Role of Growth Hormone Therapy in Craniofacial Development of Children with or without Growth Hormone Deficiency

Abstract

Objective

To evaluate effect of growth hormone (GH) therapy in craniofacial development in children with or without growth hormone deficiency.

Method

The systematic review was conducted by searching the electronic databases—PubMed, Cochrane clinical trials register, Google scholar, and EBSCO host. Randomized controlled trials and observational studies published till January 2022 were included. The risk of bias was assessed by Risk-Of-Bias VISualization (ROBVIS) tool. The risk of bias of the included studies was presented as a “traffic light” plot of individual studies and a summary diagram. Data was studied by two authors and any dispute was resolved by another reviewer.

Result

A total of 964 articles were obtained through electronic database search. After eliminating the duplicates, 13 articles met inclusion criteria. Of the 13 studies, 8 studies had moderate risk of bias, 2 had serious risk of bias, and 1 had critical risk of bias as per the ROBINS-I assessment. According to the RoB 2, two studies were having high risk of bias.

Conclusion

The maxillary length, the mandibular length, and the cranial base length increased post-GH therapy, causing an overall increase in the facial height. The limitation of GH therapy was in the transverse direction as maxillary and mandibular arch dimensions remained almost equal to those in the untreated subjects. Dentition had minimal influence of GH therapy.

Registration

The systematic review was registered in the International Prospective Register of Systematic Reviews database under CRD42021257044.

Keywords

Craniofacial development growth hormone growth hormone therapy mandibular growth orthodontic

Introduction

Understanding the growth and development of craniofacial complex is an integral part of orthodontics. Since the beginning of dentofacial orthopedics, efforts have been made to fabricate appliances for modifying/redirecting the facial growth in a favorable way. Genetics, hormones, nutrition, and environment are some of the multiple factors that impact craniofacial growth.¹

Growth hormone is one such hormone which has a significant role in craniofacial growth. An excess or lack thereof causes jaw deformities which may hamper the aesthetic harmony of face due to disproportionate facial features. GH, which is secreted by the pituitary gland, plays an important role in longitudinal bone growth.² Growth hormone deficiency (GHD) is a disease that leads to growth disturbances, mainly short stature, because of inhibited pituitary gland hormones. The etiology can be classified as idiopathic, organic, or genetic.³

Since the first patient was treated with pituitary-derived GH in 1958,⁴ numerous studies have documented beneficial effects of GH treatment on linear growth in both GH-deficient and non-GH deficient subjects (idiopathic short stature).^{5, 6} Study by Segal et al⁷ focused on effects of GH on other GH-dependent areas such as hand and foot size apart from head circumference.

A case report by Newman and Newman⁸ included a longitudinal study of six years of an 11-year-old male with hypopituitarism and retrognathic mandible. GH along with orthodontic therapy enhanced the condylar growth and thus increased the mandibular length post treatment. Wang et al⁹ conducted an experiment on adolescent rat model to analyze the role of GH in supplementing orthodontics/functional appliance therapy and found enhanced condylar growth at the end of experiment. Another case of a girl with idiopathic short stature reported by Hwang and Cha¹⁰ showed positive effects of GH therapy with orthodontic treatment on facial profile improvement. The lack of randomized controlled trials (RCTs) in this subject could be attributed to ethical issues of leaving a group of patients untreated as the effect of GH is dependent on the age at which therapy is started other than the length of administration.

The primary question was—“Does growth hormone therapy play a role in enhancing craniofacial growth in growth hormone-deficient children or those who may not have growth hormone deficiency (such as idiopathic short stature)?” This systematic review aims to shed light on the existing studies on GH therapy and its effects on craniofacial development in children. Secondary aim was to assess whether GH therapy supplements orthodontic treatment in improving the profile of children with or without GHD.

Material and Methods

Protocol and Registration

This systematic review was registered in the International Prospective Register of Systematic Reviews database under CRD42021257044 (PROSPERO database (http://www.crd.york.ac.uk/PROSPERO)). It was undertaken to answer the question whether GH therapy plays a role in craniofacial development in children and whether it supplements in improving the craniofacial development in children with or without GHD.

It followed the PICO criteria¹¹ where the population (P) was children with or without GH deficiency, intervention (I) was GH administration, control was children who did not receive GH therapy, and outcome (O) was changes in the craniofacial development.

Selection Criteria

Inclusion criteria:

RCTs, controlled clinical trials, and prospective and retrospective longitudinal studies. No restrictions were set for sample size.

Only human studies were included.

Articles written in English were included.

Studies published till January 2022 were included.

Exclusion criteria:

Abstracts, lab investigations, descriptive studies, case reports, case series, reviews, and papers with an opinion were disregarded.

In order to eliminate the effects of genetics and other interventions as additional confounding factors, studies done only on syndromic patients (such as Down syndrome, Silver Russell syndrome, etc.) and involving other interventions such as therapy with other hormones along with GH therapy were excluded.

Search Strategies

Two writers (SK and US) each conducted the primary research for this systematic review, while the third author (SB) dealt with any conflicts. From their launch date until January 2022, the following electronic databases were searched: PubMed, Google Scholar, Cochrane Library, and EBSCO host. On the basis of the lists of references from the articles that were obtained from the main databases, a number of manual searches were also carried out. There were just English-language articles present.

Medical Subject Headings (MeSH) terms were mixed with keywords, free-text phrases, and the proper Boolean operators for PubMed in the search process. Each database required a different search approach. A similar collection of MeSH terms and phrases was used for an advanced search on each database. Table 1 lists the specific MeSH phrases and keywords, as well as the combinations of MeSH terms and keywords or free-text words, that were employed in various databases.

Table 1.

MeSH Terms and Keywords Used for Research.

Search Number	MeSH Terms and Keywords Used in Study (PubMed and Cochrane Clinical Trials)
1	(“human growth hormone/therapeutic use”[MeSH Terms]) AND (“mandible”[MeSH Terms])
2	(“human growth hormone/therapeutic use”[MeSH Terms]) AND (maxilla[MeSH Terms])
3	(growth hormone[MeSH Terms]) AND (“mandible”[MeSH Terms])
4	(“growth hormone”[MeSH Terms]) AND (“maxilla”[MeSH Terms])
	Boolean phrases used (All Text of EBSCO host)
1	growth hormone therapy in children AND craniofacial growth
2	growth hormone therapy in children AND maxilla
3	growth hormone therapy in children AND mandible
4	Human growth hormone AND craniofacial growth
	Other search strategies (Google scholar)
1	(maxilla) OR (mandible) “growth hormone therapy”
2	(maxilla) OR (mandible) OR (craniofacial) “growth hormone therapy in children”

The list of search engines used and the results obtained are presented in Table 2. Table 3 presents the articles that were excluded after reading along with the reason for exclusion. The studies’ identification and selection process is displayed as a PRISMA flow diagram, as seen in Figure 1.

Table 2.

List of Search Engines and the Results Obtained.

Search Engine	Number of Articles
PubMed	94
Cochrane Clinical Trial	21
EBSCO host	26
Google Scholar	823
Total	964

Table 3.

List of Excluded Studies.

No.	Title	Reason for Exclusion
1	. 2007;13(4):210–212. Pediatr Endocrinol Diabetes Metab Kawala B, Matthews-Brzozowska T, Bieniasz J, Noczyńska A. Dental and skeletal age in children with growth hormone deficiency treated with growth hormone-preliminary report.	Original language of report is Polish.
2	. 2010;48(6):591–595.Rev Med Inst Mex Seguro Soc Salas-Flores R, González-Pérez B, Barajas-Campos RL, Gonzalez-Cruz B. Changes on craniofacial structures in children with growth-hormone-deficiency.	Only summary is available in English. Full text is available is Spanish.
3.	. 1991;99(1):44–47. doi:10.1111/j.1600–0722.1991.tb01021.x. Scand J Dent Res Dahllöf G, Forsberg CM, Näsman M, et al. Craniofacial growth in bone marrow transplant recipients treated with growth hormone after total body irradiation.	Ethinylestradiol and thyroid hormone supplements given along with growth hormone.

Figure 1.

Source: Moher D, Liberati A, Tetzlaff J, Altman DG; The PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med. 2009;6(7):e1000097. doi:10.1371/journal.pmed.1000097.

Results

A total of 964 articles were identified after the electronic search (PubMed, Cochrane Library, Google Scholar, EBSCO host). Duplicate articles were eliminated and 117 articles were selected for primary screening of titles and abstracts. A total of 16 articles qualified for full-text reading out of which 13 articles finally met the inclusion criteria and were included in the systematic review. Due to heterogeneity of method of assessment, study sample, intervention, and duration of therapy, meta-analysis could not be done.

Data was collected under the following headings: general information (the name of the authors and the year of publication), participants (sample size, age, and gender), intervention, method of assessing changes due to GH therapy, primary aim of the study, and conclusion.

A summary of the included studies has been shown in Table 4.

Table 4.

Summary of the Studies Included.

Sr No.t	Author, Location, and Year of Publication	Sample Size, Study Sample	Study Design	Intervention	Method of Assessment	Primary Aim	Conclusion
1.	Bevis et al¹²	9 (8 males, 1 female) hypopituitary dwarfs. Age: 8–19 years	Observational study	2–3 units of human growth hormone (hGH) intramuscularly for 18 months	Lateral cephalograms	Analyze how the facial structures of hypopituitary dwarfs respond to hGH.	Condyles, maxillary sutures, and cranial base sutures showed major changes. Mandibular growth occurred in prognathic direction. Growth rates accelerated.
2.	Ito et al¹³	29 (Initially 26 males, 6 females)Age: 6–13 years	Randomized controlled trial	Recombinant human growth hormone (rhGH) at 0.10 mg/kg subcutaneously three times/week	Hand wrist radiographs for skeletal age. Dental records—clinical examination, lateral cephalometric radiograph, panoramic radiograph, occlusal radiographs, impressions, and photographs	Assess tooth development in children with idiopathic short stature, both before and after recombinant growth hormone (rhGH) therapy.	Tooth formation was initially delayed. Degree of reduction in stature exceeded the initial degree of delay in tooth formation. rhGH therapy had a significant influence on acceleration or gain in stature but did not have a significant influence on tooth formation.
3.	Dahllof et al¹⁴	9 children (8 females, 1 male) who had undergone bone marrow transplantation (BMT).Age: <12 years	Observational study	0.1 IU/kg body weight/day for 3.5 ± 1.5 years	Lateral cephalograms	Examine the impact of growth hormone (GH) treatment on the development of the craniofacial structure in children with low growth velocity following bone marrow transplantation.	The BMT children not treated with GH exhibited significantly reduced mandibular length and alveolar height. In the GH-treated group, no significant differences were found in craniofacial growth increments compared with controls. Although exogenous GH therapy in this group of children did not induce a catch-up growth, it prevented further loss in growth potential.
4.	Richey et al¹⁵	28 (22 males, 6 females) nongrowth hormone-deficient short statured children.Age: <9 years for females, <10 years for males	Observational study	0.10 mg/kg recombinant human growth hormone (rhGH) subcutaneously three times/week for the first year followed by 0.3 mg/kg rhGH three times/week for six years	Dental casts, lateral cephalograms, occlusal radiographs, and intraoral photographs	Measure arch dimensions before treatment of short statured children and monitor the changes over the course of five years of rhGH treatment.	Recombinant human growth hormone therapy had a major impact on statural growth of children with idiopathic short stature but had no significant effect on maxillary and mandibular arch development.
5.	Cantu et al¹⁶	40 (21 males, 19 females) idiopathic growth-hormone-deficient (IGHD) children. Age: 5–18 years	Observational study	Growth hormone 0.3 mg/kg/week subcutaneously 3–6 times/week for 0.2–2 years and 2.0+ years in two respective groups	Lateral cephalograms	Assess the maturation and differential growth of craniofacial structures in IGHD children throughout replacement therapy.	Posterior facial height (Sella-Gonion) showed significant improvement. Catch-up growth following GH therapy appears to be most pronounced for tissues under intrinsic control. GH replacement therapy should be commenced as early as possible for catch up growth to occur.
6.	Erum et al⁵	21 (12 females, 9 males) prepubertal, nongrowth hormone-deficient children born small for gestational age. Age: 2–8 years	Randomized controlled trial	0.2–0.3 U/kg/day growth hormone subcutaneously for two years	Lateral cephalograms	Evaluate effect of high-dose growth hormone on craniofacial growth in children born short for gestational age.	SNB (Sella-Nasion-point B) angle increased. The increase in SNB angle was more when growth hormone therapy was started at younger age High-dose GH treatment over two years leads to craniofacial catch-up growth.
7.	Forsberg et al¹⁷	10 (9 females, 1 male)Mean age: 12.2 ± 3years	Observational study	0.1 IU/kg body weight/day for 3.6 ± 1.3 years	Lateral cephalograms	Assess impact of growth hormone on craniofacial development in children suggesting diminished growth potential due to total body irradiation.	Enhanced condylar growth restored the mandibular growth potential and normalized the condyle-fossa relationship. Cranial base changes were minimal and not significant.
8.	Segal et al⁷	52 children (gender-wise distribution not mentioned) with growth hormone deficiency. Mean age: 12.2 ± 4.3 years	Observational study	0.3 mg/kg/day rhGH subcutaneously for two years	Frontal and lateral photographs, head circumferences measured using measuring tape	Evaluate the effects of growth hormone (GH) therapy on craniofacial growth and body proportions in children with growth hormone deficiency.	The vertical facial proportions in subjects treated with rhGH was like normal relatives. Facial width was smaller in GH-treated subjects than in normal relatives. Growth hormone treatment with conventional doses partially corrects craniofacial deficits but appears to result in excessive head circumference growth.
9.	Funatsu et al¹⁸	57 (33 males, 24 females) patients with idiopathic growth hormone deficiency (IGHD).Age: 4.5–16.7 years	Observational study	0.17 mg/kg rhGH 6–7 times/week for average 1.2 years and 3.3 years in short-term and long-term groups, respectively	Lateral cephalograms	Analyze the effects of growth hormone (GH) therapy on craniofacial growth in three groups based on the length of GH therapy.	Long-term GH therapy showed increased growth of the craniofacial skeleton, especially the maxilla and ramus. GH accelerates craniofacial development, which improves occlusion and the facial profile.
10.	Kjellberg et al⁶	46 males with short stature	Observational study	0.03–0.06 mg/kg/day GH injected for 5.7 years	Lateral cephalograms	Evaluate long-term effects of growth hormone therapy on craniofacial growth.	Anterior rotation of the mandible, mandibular corpus length, and anterior face height of the GH-treated boys were greater at the end of the study compared with the boys in the reference group. Craniofacial growth pattern improved significantly without acromegalic features.
11.	De Faria et al¹⁹	20 (12 males, 8 females) patients with growth hormone deficiency (GHD). Age: 11.8 ± 1.7 years	Observational study	0.1–0.15 U/kg/day GH, subcutaneously 2–11 years	Lateral cephalograms, facial photographs	Estimate action of growth hormone on craniofacial development and extremity growth in patients with growth hormone-deficiency.	Posterior base of the skull (Sella-Articulare), lower jaw (Condylion-Gnathion) and lower third of the face (Nasion-menton) increased.GH treatment with standard doses in GH-deficient patients improved the facial profile in retrognathic patients.
12.	Choi et al²⁰	36 children (20 males, 16 females). 18 with growth hormone deficiency (GHD) and 18 with idiopathic short stature (ISS). Mean age: 11.3 ± 1.8 years	Observational study	0.23 mg of rhGH /kg/day (mean dose), six times weekly for two years	Lateral cephalograms	Comparing children with ISS and those with growth hormone deficit (GHD), assess the impact of GH therapy on craniofacial growth.	Growth of the condyles was influenced more in girls and mandibular growth was in the vertical direction after GH therapy. Craniofacial growth increased toward the norm in children with ISS or GHD during growth hormone treatment.
13.	Partyka et al²¹	110 children (27 males, 83 females) with hypopituitarism. Mean age: 13 ± 2.5 years	Observational study	Dosage of growth hormone not mentioned	Intraoral examination for dental age estimation, hand wrist radiographs for skeletal age estimation	Assess bone and dental age and analyze the state of dentition in children with GH deficiency treated with growth hormone, depending on the duration of treatment.	Dental age in children in the control group was ahead of birth age, which proved acceleration phenomenon. A longer period of growth hormone therapy enhanced its effect on the cranial-facial complex.

Abbreviations. GHD, growth hormone deficient; hGH, human growth hormone; ISS, idiopathic short stature; rhGH, recombinant human growth hormone.

Risk of Bias Assessment

The risk of bias was assessed by Risk-Of-Bias VISualization tool (ROBVIS) tool. The risk of bias of the included studies is presented as a “traffic light” plot of individual studies and a summary diagram (Figures 2 –5). The domains of bias that were assessed are mentioned in Figures 2 and 3. The ROBINS-I tool for nonrandomized studies and RoB 2 tool for randomized controlled studies were used in the ROBVIS. Of the 13 studies, 8 studies had moderate risk of bias, 2 had serious risk of bias, and 1 had critical risk of bias as per the ROBINS-I assessment. According to the RoB 2, two studies were having high risk of bias. The overall summary of risk of bias is presented in the summary graphs.

Figure 2.

Source: https://www.riskofbias.info/welcome/home/current-version-of-robins-i

Figure 3.

Source: https://www.riskofbias.info/welcome/rob-2–0-tool

Figure 4.

Source: https://www.riskofbias.info/welcome/home/current-version-of-robins-i

Figure 5.

Source: https://www.riskofbias.info/welcome/rob-2–0-tool

Discussion

The aim of the present systematic review was to assess whether GH therapy enhances the craniofacial development, especially the dimensions of maxilla and mandible in children with or without GH deficiency. A total of 13 studies met the eligibility criteria and were included in this systematic review and the risk of bias assessment was done using ROBVIS tool.

All the studies except the study conducted by Richey et al and Partyka et al used serial lateral cephalograms to analyze and measure the growth changes occurring in the study subjects. Richey et al as well as Bevis et al included dental casts to measure maxillary and mandibular arch width changes after GH therapy.^{12, 15} Partyka et al used hand wrist radiographs and conducted intraoral examination for skeletal age and dental ages determination, respectively.²¹ Photographic and anthropometric measurements were involved in studies done by Segal et al,⁷ Ito et al,¹³ Richey et al,¹⁵ and Faria et al.¹⁹

Craniofacial components such a mandibular length, ramal length, anterior facial height, and anterior cranial base length showed a positive and clinically significant change in dimensions after GH administration. Transverse dimension of maxillary and mandibular arch did not show significant change. Evaluation of transverse dimension on study models by Richey et al¹⁵ and Bevis et al¹² showed similar results and proved that GH therapy had minimum effect on it and was clinically insignificant. The maxillary and mandibular arch dimensional changes noted by Bevis et al ranged between 0 and 1 mm with majority of the values less than 0.5 mm.¹²

One of the most common aesthetic problems observed in patients with GH deficiency is facial convexity. Due to the anterior growth of mandible, the facial angle improved as per the results of three studies. Even though the corpus length was not much affected by GH replacement therapy, the total mandibular length (Condylion-Pogonion) and ramal length (Articulare-Condylion or Condylion-Gonion) were significantly increased and this was attributed to the accelerated growth of condylar cartilage. Condylar growth direction changed from forward-backward direction to backward-upward direction as observed by Forsberg et al.¹⁷ According to Ito’s study, mandibular growth not only improved but exceeded than those in control group. However, disharmony of facial profile was not observed.¹³ Increase in the ramal height was observed in three studies. However, the catch-up growth in ramal height was the least as per the results of Cantu et al.¹⁶

A positive effect of GH therapy on maxillary length was found in only two of the six studies that measured maxillary length changes. The improved growth in maxillary length as explained by Kjellberg might be due to stimulative effect on membranous as on endochondral bone formation by growth.⁶

Changes in the anterior cranial base were reported in eight studies. All suggested a positive effect of growth on sphenooccipital synchondroses which led to the lengthening of anterior cranial base. It was also noted that the effect of GH on this synchondroses is however age dependent and thus failed to have much impact on the catch-up growth in the subjects above the age of seven years, which is approximately the age of fusion of sphenooccipital synchondroses.²⁰ Similarly, posterior cranial base length and posterior facial height also increased significantly in all the four studies which included them as a parameter.

Dental effects were specifically paid attention to by the study conducted by Partyka et al,²¹ Ito et al¹³ where they found that dental age was retarded or delayed in children with GH deficiency and in children with idiopathic short stature, respectively. Tooth formation or dental age was not significantly influenced by GH therapy in either of the studies. Bevis et al also concluded that dental age improved only slightly as compared to other parameters.¹²

Finally, only one study by Kjellberg et al included myofunctional appliance therapy in certain subjects and found that it supplemented the effect of GH in improving the mandibular growth in a sagittal direction.⁶

Although there was a moderate risk of bias in most of the studies, all studies suggested that the efficacy of GH therapy depends on the timing of administration as growth of different craniofacial components ceases at different times. The earlier the administration of GH, the better is the corrective growth of maxilla and mandible in a sagittal direction. This favorable growth of mandible improved facial profile and made it more harmonious. Maxillary and mandibular arch dimensions did not improve significantly. Dental changes were also not considerable post GH therapy.

Limitation

The limitation of this systematic review was the limited number of RCTs available to know whether there is additive effect of GH therapy in children undergoing myofunctional therapy. A meta-analysis could not be carried out as there was a lot of heterogeneity among studies. All studies displayed heterogeneity regarding the parameters assessed on lateral cephalograms to measure effect of GH.

Future Scope

Future research is required to assess whether GH therapy in conjunction with myofunctional therapy can accelerate profile improvement in children with a retrognathic profile. Also, it is necessary to evaluate whether targeted supplementation of GH in adults undergoing orthodontic treatment can aid in improving sagittal dimensions of maxilla and mandible as most of the present studies were conducted only on children. Targeted supplementation of GH may not only improve a retrognathic, convex profile but also aid in correcting facial asymmetry caused by conditions such as unilateral mandibular hypoplasia.

Conclusion

GH therapy plays a significant role in craniofacial development of children with or without GH deficiency and has an enhancing effect on the maxillary length, the mandibular length, and the cranial base length, causing an overall increase in the facial height.

The limitation of GH therapy is mainly in the transverse direction as arch dimensions remained almost equal to those in the untreated subjects.

Footnotes

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Ethical Approval

Not applicable.

Funding

The authors received no financial support for the research, authorship and/or publication of this article.

Informed Consent

Not applicable

ORCID iDs

Sharvari Sunil Khedkar

Pritam Khorgade

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Role of Growth Hormone Therapy in Craniofacial Development of Children with or without Growth Hormone Deficiency—A Systematic Review

Abstract

Objective

Method

Result

Conclusion

Registration

Keywords

Introduction

Material and Methods

Protocol and Registration

Selection Criteria

Search Strategies

MeSH Terms and Keywords Used for Research.

List of Search Engines and the Results Obtained.

List of Excluded Studies.

Results

Summary of the Studies Included.

Risk of Bias Assessment

Discussion

Limitation

Future Scope

Conclusion

Footnotes

Declaration of Conflicting Interests

Ethical Approval

Funding

Informed Consent

ORCID iDs

References