|Year : 2022 | Volume
| Issue : 2 | Page : 137-142
A prospective study of etiology and clinical characteristics of children with short stature and response to treatment
Vijay Sheker Reddy Danda, Madhavi Verpula, Srinivas Rao Paidipally, Krishna Reddy Thaduri, Piyush Lodha, Sandeep Reddy Devireddy
Department of Endocrinology, Gandhi Medical College/Gandhi Hospital, Secunderabad, Telangana, India
|Date of Submission||02-May-2021|
|Date of Acceptance||06-Aug-2021|
|Date of Web Publication||24-May-2022|
Dr. Vijay Sheker Reddy Danda
Department of Endocrinology, Gandhi Medical College/Gandhi Hospital, Secunderabad - 500 003, Telangana
Source of Support: None, Conflict of Interest: None
OBJECTIVE: To study the etiological and clinical profile of children presenting with short stature and to assess growth velocity in children after 6 months of treatment.
METHODS: This prospective observational study was conducted between January 2017 to May 2018. One hundred consecutive children attending the outpatient department for short stature were thoroughly evaluated clinically and investigations were done as deemed necessary. The cases were followed up for 6 months to assess the growth velocity.
RESULTS: Female to male ratio was 1.56. Nutritional short stature (NSS) and normal variant short stature were the most prevalent, with the equal frequency of 19% each, followed by endocrine and other causes. The significant number of children had Vitamin D deficiency/insufficiency (92%). mid-parental height (MPH) was below-1 standard deviation score (SDS) from the national standard in all the children studied.
CONCLUSION: In the present study, normal variants of short stature and NSS were the most common causes of short stature, followed by endocrine disorders. Vitamin D status was low in the majority of the children (92%), with possible contribution to short stature in all groups irrespective of primary diagnosis and needs further exploration. Growth hormone (GH) therapy in select non GH deficiency short stature can be promising. We also noted that maternal, paternal heights, and consequently, MPH was below the national standard in 100% of children. This may implicate ethnic variations and maybe a call for local growth charts. It needs further studies to look for factors responsible for lower MPH in our cohort.
Keywords: Hypopituitarism, short stature, Vitamin D deficiency
|How to cite this article:|
Danda VS, Verpula M, Paidipally SR, Thaduri KR, Lodha P, Devireddy SR. A prospective study of etiology and clinical characteristics of children with short stature and response to treatment. Indian J Health Sci Biomed Res 2022;15:137-42
|How to cite this URL:|
Danda VS, Verpula M, Paidipally SR, Thaduri KR, Lodha P, Devireddy SR. A prospective study of etiology and clinical characteristics of children with short stature and response to treatment. Indian J Health Sci Biomed Res [serial online] 2022 [cited 2022 Jun 25];15:137-42. Available from: https://www.ijournalhs.org/text.asp?2022/15/2/137/345836
| Introduction|| |
Normal growth is one of the fundamental characteristics of childhood and adolescence., Deviation from a normal pattern of growth can be a manifestation of many physiologic and pathologic conditions including endocrine and nonendocrine disorders. The most common causes of short stature beyond the first 2 years of life are familial short stature (FSS) and constitutional delay in growth and puberty (CDGP), which are normal, nonpathologic variants of growth pattern. Recently, there has been the appreciation of genetic factors in the causation of idiopathic short stature (ISS). Wood et al., in their study, showed that all common variants together captured 60% of heritability. A comprehensive clinical profile can help in understanding and addressing the problem. We looked at the etiological profile of short stature in children from South India referred to our tertiary care center.
Aims and objectives
The primary objective was to study the etiological and clinical profile of children presenting with short stature and assess growth velocity after 6 months of management.
Patients and methods
This prospective observational study was conducted in a tertiary care center, between January 2017 and May 2018. Written informed consent was taken from the parents of each subject and the study was approved by the institutional ethics committee. One hundred consecutive children, <18 years old, attending the Endocrinology outpatient, for short stature were evaluated. Short stature was defined as height <-2 standard deviation score (SDS) (WHO growth chart from 0 to 5 years/IAP 2015 growth chart in children >5 years), or height velocity <5th percentile (where available). Institutional ethics committee/Gandhi Medical college DCGI Regd No: ECR/180/Inst/AP/2013/RR-16, Date. 21-06-2017 Certificate No. IEC/GMC/2019/2/10.
Height, weight, lower body segment, upper body segment, and head circumference were recorded in all the cases. Both parents' height was measured, and mid-parental height (MPH) was obtained by the following formula:
MPH = (maternal height + paternal height)/2 + 6.5 cm for boys and-6.5 cm for girls.
Skeletal age (bone age [BA]) was estimated from Greulich and Pyle's standard chart.
Complete blood picture, plasma glucose, liver function tests, renal function tests, serum albumin, calcium, phosphorous and alkaline phosphatase were checked in all children. T3, T4, thyroid-stimulating hormone, and 25-hydroxy-Vitamin D were tested by chemiluminescence immunoassay (CLIA) method. Follicle-stimulating hormone, luteinizing hormone, estradiol, total testosterone, serum cortisol (basal and stimulated) were performed by CLIA where indicated. Insulin-like growth factor-1 (IGF1) and provocative growth hormone (GH) stimulation test with clonidine were done in children with clinical suspicion of disorder of GH/IGF1 axis (height <-3SDS, no evidence of chronic systemic illness, no evidence of severe nutritional deficiency, clinically and biochemically euthyroid]. After overnight fasting, clonidine was given at a dose of 0.15 μg/m2 body surface area. Samples were drawn for GH at 0, 30, 60, and 90 min. Enzyme-linked immunosorbent assay assay was used. Sex steroid priming was done with Ethinyl estradiol in girls and testosterone in boys when indicated. Magnetic resonance imaging of pituitary and karyotyping were done where indicated. Diagnosis of nutritional short stature (NSS) was made based on the presence of features suggestive of nutritional deficiency like-low weight compared to height, signs of nutritional deficiency (glossitis, cheilosis, etc.), low hemoglobin, albumin and 25-hydroxy-vitamin D levels, with no peculiar signs of other causes like GH deficiency or syndromic short stature. Height gain in all the cases was monitored at 3 months and then at 6 months from the initial evaluation.
Chi-square test was done as a test of significance for categorical data. ANOVA test was done as a test of significance for continuous data.
| Results|| |
A total of one hundred children referred for short stature were evaluated. Female-to-male ratio was 1.56. NSS was the most common diagnosis accounting for 19%, followed by hypopituitarism (18%). Normal variants including ISS, CDGP, and FSS accounted for about one-fifth of the cases (19%). The various etiologies of short stature found, are presented in [Table 1].
Among the 18 children with hypopituitarism, 2 had craniopharyngioma status postsurgery, postradiotherapy, 2 had septo-optic dysplasia and 1 child had beta-thalassemia major with secondary hemosiderosis with panhypopituitarism. The child with beta-thalassemia had components of nutritional deficiency, chronic illness, treatment-related side effects, and endocrine problems (panhypopituitarism). The remaining 13 children had isolated GH deficiency (IGHD).
Rare syndromes diagnosed in our cohort include Laurence Moon Biedl (LMB) syndrome, Aarskog-Scott syndrome, Mauriac syndrome, and Blooms syndrome one case each. The child with Aarskog Scott Syndrome was given a trial of GH therapy and he responded well. The child with Blooms Syndrome was found to have associated GH deficiency, an exceedingly rare association. He was, however, not offered GH therapy in view of the inherently increased risk of malignancies.
Males and females were equally affected by NSS. Hypopituitarism as a cause was significantly more common in males (78% vs. 22%), whereas primary hypothyroidism was more common in girls (85% vs. 15%). 52% of children presented between 13 and 18 years of age and only 12% were between 1 and 5 years of age. NSS presented more commonly between 6 and 12 years of age. All other causes were seen more commonly between 13 and 18 years of age.
In the present study, 92% had low 25 hydroxyvitamin D levels (80% deficient, 12% insufficient). There was no significant difference among the groups. Nutritional rickets was present in only one child. The rest of the children did not have any specific symptoms or signs of Vitamin D deficiency. Two children had toxic levels due to excess Vitamin D supplementation, erroneously prescribed for purported nutritional rickets. One of those children had skeletal dysplasia and the other had septo-optic dysplasia with panhypopituitarism. They, however, did not have hypercalcemia and did not need any hospitalization or specific treatment for the toxicity.
Twenty-one percent had overt hypothyroidism (OH) and 9% had subclinical hypothyroidism (SCH). The rate of OH was higher in girls with TS (33.3%). All children had height SDS (HSDS) <-3SDS. Mean HSDS was −3.69. Children with hypopituitarism had lowest HSDS (−4.77SDS) and NSS group had the highest mean HSDS (−3.15). Adult equivalent BMI was charted for all children. Maximum BMI of 22 kg/m2 was seen in TS children and a minimum BMI of 17.30 kg/m2 was seen in NSS children.
Mean maternal height was lower than the national standard for females (IAP 2015 chart) in all children. The highest value was seen in the primary hypothyroidism group (−1.05SDS) and least in the normal variant group (−1.69SDS). Paternal height was also lower compared to the national standard as per IAP 2015 chart. Similar to maternal HSDS, mean paternal HSDS was highest in the primary hypothyroidism group (−1.09SDS) and least in the normal variant group (−1.63SDS). MPH was low in all groups, being least in the normal variant group (−1.69SDS).
Among the hypopituitarism group, out of 18 children, 6 children were initiated on GH replacement. In these children, the average height increment after the first 3 months was 2.4 cm (range 1 cm to 4 cm). 2 out of 9 TS girls were started on GH replacement. One girl had an increment of 3 cm and the other had an increment of 1 cm over the 3 months. None of the children had any adverse effects that warranted termination of treatment or dose reduction. Height increment was highest in the hypopituitarism group who received GH replacement and was least in the TS group. In all the groups, height increment was lower in the first 3 months following treatment, compared to the next 3 months.
| Discussion|| |
In the present study, girls were more numerous than boys, with a female to male ratio of 1.56:1. In most of the other studies, including Papadimitriou et al. Majcher et al., from the west and Bhadada et al., Velayutham et al., from India, the sex ratio was reverse with more boys than girls in the study. Age at presentation varied with the diagnosis. NSS children, as a group presented at a younger age compared to the other diagnostic groups. The age of presentation concurred with other studies published from India. Majority of girls with TS presented after 13 years of age. This late presentation is probably because the parents believe the child will eventually grow and the child is brought to attention when the pubertal onset is also delayed along with deficit in stature.
In the present study, normal variants, NSS and GHD were almost equally prevalent at 19%, 19%, and 18%, respectively. The proportions varied widely across the globe and varied with whether the study was performed in specialty endocrine clinic or the general population. In the Utah growth study only 5% prevalence of endocrine disorder was reported. Similarly, in a cross-sectional population-based study by Velayutham et al., in a South Indian district of Madurai, Tamil Nadu, India, normal variants (66.67%) were the most common etiology, followed by hypothyroidism (13.79%) and GHD (9.2%). The present study being conducted in the specialty endocrine department, endocrine causes were more common compared to the population screening studies. Studies conducted in specialty clinics had more frequency of endocrine causes, likely because the normal variants could have been screened at referral points and owing to high index of suspicion. [Table 2] highlights the most common etiologies found in various previous studies.
In the present study, the NSS was more prevalent than in many of the other studies from the West, the middle East and Asia,,, and India.,, It is probably because the population attending the hospital belonged to low socioeconomic status.
Three children were found to have iatrogenic Cushing's syndrome as the cause of short stature. One was a female child with CAH (21 hydroxylase deficiency), the second was a male child with Hansen's disease, and the third was a male child with suspected SLE. All the three were started on the appropriate dose of glucocorticoids and advised follow-up but were lost to follow-up for varying periods before being referred for short stature. Glucocorticoids exert multiple growth-suppressing effects, interfering with endocrine (e.g., endogenous GH secretion) and metabolic (e.g., bone formation, nitrogen retention, collagen formation) processes essential for normal growth. Relatively small oral doses of daily exogenous GC, alternate-day oral GC therapy, and even inhaled GC are capable of slowing growth in some children. These growth-inhibiting and catabolic effects of GC can be variably counterbalanced by GH therapy. GH responsiveness depends on the GC dose and severity of underlying GC-dependent disease. Short-term risks of combined GH and GC therapy are low.
One child with untreated 46, XX CAH, reared as a male, presented after epiphyseal fusion at the age of 16 years for short stature. No further height gain was noticed in this child. Alzanbagi et al., in their descriptive study of over 5 years concluded that there was a significant effect of CAH on height, weight, and BMI.
Three children presented with skeletal dysplasias. Renal rickets was seen in one child and distal RTA in another child. Infrequent and rare syndromes we diagnosed including LMB syndrome, Aarskog-Scott syndrome, Mauriac syndrome, and Blooms syndrome. The child with Arskorg Scott syndrome was offered GH therapy. KIGS database shows evidence of HSDS improvement in Aarskog Syndrome with GH treatment. The child gained 5 cm in 6 months and 10.5 cm in 12 months. The child with Blooms syndrome had a component of intrauterine growth retardation and was born small for gestational age (SGA). He was later diagnosed to have GHD but was not offered GH replacement therapy in view of inherently high malignant potential due to chromosomal breakage syndrome.
SGA was significantly higher in the hypopituitarism group in the present study. Out of 11 children who were SGA, 5 had hypopituitarism. There is some evidence that SGA may be associated with GHD and multiple pituitary hormone disease (MPHD). Jancevska et al. reported that genetic alterations of certain transcription factors may lead to GHD, MPHD, and SGA.
Ninety-two percent of subjects had low 25 hydroxy Vitamin D levels (80% deficient, 12% insufficient). There was no significant difference among the groups and all the groups had Vitamin D deficient children. This level of deficiency was higher than was seen in the population screening study done by Mandlik et al. In their report 71% of children were insufficient and 24% were deficient. 5% were Vitamin D sufficient. It is likely because the children screened for short stature had higher percent of nutritional deficiency and also the low socioeconomic background of patients could have contributed.
HSDS was least in the hypopituitarism group. GHD children were the most affected stature-wise because the GH-IGF1 axis is the most important contributor of stature, especially in childhood and prepubertal state. Even in puberty, GH has an important facilitatory role for sex steroids in the growth spurt. BMI was least in the NSS group, as expected, as the weight age with respect to height age was most affected in this group. TS group had a relatively higher BMI. None of the groups had BMI in the obesity range.
Twenty-one percent had OH and 9% had SCH. The proportion of hypothyroidism was considerably high among TS children, 33.3% had OH and 11% had SCH. Hypothyroidism is an additional mechanism for growth retardation in TS. Monitoring the growth of TS children with disease-specific growth charts can be helpful. When the growth of a child falters in the disease-specific charts a second cause should be looked for. In the TS group, BA would be expected to be equal to chronological age (CA), but it is likely that additional nutritional factors and hypothyroidism in 33% of cases could have affected the BA.
In the present study, a significant number of children had consanguineous parentage. This could be attributed to the local cultural practices. It is possible that any genetic variations responsible for the heritability of height might be more pronounced in children with consanguineous parentage.
MPH was low in all groups, irrespective of diagnosis. MPH SDS was least in the NVSS group, −1.69. All the parents had a stature which was less than the national standard according to the IAP 2015 growth chart and Agarwal chart from 2007. It was significantly more affected in the normal variant group but was affected to some extent, in all the groups. It might be postulated that all children, irrespective of cause, had some familial component to their growth retardation. It could also be that the national standard does not adequately represent the local population. More research is needed to see if it would be appropriate to have local normative data for the growth chart.
Height gain after 6 months of treatment in various groups is depicted in [Figure 1]. In children with hypopituitarism, height increment over 6 months was significantly higher in the children on GH replacement therapy, compared to those who were not on GH therapy (5.25 cm vs. 1.73 cm). Height increment was least in TS children. When the children on GH replacement were considered separately, which included 6 children with hypopituitarism, 2 children with TS and one child with Aarskog-Scott Syndrome, the mean height increment was 5.31 cm over 6 months. This was at par with the increment in IGHD children alone. It may be concluded that the children with TS and specific syndromes benefit from offering GH therapy when there are no contraindications to the same.
|Figure 1: Treatment response in various groups at 6 months after initiation of treatment|
Click here to view
The sample size was small and the study was done in the Department of Endocrinology, in a tertiary referral center, thus the sample may not be representative of the community.
| Conclusion|| |
In the present study, conducted at the Department of Endocrine clinic, normal variants of short stature and NSS were equally prevalent. NSS was the most common single pathological cause with hypopituitarism as a close second. As a group, endocrine disorders were the most common cause of pathological short stature, with hypopituitarism being the most common among the endocrine causes, followed by primary hypothyroidism. Vitamin D status was low in most of the children, with the possible contribution to short stature in all groups irrespective of primary diagnosis. Maternal, paternal heights, and consequently the MPH was below the national standard in 100% of children. Whether this is an ethnic difference, or any other factor was in play needs to be answered. Extensive local normative data might be helpful. GH therapy in nonGHD short stature can be promising, in select cases.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]