Malnutrition is the most common cause of short stature and growth failure worldwide. Many families do not follow recommended dietary guidelines because of poverty, lack of knowledge, or lifestyle. Some children and adolescents have dysfunctional eating patterns, participate in activities that promote weight control or weight loss, and/or have overt eating disorders. Undernutrition, commonly represented by low weight-for-length or body mass index, may be an isolated factor or due to underlying disease that either interferes with nutritional intake or absorption, or increases energy needs.13 Micronutrient deficiencies, such as iron, zinc, or vitamin D deficiency can interfere with growth.
Many systemic and chronic diseases are associated with poor growth and, in some cases, growth failure may be the presenting and only sign of the underlying disease. Diseases that may affect growth include gastrointestinal disease (eg, celiac disease, Crohn’s disease, chronic liver disease), renal disease (eg, renal tubular acidosis, chronic kidney disease), pulmonary disease (eg, severe asthma, cystic fibrosis), cyanotic heart disease, metabolic disease (eg, inborn errors of metabolism, poorly controlled diabetes mellitus), rheumatologic disease (eg, juvenile idiopathic arthritis), chronic infections (eg, tuberculosis, HIV), and cancer before or after diagnosis and treatment. Some treatments may interfere with growth, including medications (eg, prolonged and/or excessive corticosteroids, stimulants, antineoplastic agents) and radiation therapy to the head, neck, and spine.
Infants with a birth weight or length less than 2 SD below mean for gestational age are classified as small for gestational age (SGA). Infants may be SGA related to maternal, placental, or fetal factors and have health risks including poor growth. Most infants born SGA have catch-up growth by 2 years of age; however, approximately 10% fail to have sufficient catch-up growth and should be referred to endocrinology.14
Hypothyroidism is the most common endocrine cause of growth failure. Compromised linear growth is far more common than weight gain in children with hypothyroidism. Bone age is often delayed and, as a consequence, puberty may be delayed as well. Occasionally, children with severe hypothyroidism have precocious puberty. Other signs and symptoms may be subtle and their presence varies from child to child, including lethargy, constipation, cold intolerance, dry skin, goiter, bradycardia, fluid retention, delayed deep tendon reflexes, muscle hypertrophy, and decreased school performance. Infants with untreated hypothyroidism are at risk for mental retardation. Children with hypothyroidism are treated with thyroid hormone replacement.
Growth hormone deficiency (GHD) affects approximately 1 in 4000 to 10,000 children. GHD can result from disruption of the GH axis in the higher brain, hypothalamus, and pituitary, and can be congenital or acquired.15 Children with GHD may have a cherub-like facial appearance with flat nasal bridge and midface hypoplasia. Midline defects, such as a single central incisor or cleft palate, may be present.16 Children with congenital GHD may present with neonatal hypoglycemia, prolonged jaundice, micropenis, and early growth failure.16 Because bone age is delayed, puberty is commonly delayed in a child of pubertal age. The majority of cases of pediatric GHD are isolated and idiopathic; these children may have no obvious physical findings other than growth failure. Organic causes include central nervous system tumors, malformations, radiation, trauma, infection, leukemia, and histiocytosis.17–19 All children with GHD should undergo contrast-enhanced MRI of the brain prior to treatment, with narrow cuts through the hypothalamic-pituitary region, to identify structural abnormalities of the pituitary and rule out an intracranial tumor. They should also be monitored for other pituitary hormone abnormalities. Patients with hypopituitarism and/or history of cranial irradiation are at risk for ongoing GHD into adulthood.20 GH insensitivity syndromes—inherited disorders in which there is severe growth failure, normal or elevated levels of GH, and low levels of IGF-1 and IGFBP-3—are very rare. These children do not respond to GH treatment but may respond to IGF-1 therapy.13
Cushing syndrome is characterized by obesity with central fat distribution and concomitant growth failure, unlike the weight gain associated with exogenous obesity. Other signs and symptoms include hypertension, skin changes (eg, hirsutism, striae, acanthosis nigricans, acne, easy bruising), virilization, delayed puberty and amenorrhea, headaches, glucose intolerance, fatigue, osteopenia or osteoporosis, delayed bone age, and neuropsychological changes.21 Cushing syndrome is very rare in children and results from prolonged exposure to excess glucocorticoids.22 Causes include adrenal tumors, pituitary tumors, and ectopic ATCH-producing tumors. Exogenous steroid use to treat chronic illnesses (eg, Crohn’s disease, juvenile idiopathic arthritis, or asthma) may lead to similar symptoms.
Children with delayed puberty grow slower compared to their peers during the adolescent age. On the other hand, children with precocious puberty, whether gonadotropin-dependent or gonadotropin-independent, have increased secretion of sex steroids. The increased secretion of these hormones leads to accelerated growth and rapid advancement in skeletal maturation. When precocious puberty is left untreated, early epiphyseal closure can lead to adult short stature.
Idiopathic short stature is a condition in which the child’s height is less than 2 SD below the mean for age and sex in the absence of familial short stature; constitutional delay; or systemic, endocrine, nutritional, or chromosomal abnormalities.23 These children do not have GH deficiency, although GH treatment may be considered.
Turner syndrome affects approximately 1 in 2500 females at birth. Girls with Turner syndrome have a complete or partial absence of 1 of their 2 X chromosomes, with or without cell line mosaicism. The major features are short stature, growth failure, and gonadal dysgenesis. The clinical spectrum of abnormalities is broad but variable from girl to girl. Karyotype should be considered in “any female with unexplained growth failure or pubertal delay or any constellation of the following clinical findings: edema of the hands or feet, nuchal folds, left-sided cardiac anomalies especially coarctation of the aorta or hypoplastic left heart, low hairline, low-set ears, small mandible, short with GV less than the 10th percentile for age, markedly elevated levels of FSH, cubitus valgus, nail hypoplasia, hyperconvex uplifted nails, multiple pigmented nevi, characteristic facies, short 4th metacarpal, high arched palate, or chronic otitis media.”24
PWS is a rare genetic disorder in males and females that arises from lack of expression of paternally imprinted genes on chromosome 15 (q11-13) and is the most common syndromic form of obesity.25 Characteristics include hypotonia and feeding problems in infancy, developmental delay and learning problems, behavior and psychiatric problems, hypogonadism, hyperphagia leading to obesity, and short stature. GH therapy is used in children with PWS who do not have upper airway obstruction or sleep apnea to improve linear growth and body composition.
Short stature homeobox-containing gene (SHOX) deficiency results from a mutation in SHOX gene on the distal end of the X and Y chromosomes.26 Children with SHOX deficiency have short stature and skeletal deformities. The SHOX mutation is associated with Turner syndrome and other conditions.
Noonan syndrome is an autosomal dominant non-chromosomal disorder affecting 1 in 1000 to 2500 live births, although de novo mutations may occur. Common characteristics include facial dysmorphism, short stature, chest deformity, and congenital heart disease (eg, pulmonic stenosis, hypertrophic cardiomyopathy).27,28
Trisomy 21 is associated with short stature, although these children are identified by other characteristics. Other syndromes are associated with intrauterine growth retardation and postnatal growth failure, such as Russell-Silver syndrome, Cornelia de Lange syndrome, and Seckel syndrome.
Causes of disproportionate short stature (limbs disproportionately short for trunk, or trunk disproportionately short for limbs) include skeletal dysplasias, osteogenesis imperfecta (although they may have proportionate short stature if bone fragility leads to generalized fractures), and spinal irradiation.
Indications for GH Therapy
FDA-approved indications for recombinant human GH (somatropin) in the pediatric and adolescent populations include GHD, chronic renal insufficiency, Turner syndrome, PWS, SGA without catch-up growth, idiopathic short stature, SHOX deficiency, Noonan syndrome, and transition patients with documented and persistent growth hormone deficiency.” 20,29,30
Efficacy and Safety of GH Treatment
The primary goals of GH therapy are to restore normal growth in children with GHD and to enable them to achieve a normal height relative to their target height if treated at an early age. Higher doses and continuous therapy typically demonstrate greater efficacy.31 IGF-1 levels can be useful in determining optimal GH dosage for each patient.31 The use of GH therapy in non-GHD children can also increase adult height for patients with Turner syndrome, Noonan syndrome, chronic renal insufficiency, SGA, SHOX deficiency, and PWS.32 There is only a modest increase in height for children with idiopathic short stature, and this result is somewhat unpredictable.32
Contraindications to GH treatment include acute critical illness, children with PWS who are severely obese or have severe respiratory impairment, active malignancy, active proliferative or severe non-proliferative diabetic retinopathy, growth promotion in children with closed epiphyses, and known hypersensitivity to somatropin or excipients.33
The most frequently observed adverse reactions include injection site reactions/rashes and fluid retention (ie, edema, arthralgia, myalgia).33 The most serious adverse reactions include glucose intolerance, headaches due to intracranial hypertension, significant diabetic retinopathy, slipped capital femoral epiphysis and progression of preexisting scoliosis in children, pancreatitis, secondary neoplasms in patients with a history of cranial radiation for first neoplasm, and sudden death in patients with PWS with risk factors such as sleep apnea.33 Rarely a patient may develop neutralizing antibodies to GH, which reduces its effectiveness.34 While studies have shown GH to have a favorable safety profile, the long-term safety has been the subject of clinical debate.35–37
Clinical Advances in GH Delivery Systems
GH is prescribed as a daily subcutaneous injection. There is no evidence that time of administration makes a difference, although bedtime is generally chosen because the pituitary gland release of GH peaks during sleep. Innovations in GH delivery devices include single-use syringes preloaded with GH and diluent, reusable and disposable pen injection devices with multi-dose vials, small-gauge needles, automatic needle insertion, electronic injection, and needle-free devices. Since the introduction of pen injection devices for the administration of GH, treatment adherence has improved.38
GH continues to be an area of research. There is still controversy over what dose gives the best results with the least risk. Research continues to investigate which diseases benefit from GH therapy. Some growth disorders will not respond to GH therapy. Newer formulations of GH therapy are in clinical trials. LB03002, a once-weekly sustained release injection, has been assessed in children with GHD and was comparable to daily injections.39,40 Another once-weekly therapy has been shown to be effective in children with GHD. Participants demonstrated the typical catch-up growth that occurs with daily administration.41 A phase 3 trial is underway to assess VRS-317 in children with GHD. The trial will assess once weekly, semi-monthly, and once monthly administration.42 Investigations are ongoing to assess dosing options, additional indications, and new formulations.
Health Consequences of Delayed Diagnosis
Failure to recognize pathologic growth can lead to missed or delayed diagnoses of systemic, endocrine, nutritional, and genetic disease. Children may be referred and evaluated too late to receive effective treatment for their condition. Early diagnosis and treatment can improve the clinical outcomes of disease. In addition, time is needed to reverse growth deficits and once epiphyses are closed, stature will not improve. GHD is also associated with decreased bone mineral density and adverse effects on body composition and lipid metabolism. Delayed diagnosis can preclude opportunities for bone mineral density to increase with GH therapy, contributing to osteoporosis and other problems in adulthood.43 The following cases demonstrate some consequences of delayed diagnosis and treatment.
Clinical Case 1
A 4-year, 2-month-old male presented for a well-child visit. His primary care clinician was concerned that his height was less than what was recorded at previous 2 visits (Figure 3). Height was re-measured and was the same as the previous measurement that day. His mother reported that he had been previously measured with his shoes on. History was remarkable for septo-optic dysplasia diagnosed at 15 months of age. The MRI had showed bilateral optic nerve hypoplasia and absence of septum pellucidum. Physical examination was remarkable for nystagmus, strabismus, pale optic discs, and developmental delay. His primary care clinician was not aware of the association of septo-optic dysplasia with pituitary dysfunction. Endocrinology evaluation was remarkable for bone age of 2 years, hypoglycemia, and low IGF-1 and IGFBP-3. GH stimulation testing revealed a peak GH of 1.2 ng/mL (normal response >10 ng/mL) and a normal cortisol response. (Note: Some endocrinologists would not perform a GH stimulation test due to his growth failure, low IGF-1 and IGFBP-3, and known risk factor for GHD). A repeat MRI confirmed previous findings as well as absence of the posterior pituitary bright spot. He was started on GH therapy and monitored for other pituitary hormone abnormalities.
Clinical Case 2
A 17-year, 6-month-old female was referred to endocrinology for primary amenorrhea. History was remarkable for being small for gestational age, recurrent otitis media, and difficulty with math. GV was less than expected; height was -2.9 SD and significantly less than target height range (Figure 4). Physical examination was remarkable for high arched palate, mild thyromegaly, grade I/VI systolic ejection murmur over right upper sternal border, multiple nevi, breasts Tanner stage II, and pubic hair Tanner stage IV. Bone age was 15 years. Initial laboratory studies were remarkable for anemia, elevated TSH and slightly low free T4, elevated tTG IgA antibodies, markedly elevated LH and FSH, and prepubertal estradiol. A standard 30-cell karyotype was performed and revealed 45,X/46,XX (mosaic Turner syndrome). Further evaluation confirmed comorbidities of iron deficiency anemia, autoimmune hypothyroidism, celiac disease, small uterus and streak ovaries, bicuspid aortic valve, horseshoe kidney, mild sensorineural hearing loss, nonverbal learning disorder, and osteopenia. She was subsequently started on levothyroxine, estrogen replacement, calcium, and vitamin D, and referred to other specialties and services. Since her epiphyses were nearly fused, it was too late to prescribe GH therapy.
Growth should be monitored throughout childhood, and growth charts are indispensable tools that should be used at each visit. Normal growth variants include familial short stature or constitutional delay. Abnormal growth variants include systemic, endocrine, and genetic disorders. Referrals to appropriate specialists should be made as necessary. Delaying treatment can result in poor outcomes for the child. Patient and family education should stress the importance of adherence to therapy. Novel GH formulations and dosing strategies are currently in development. Clinicians should be aware of signs and symptoms, appropriate diagnostic strategies, and treatment indications so that they can improve outcomes for their patients.
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