dwarfism

Family history

• History of pubertal development. Age of menarche in mother and age of physical changes or cessation of growth in father may give information that supports the diagnosis of constitutional growth delay.
• Family history of chronic diseases (e.g., inflammatory bowel disease, neurofibromatosis, mental retardation and calcium problems, renal disease). The child’s symptoms of these diseases are very important.

Physical Examination

• Abnormal facial features, shortening of fourth or fifth metacarpals, cognitive impairment, and skin lesions may be suggestive of genetic disorders.
• Arm span and upper-to-lower segment (U/L). Determination of the arm span and U/L ratio (lower segment is the measurement from the symphysis pubis to the floor) is useful to determine the etiologies of short stature. Examples:
• Short arm span or small legs and normal trunk (increased U/L ratio) may indicate skeletal dysplasia or hypothyroidism.
• Long arms and decreased U/L ratio may indicate hypogonadism.
• Arm span longer than height may also suggest abnormal spine growth.
• The U/L ratio varies with age and race: 1.7 at birth, 1.4 at 2 years, 1 at 10 years, ~0.9 at adulthood

Calculating midparental height (in centimeters)
For girls: (Father’s Height – 13 centimeters) ± (Mother’s Height)/2
For boys: (Mother’s Height ± 13 centimeters) ± (Father’s Height)/2
Target height is midparental height ± 2 SD (1 SD = 5 cm)

Measurement of growth
The growth curve is the most valuable instrument for assessing the problem. The pattern of growth of a normal child is very consistent, and deviations in the process may warrant concern and further evaluation.
Obtain length up to age 2 and height onward. Note that at age 3, the height at 50th percentile is 95 cm and for length is 96.5 cm.
It is important to be consistent and systematic in the way height is obtained. Always measure it without shoes, and when plotting the patient in the growth curve, be as accurate as possible regarding the actual age of the child. Be sure to correct for genu recurvatum or leg length asymmetries when obtaining the measurements. Do not forget that pediatric patients do not shrink, so if unsure of your measurement, remeasure the patient again.
It is strongly recommended that you use the metric system. The tendency to round off numbers becomes problematic when an inch is the measure.
BA: gives a level of bone maturation based on centers of ossification and closure of epiphyses.
Up to a CA of 2 years, a hemiskeletal BA is more accurate; after that, obtain a left hand/wrist radiograph using the method of Greulich and Pyle.

Laboratory Studies

• General screening tests: CBC with differential; BMP; urinalysis; bone age; T4 and TSH; IGF-1 (>5 years of age)
• Specialized tests: karyotype; growth hormone stimulation test; dexamethasone suppression test
• Growth hormone stimulation test
• There is no gold standard test for the diagnosis of growth hormone deficiency.
• Growth hormone stimulation tests are needed because of the pulsatile nature of growth hormone release. A growth hormone level by itself is meaningless in the evaluation of short stature. Provocative agents include clonidine, L-dopa, arginine, insulin, glucagon, and growth hormone–releasing hormone.
• The tests should be performed by an endocrinologist.
• Up to 25% of normal children fail any given stimulation test, so it is important to consider the rest of the clinical picture and document abnormal results using two different agents to classify a patient as growth hormone–deficient. It is considered a pass if the stimulation test has a peak growth hormone response >8 ng/mL.

Treatment (Growth Hormone Therapy)
Food and Drug Administration–approved indications for the use of growth hormone

• Growth hormone deficiency
• Turner syndrome
• Renal insufficiency
• Prader-Willi syndrome
• SGA
• Idiopathic short stature (predicted target height: girls: <4?11; boys: <5?3)

Effectiveness: best response in the first year of therapy

Administration and dosage

• Give as a subcutaneous injection starting at 0.3 mg/kg/wk given 6–7 day/wk.
• For patients with Turner syndrome, give 0.35 mg/kg/wk.

Cost: expensive
Adverse effects: slipped capital femoral epiphysis, glucose intolerance/diabetes, pseudotumor cerebri, scoliosis.