Constitutional Growth Delay


Article Author:
Daniela Aguilar


Article Editor:
Gabriel Castano


Editors In Chief:
David Wood
Andrew Wilt
Hajira Basit


Managing Editors:
Avais Raja
Orawan Chaigasame
Khalid Alsayouri
Kyle Blair
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beenish Sohail
Hajira Basit
Phillip Hynes
Sandeep Sekhon


Updated:
4/8/2019 8:13:03 PM

Introduction

Constitutional growth delay can result from several factors that result in short stature. Also, short stature can occur with different diseases, none the less, the definition of short stature is the same for both conditions; two standard deviation or more below the mean for children of that same-sex and chronologic age. Ideally, this should be matched to people of the same race as well, as stature variates depending on ethnic group. In some cases, short stature may be just part of the normal growth of the individual.

Familial (genetic) and constitutional are by far the most common causes of short stature and delay, which are benign, but the workup is done to identify those at risk of other more severe and probably treatable diseases (GH deficiency or idiopathic short stature (ISS). Early in childhood one of the most common causes is FFT.[1]

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 a delay 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, proinflammatory cytokines that some times 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 the growth hormone (GH) along 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 clniican 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) its 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 its 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 a delay 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 cortrosyn; 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

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: 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. Some times 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 follow the curve that correlates most of the times with their bone age.[10]

Complications

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

Enhancing Healthcare Team Outcomes

Short stature is present in about 10% to 15% of the general population, and it should be part of an interprofessional team of nurses and primary care providers in providing appropriate screening. A good follow up protocol, and well-documented growth charts are required to know when would be beneficial a referral to the pediatric endocrinologist.

It is important to remember that only about 3% of short stature patients have an actual endocrinologic problem that will need further treatment, which is why it is important to take a good history. If there is a concern in growth delay after proper height documentation, the patient needs to be sent for GH levels, IGF-1 and bone age. If this results within normal limits including a delay in bone age that correlates with the height of the patient, most likely it is safe to continue to monitor the patient. If taking this approach, and any of the laboratory workup or bone age are uncertain, or this type of lab workup cannot be done or properly interpreted, a specialist referral is in order. 

These are other recommendations on when to refer a patient[13]:

  • Any patient who is below two standard deviations on their height
  • Any patient whos growth velocity is below the expected one in a 6 to 12 months period follow up. (please see up for normal growth velocities by age)
  • Any patient that crosses two percentile lines for their height (even if still within "normal" standard deviations)
  • Patient with known or suspected comorbidities (thyroid disorder, turner, septo-optic dysplasia, etc.) - this type of population will need a full workup

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Constitutional Growth Delay - Questions

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Which of the following is not true about constitutional delay?



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A 12-year-old male has been persistently -2.4 standard deviations for height, with a growth velocity of 5 cm/year for the past three years, no onset of puberty yet. There is no relevant past medical history, and all his lab workup has been within normal limits. Growth hormone (GH), IGF-1, thyroid stimulating hormone, T4, and bone age are as expected. The father is 166 cm and the mother 157 cm. What should the family be told?



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A 10-year-old male with a complaint of short stature for three years. On past medical history, he had normal birth weight and length; the parents only notice dry skin. Vital signs are normal with height 109.4 cm and weight 27 kg. On physical exam, only positive is epicanthal folds with coarse facial features, dry, coarse hair, and dry skin. What lab workup would most likely reveal the most likely diagnosis?



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A 12-year-old female was referred for being short with 3.9 standard deviation score and normal weight. The mother denies any past medical history, and other than her short stature patient has been developing properly. There is a delay in puberty as well. Laboratories show TSH 5.5 mU/l, with low T4, elevated FSH, while IGF1 and IGBP3 are within normal limits. Will the patient be able to have children?



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A 5-year-old female that is brought in for a well-child exam with no past medical history. Vital signs are all within normal limits. The growth chart can be seen below. The mother is concern about her height, she believes she is too short compared to her classmates. The mother is 150 cm, base on the growth chart, what is a possible answer to the parents?

(Move Mouse on Image to Enlarge)
  • Image 9816 Not availableImage 9816 Not available
    image from the CDC, growth chart plotted by me
Attributed To: image from the CDC, growth chart plotted by me



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An 11-year-old female is seen for the first time in your clinic for a well child exam. The patient has no relevant past medical history, vital signs within normal limits, and she still has not had her first period. The patient plays soccer and is very active. The mother is 159 cm and dad 173 cm. The parents want to know if her growth is acceptable. Based on her growth chart what should the parents be told?

(Move Mouse on Image to Enlarge)
  • Image 9817 Not availableImage 9817 Not available
    from the CDC, plotted by me
Attributed To: from the CDC, plotted by me



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Constitutional Growth Delay - References

References

Colindres JV,Lee YK,Gonzalez MS,Shepherd P, Meeting Report: 2016 Annual Meeting of the Endocrine Society Boston, MA (April 1-4, 2016) Selected Highlights. Pediatric endocrinology reviews : PER. 2016 Sep;     [PubMed]
Hussein A,Farghaly H,Askar E,Metwalley K,Saad K,Zahran A,Othman HA, Etiological factors of short stature in children and adolescents: experience at a tertiary care hospital in Egypt. Therapeutic advances in endocrinology and metabolism. 2017 May;     [PubMed]
Rohani F,Alai MR,Moradi S,Amirkashani D, Evaluation of near final height in boys with constitutional delay in growth and puberty. Endocrine connections. 2018 Mar;     [PubMed]
Macfarlane A, Epidemiology of short stature due to growth failure. Journal of medical screening. 1995;     [PubMed]
Wei C,Candler T,Crowne E,Hamilton-Shield JP, Interval Outcomes of a Lifestyle Weight-Loss Intervention in Early Adolescence. Children (Basel, Switzerland). 2018 Jun 15;     [PubMed]
Brooks AJ,Waters MJ, The growth hormone receptor: mechanism of activation and clinical implications. Nature reviews. Endocrinology. 2010 Sep;     [PubMed]
Tommiska J,Wehkalampi K,Vaaralahti K,Laitinen EM,Raivio T,Dunkel L, LIN28B in constitutional delay of growth and puberty. The Journal of clinical endocrinology and metabolism. 2010 Jun;     [PubMed]
Kurnaz E,Çetinkaya S,Aycan Z, Near final height in patients with idiopathic growth hormone deficiency: A single-centre experience. Journal of paediatrics and child health. 2018 Nov;     [PubMed]
Bidlingmaier M,Freda PU, Measurement of human growth hormone by immunoassays: current status, unsolved problems and clinical consequences. Growth hormone     [PubMed]
Derraik JGB,Miles HL,Chiavaroli V,Hofman PL,Cutfield WS, Idiopathic short stature and growth hormone sensitivity in prepubertal children. Clinical endocrinology. 2019 Mar 25;     [PubMed]
Krieger CC,Morgan SJ,Neumann S,Gershengorn MC, Thyroid Stimulating Hormone (TSH)/Insulin-like Growth Factor 1 (IGF1) Receptor Cross-talk in Human Cells. Current opinion in endocrine and metabolic research. 2018 Oct;     [PubMed]
Gravholt CH,Andersen NH,Conway GS,Dekkers OM,Geffner ME,Klein KO,Lin AE,Mauras N,Quigley CA,Rubin K,Sandberg DE,Sas TCJ,Silberbach M,Söderström-Anttila V,Stochholm K,van Alfen-van derVelden JA,Woelfle J,Backeljauw PF, Clinical practice guidelines for the care of girls and women with Turner syndrome: proceedings from the 2016 Cincinnati International Turner Syndrome Meeting. European journal of endocrinology. 2017 Sep;     [PubMed]
Collett-Solberg PF,Jorge AAL,Boguszewski MCS,Miller BS,Choong CSY,Cohen P,Hoffman AR,Luo X,Radovick S,Saenger P, Growth hormone therapy in children; research and practice - A review. Growth hormone     [PubMed]

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