Effect of Recombinant Human Growth Hormone Treatment in a Patient with Short Stature Associated with the Ring Chromosome 17 Syndrome

Background Ring chromosome 17 syndrome is a rare hereditary disorder whose prevalence is less than 1 : 1.000.000. We present a ten-year-old patient with ring chromosome 17 syndrome who had short stature and was treated with recombinant human growth hormone (rhGH). Case Report. A ten-year-old male scholar had moderate left conductive deafness, left kidney hypoplasia with hypertension, epilepsy, malformations in hands, feet, and abdomen, and disproportionately short stature. Despite no evidence of growth hormone deficiency, rhGH treatment was indicated as a therapeutic test due to his decelerated growth velocity and severe short stature. As a result, his growth velocity increased by 4.2 cm per year and his stature Z-score increased (from −5.87 to −5.23). Conclusion The patient's severe short stature may be related to genetic, environmental, and hormonal factors and the positive response to rhGH may indicate abnormalities in the somatotropic axis that were mitigated with the treatment. Although rhGH associated with adequate comorbidities controls improved his growth velocity and height Z-score, its effects in the long term are still unclear.


Introduction
Te ring chromosome syndrome is caused by the breakage of the distal portions of both chromosomes' arms and the subsequent fusion of its two ends.Tis abnormality can involve chromosomes such as 14, 17, and 20 and occur during meiosis or mitosis in the early embryo development, and it causes telomeric and genetic loss.Its phenotype depends on the number of genes lost, gene regulation, and mosaicism degree [1][2][3].
Te present study aims to present a patient with ring chromosome 17 syndrome and severe short stature without the involvement of Miller-Dieker's critical region and its singular response to recombinant human growth hormone (rhGH) treatment.

Case Report
Informed consent for a case report was obtained.
PHLS is a ten-year-old boy born via C-section due to his mother's preeclampsia at 35 weeks of gestational age.According to Intergrowth-21st growth curves, he was smaller than average for his gestational age, with a birth weight of 1905 g (Z-score: −1.41), a birth length of 42 cm (Zscore: −2.01), and a birth head circumference of 31 cm (Zscore: −0.8).His parents are nonconsanguineous.
Since birth, he presented a broad nasal bridge, epicanthal folds, low-set ears, ffth left fnger brachydactyly, bilateral clinodactyly of frst and ffth fngers and third toes, and fourth and ffth right toes syndactyly.Also, since birth, he had bilateral cryptorchidism, umbilical hernia, and diastasis recti, which were fxed surgically at ten and seven months (Figure 1).During his frst two years, he evolved with delayed developmental milestones, moderate left conductive deafness, cafe-au-lait spots, and reduced growth velocity.Moreover, he was diagnosed with epilepsy after vaccination at six months old.He used phenobarbital regularly until he was nine, when it was suspended due to the absence of new seizures.Also, he had left kidney hypoplasia with consequent hypertension, which was diagnosed at the age of nine and treated with 2.5 mg amlodipine.Tere were no relevant chronic diseases or similar cases in the family, and his parents had no abnormalities in their karyotype.
At ten years and four months of age, his G band karyotype revealed a ring 17 chromosome (46 XY. r (17) (p13q25)), and he was referred to a pediatric endocrinology service to investigate his short stature.At that time, he was prepubertal; according to the World Health Organization (WHO)'s growth charts, he presented severely disproportionate short stature as his height Z-score was −5.64, i.e., below his familial growth channel (mid parental height Zscore: −0.02), slightly reduced arm span to height ratio (0.97), and eutrophy with a body mass index Z-score of −0.94.
Moreover, he had a neuropsychomotor development delay at that time, and the neurology department followed him without any prescribed medications.He maintained the use of 5 mg amlodipine due to hypertension, which was controlled.
At eleven years of age, screening laboratory tests did not present changes concerning the liver and kidney function, osteometabolic profle, thyroid function, or blood cortisol levels.Also, at that age, the X-ray revealed bone age compatible with chronological age, an undefned distal phalanx on his left ffth fnger, and an extra numeracy right toe between the fourth and ffth toes.
At eleven and fourteen years of age, regarding the somatotropic axis, insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP-3) levels were normal.Also, at fourteen years of age, the growth hormone (GH) stimulation test with clonidine was responsive with a peak GH level of 10.20 ng/ml at 90 minutes (reference >5 ng/ml).Moreover, magnetic resonance imaging showed no alterations in the hypothalamic-pituitary region at that age.
Due to his slow growth velocity, rhGH treatment was started with 0.10 UI/kg/day (0.033 mg/kg/day) as a therapeutic test at 14 years old and fve months.After detecting no adverse efects, the dosage was increased to 0.15 UI/kg/day (0.045 mg/kg/day) and maintained as the usual dosage with IGF-1 and IGFBP-3 levels in their reference range.As a result of 16 months of treatment, his growth velocity increased from 3.5 cm per year to 7.7 cm per year, and his stature Z-score increased (from −5.87 to −5.23) according to the WHO's growth charts.During this period, he had no treatment complications.
Currently, at ffteen and nine months of age, he presents a delayed bone age compared to chronological (bone age: 13 years and chronological age: 15 years), he is pubertal with Tanner and Marshall staging G2P3.Nowadays, he maintains follow-ups with endocrinology, neurology, speech therapy, and nephrology without any complications or new symptoms, and he is still using 5 mg amlodipine, which is being reduced due to his blood pressure stabilization.

Discussion
Tis case report presents new fndings that contribute to understanding the potential therapeutic efect of growth hormone in a patient with short stature associated with the ring chromosome 17 syndrome.
Te ring chromosome 17 syndrome is a rare chromosomal condition described in 1971, with only 20 other cases reported in the literature, and 14 of those not associated with the Miller-Dicker syndrome [5,6].
Tere are two main theories regarding the ring chromosome's formation.First, the DNA breakage in both subtelomeric regions causes the arms to merge, losing telomeres and distal chromosomal genetic material, the primary mechanism related to the 17 chromosomes.Te second one is a telomere maintenance dysfunction, resulting in the shortening and merging of both terminal portions.Both can occur in gametogenesis, especially paternal, and in the mitosis of embryonic cells related to mosaicism.Moreover, the embryonic age determines the severity of the patient's phenotype [2,3].
Te ring chromosome 17 syndrome's phenotype is related to deletion and gene expression.Surace et al. described that telomere loss afects the expression of nearest genes due to the "telomere position efect" (TPE) phenomenon, in which subtelomeric regions show more epigenetic plasticity, with gains or losses of the gene function.Besides, genes located in the break spot may lose or depart from their regulatory regions.Tus, the phenotype depends on the genes involved in the deletion or shortening of the telomeres, TPE, and gene expression regulation [1,2,6].
Furthermore, ring chromosomes are mitotically unstable with secondary alterations in the cell division process, such as monosomies and double rings.Terefore, there are higher chances of mosaicism, in which the phenotype depends on the mosaicism's rate and cellular distribution in diferent tissues [1,3].
Tis case report describes a nonmosaic patient, without supernumerary chromosomes, with one ring chromosome arms.Since the ring chromosome 17 syndrome's phenotype is related to the preservation of Miller-Dicker's critical region (17p13.3),the patient's milder phenotype suggests that this critical region is partially or entirely preserved [4][5][6].
Deleting Miller-Dicker's critical region results in a more severe phenotype with lissencephaly, multiple craniofacial malformations, delayed developmental milestones, and reduced life span.Te patient did not have any of these characteristics but had classic ring chromosome 17 syndrome characteristics such as mildly delayed developmental milestones, short stature, epilepsy, craniofacial malformations, and cafe-au-lait spots.He also presented some less common characteristics such as left deafness, brachydactyly, clinodactyly, syndactyly, left kidney hypoplasia, bilateral cryptorchidism, and some abdominal wall malformations such as umbilical hernia and diastasis recti [4,5].
One of the patient's main characteristics was his disproportionately short stature (height Z-score below three and reduced arm span/height ratio), which may suggest skeletal abnormalities contributing to his short phenotype.Moreover, his short stature was aggravated by his comorbidities, such as left kidney hypoplasia, hypertension, epilepsy, long-term medications use, and surgical interventions.Tey may have impaired his growth velocity during critical height gain phases such as early infancy and prepuberty.
Environmental, hormonal, and genetic factors infuence a child's stature.Bone and growth plate abnormalities are factors that signifcantly decrease height gain.Chronic diseases and their treatments, such as epilepsy with anticonvulsant drug use, can directly afect bone accrual and elongation and reduce fnal stature.Also, they may impair the somatotropic axis by promoting suboptimal GH secretion or impairing IGF-1-IGFBP-3 action continuously or transiently [7].
Notably, the integrity of the somatotropic axis guarantees an adequate child's growth, as GH and IGF-1 are critical regulators of longitudinal bone growth and skeletal maturation throughout life.So, laboratory and radiology evaluations are needed in growth disorders, but the current methods have limitations.For example, although IGF-1 serum concentrations show slight circadian variation, their levels can be reduced in undernutrition and chronic diseases or normal in growth hormone defciency.Moreover, GH stimulation tests may not have a great sensibility to identify partial growth defciency or GH resistance or may fail to respond in healthy peripubertal and obese children.Tese inaccuracies occur because the stimuli are not physiological and do not replicate normal secretory dynamics.Also, the periodic secretion of somatostatin might infuence the somatotroph response [8,9].
Despite no anatomical abnormalities in the hypothalamic-pituitary region or laboratory evidence of growth hormone defciency in the patient's diagnostic workup, rhGH treatment was indicated as a therapeutic test due to the absence of previous reports of rhGH treatment in ring chromosome 17 syndrome and the presence of comorbidities that could impair the somatotropic axis.In addition, the higher dose of rhGH was intended to overlap a possible GH resistance.As a result, the rhGH treatment improved his growth velocity and height Z-score.Tis positive efect may indicate abnormalities in the somatotropic axis, such as GH resistance, impaired IGF-1-IGFBP-3 Case Reports in Pediatrics actions, or a partial growth defciency that was mitigated using rhGH.Also, the comorbidities control and the onset of puberty probably contributed to his height improvement [7,10].While this case report provides valuable insights into the potential therapeutic use of rhGH in a patient with ring chromosome 17 syndrome and severe short stature, it is essential to acknowledge certain limitations.First, the rarity of ring chromosome 17 syndrome inherently limits the generalizability of the fndings to a broader population.In addition, the observed positive response to rhGH treatment raises intriguing questions about other underlying genetic and hormonal factors contributing to the patient's growth impairment.Moreover, this case report does not provide conclusive evidence regarding the long-term efectiveness of rhGH in individuals with this syndrome.Despite these limitations, this case report underscores the importance of meticulous documentation and exploration of rare genetic conditions, as it may shed light on novel treatment approaches and enhance our understanding of the underlying mechanisms involved.
In conclusion, although the patient had a satisfactory response to rhGH, careful surveillance is mandatory to understand the medication benefts and possible efects in the long term in the ring chromosome 17 syndrome.