Constitutional Growth Delay

Etiology

Constitutional growth delay is seen in approximately 15% of children and can appear at different stages of their development. It's important to remember that growth velocity varies accordingly. Between 3 to 6 months to 2 to 3 years of age, the expectation is that some children will cross percentiles in their growth and weight charts without actual concerns for a delay in growth. This tendency will typically resume to a standard rate after this period. After four years of age, there is constant steady growth. It is not until puberty when one will notice that the child starts to divert from the curve, usually because they have late onset of puberty that corresponds to delayed bone age.[2][3]

Constitutional growth delay and familial short stature are the most common cause of short stature, which means, the child is growing at his/her normal rate and will eventually catch up to the curve if dealing with constitutional delay. In the second disease, familial short stature, the infant has a constant growth rate, but one or both parents are short. This situation typically occurs in parents whom mothers are below 152 cm and fathers 160 cm respectively. Within the differentials of this disease we find, endocrine disorders, that account for GH and IGF-1 disorders, pro-inflammatory cytokines that sometimes have direct affection at the growth plate. Deficiencies in intracellular pathways like SHOX gene affection, problems with cartilage and even paracrine mechanisms are also other causes for stature alteration.[3]

Hussein et al. conducted a prospective study in which they classify the short stature etiology, and found within their population that 26% were the result of endocrine disorders; 11.8% ad GH deficiency, of which 63.6% had normal GH variants, 15.8% had constitutional growth delay, while a combination of both was present in about 5%.[2]

Epidemiology

Estimates are that about 15% of patients referred to a specialist due to short stature have constitutional growth delay. It is twice as common in boys compared to girls; although some of the male referrals may be just concerns regarding their height compared to their peers rather than an actual delay.

The disease of constitutional growth delay is a diagnosis of exclusion. Therefore the proper way to assess this medical diagnosis is by short stature, which by definition affects about 3% of the population — defined as a growth velocity below 5cm a year (in the childhood age). This linear velocity change depends on the age group, that’s why it is also necessary to assess short stature and growth delay at different stages in life as it presents differently in a toddler (6  to 7cm), vs. childhood (5.5cm) and adolescence (girls 8 to 12cm boys 10 to 14cm).[4]

Pathophysiology

Normal growth is regulated by more than just genetics and hormonal principles; environmental factors such as psychological influences, physical activity, nutrition even climate play a role in how children grow.[5]

It is growth hormone (GH) along with insulin-like-growth factor 1 (IGF-1) the central mediators in growth. GH gene located on 17q22 is regulated under a very complex hormonal network, as every tissue in our body has a way to stimulate somatotrophs and GH expression; this occurs through the POU1F1. Its daily secretion occurs in a pulsatile matter, and there are times that if measured it is undetectable. Current thinking is that there are approximately ten pulses of secretions a day lasting about 90 minutes, each one of them 2 hours apart.[6]

Currently, the focus is on growth; linear growth velocity is a reliable indicator of a child's general health, mediated by different hormones and systems in the body, with the primary drivers being growth hormone, insulin-like growth factor 1, androgens, and thyroid hormone. All of these result in chondrogenesis. While at the same time steroids (glucocorticoids) inhibit chondrogenesis. It is important to remember that thyroid deficiency looks similar to GH deficiency and if suspicious of thyroid deficiency, the clinician should first correct the thyroid abnormality before performing the GH stimulation test.

The specific pathophysiology of constitutional growth delay is not very well established; it is known that there is an overall delay, meaning, all tissues are affected, which is why patients normally catch up on their normal growth pattern, it just starts later. Dr. Tommiska studied the gene LIN28B, which is believed to play a role in constitutional growth delay.[7]

Evaluation

Serial measurements of height are an essential parameter, remembering that growth, while continuous, is not always linear and that each phase is different (infantile, childhood, and pubertal). The infantile stage (0 to 24 months) is when the baby starts to grow at its own pace, there are no maternal factors, so it is natural for them to cross percentile curves (down or up). At this period the correlation to adulthood height will be 0.80 vs. intrauterine correlation is only 0.25.[8]

Remember to calculate the Z-scores and the mid-parental height with the following equation:

• For girls, subtract 13cm (5 inches) from the father’s height; that value is added to maternal height and averaged
• For boys, add 13 cm (5 inches) to the mother’s height; that value is added to the father’s height and averaged

After having accurate measurements and a good mid-parental height, one proceeds actually to answer the question; is the child truly short? If the child is below the 2.3 percentile, the diagnosis of short stature is made; below the 1 percentile is extreme short stature; then proceed to determine the etiology.

Any patient diagnosed with short stature should undergo further evaluation to determine if it's just constitutional growth delay or short familial statute. Further workup includes an endocrinology panel and bone age determination; this is done with an image of the left hand and wrist, most used methods to establish bone age are Greulich, Pyle atlas, and Tanner-Whitehouse 3 (TW3), this last one is believed to be the most accurate one. It’s important to remember that African Americans tend to have an advanced bone age and southeast Asians tend to have delayed bone age when compared to their peers.

As far for lab workup, it should begin with a full endocrinologic panel that will include other causes of short stature, including TSH, T4, bone age, IG1, IGFBP3, karyotype (if suspected), bone age, even imaging like MRI can be a consideration, and at last, the stimulation GH test is done. To get to this point, the clinician will need low serum concentrations of GH, IGF-1, and IGFBP-3.

GH stimulation test is the closest to there is to a gold standard to diagnose constitutional growth delay through ruling out GH deficiency. This is true for idiopathic short stature diagnosis as well. Some limitations of the study important to remember are that, increase BMI influences GH response as well as recent steroid use.

There are three approved drugs to do the stimulation, clonidine, glucagon, and cosyntropin; the test is done in a controlled environment (onsite clinic) and takes about 6 hours. Stimulant drugs are given (some IV other by mouth) and test for GH levels every 30 minutes (0, 30, 60, and 120) and then repeated with another stimulant. To diagnose GHD, there is a failure of GH to rise above 10 mcg/L with two stimulants.[9]

Treatment / Management

Specifically, for constitutional growth delay, there is no treatment other than reassurance and monitoring.

The use of GH therapy is actually approved for several diseases: GHD, renal insufficiency, Turner syndrome, Prader-Willi syndrome, SGA, idiopathic short stature., and a few others Currently no guidelines about treating constitutional growth delay.[10]

Differential Diagnosis

The differential diagnosis will vary depending on the clinical presentation as well as age; the most common differential diagnosis in infancy is the failure to thrive followed by cardiac abnormalities. As children grow the diagnosis becomes broader.

Delayed puberty: The patient will have short stature, but will also have other features that point towards a delay in puberty.

Hypothyroidism: Most often this condition is diagnosed in the first week of life, for some cases that are either mild at birth or go unrecognized, growth is very slow compared to GHD, having a very low percentile in their growth height.

GH insensitivity: there are reports of rare cases of patients who have malfunctioned GH receptors.

Turner syndrome: growth failure is universal in individuals with Turner syndrome, which results from haploinsufficiency of SHOX. Sometimes this disease has no evidence of skeletal dysplasia or other clinical anomalies but just the short stature.[11]

There is also a mass effect that results in comorbidities such as diabetes insipidus, hypopituitarism, GH deficiency.[12]

Prognosis

Excellent; children usually catch up, and growth follows the curve that correlates most of the time with their bone age.[10]

Complications

Other than psychological complications constitutional growth delay is a benign condition.[10]