Growth disorders in children and adolescents affected by syndromes or diseases associated with neurodysfunction

We have observed that one in three patients admitted to the Neurological Rehabilitation Ward for Children and Adolescents due to a syndrome or disease associated with neurodysfunction is short of stature for their age. In order to identify the relationship between growth defects (short stature) and syndromes or diseases associated with neurodysfunction, we analyzed data collected during admission to the Neurological Rehabilitation Ward for Children and Adolescents. The study applied a retrospective analysis of data collected during hospitalization of 327 children and adolescents, aged 4–18 years, affected by congenital disorders of the nervous system and/or neurological syndromes associated with a minimum of one neurodysfunction. Two assessment systems were taken into account – one system traditionally applied, and another one in accordance with indications approved by the Food and Drug Administration, related to diagnosing short stature. The findings show more frequent co-occurrence of, as well as statistically significant correlations between, short stature in certain groups: operated myelomeningocele with hydrocephalus in the subgroup of neural tube defects (p = 0.029), tetraplegia in the subgroup of spastic cerebral palsy (p < 0.001), and hypothyroidism (p = 0.04) in the entire study group.

Procedures and data analyses. The retrospective analysis took into account basic data (age, sex, principal and additional diagnosis, body height -Ht) acquired upon patient admission. The principal and additional diagnoses were determined by various specialists (neurologists, geneticists, endocrinologists, and others) prior to hospitalization at KRORE, and anthropometric measurements were performed in the KRORE admission room, following the principles adopted in the hospital. Patients were affected by various diseases or syndromes associated with nervous system damage. These were all congenital disorders and/or conditions associated with motor defects (neurodysfunctions) persisting from infancy. The conditions presented with or without encephalopathy. Based on the criteria proposed in the literature (suspected presence or suspected lack of encephalopathy, its etiopathogenesis and nature) 11 , the patients were divided into subgroups (Table 1A). Two assessment criteria systems were taken into account to identify the patients with short stature, normal body height, or tall stature. One system is traditionally applied in clinical practice and the proposed system is based on indications related to diagnosing short stature approved by the Food and Drug Administration (FDA) 12 . To perform an assessment based on all the above criteria, a z-score for body height was calculated for each person (z-score Ht). Normative values published earlier 13 were applied as a reference. This approach has been used previously 14 . The analyses examined the relationships between the co-occurring growth defects, in particular short stature, and the neurodysfunction diagnostic subgroups. The analyses also took into account additional diagnoses (symptomatic epilepsy as opposed to the genetically conditioned epilepsy syndrome, and hypothyroidism). Adjusted Standardized Residuals (ASR) were calculated. Values > 1.96 reflect a greater number, and those below <−1.96 correspond to a smaller number than a random distribution. In order to assess to what extent the differences between the groups reflect regularities in the target population, or whether they are random, methods of statistical inference were applied. The nominal nature of the characteristics subject to comparisons determined the choice of chi-square test of independence. Nominal regression was applied to examine the relationships between the variables: dependent qualitative and independent quantitative. Statistical significance was assumed at p < 0.05. Pearson's Contingency Coefficient C (Cp) can only take positive values (Cp ≥ 0). When Cp is distant from 0, it reflects some relationship, and values approaching 1 correspond to a perfect association.

Results
Patients were divided into seven subgroups. These included six subgroups representing medical conditions usually associated with encephalopathy: progressive metabolic disorders (MD) (2.1%), progressive genetically-determined epileptic syndromes (EE) (0.3%), non-progressive neural tube defects (NTDs) (7.3%), non-progressive genetic disorders (GD): chromosomal aberrations, monogenic disorders except neuromuscular diseases (7.0%), non-progressive toxic (TE) (0.3%), and non-progressive cerebral palsy (CP) (73.1%). There was additionally one subgroup representing conditions usually not associated with encephalopathy, i.e. neuromuscular diseases (NMD) (9.8%) (Table 1A). Taking into account the character and expected presence of encephalopathy 11 , the smaller subgroups were combined into two larger groups representing progressive encephalopathy (PE) (2.4%) and non-progressive encephalopathy (NPE) (88.1%). The third group represented neuromuscular diseases (NMD) (9.8%). The internal structure of subsequent subgroups was differentiated due to various diagnoses. In view of the variability of neural tube defects 15 and the key importance of further operative treatment 16 , the patients in the NTDs subgroup were divided into those operated on due to myelomeningocele with hydrocephalus (sasMMC&HCP), and those operated on exclusively due to myelomeningocele (sasMMC). The presentation also included the remaining cases where no operative treatment was applied. The subgroup with GD www.nature.com/scientificreports www.nature.com/scientificreports/ included both chromosomal aberrations and genetic mutations. It should be mentioned that some authors point to chromosomal disorders and genetic mutations as causes of short stature 17,18 . Down syndrome and Prader-Willi syndrome also belong to this group, alongside with other genetically determined diseases, including mutations of a single gene 17,18 .
The mean and the median for z-score Ht in the study group assumed values lower than −1, and higher than −2. Based on two assessment criteria -one system traditionally applied in clinical practice and the other based on indications approved by the Food and Drug Administration (FDA) 2 , related to diagnosing short stature -patients were divided into those with normal body height, short stature and tall stature (Table 1B,C).
In accordance with the traditional classification, normal body height was found in 67% of the patients, short stature in 30% and tall stature in 3% of the patients.  (Table 2A). Tall stature was found in sasMMC&HCP (N = 1), HCP (N = 1), CP (N = 7) and BMD (N = 1). The assessment based on FDA criteria showed short stature at a rate of 28% (Table 1D).
In the next stage, the analyses examined the relationships between the co-occurring growth defects, in particular short stature, and the diseases or syndromes associated with neurodysfunction, relative to the identified subgroups and within the identified subgroups.
The findings show no more/less frequent (%) co-occurrence and no statistically significant correlations between: • Proposed body height classification (Ht) and classification with regard to etiopathogenesis, presence and character encephalopathy (Table 3B). • Proposed body height classification (Ht) and NTDs (Table 4B).
• The findings show more/less frequent (%) co-occurrence and no statistically significant correlations between: • Traditional body height classification (Ht) and units and syndromes associated with neurodysfunction. Normal body height more frequently co-occurs with CP (71%), less frequently with sasMMC&HCP (36%). Short stature more frequently co-occurs with sasMMC&HCP (N% = 59%), less frequently with CP (26%), and tall stature more frequently co-occurs with BMD (33%) and HCP (100%). However, the correlation is not statistically significant (p = 0.172) (Table 2A). • Proposed body height classification (Ht) and units and syndromes associated with neurodysfunction. Normal body height less frequently co-occurs with sasMMC&HCP (47%), and short stature more frequently co-occurs with sasMMC&HCP (53%). The correlation is not statistically significant (p = 0.997) (Table 3A). • Traditional body height classification (Ht) and classification with regard to etiopathogenesis, presence and character encephalopathy. Normal body height more frequently co-occurs with CP (71%), and less frequently with NTDs (46%). Short stature less frequently co-occurs with CP (26%). The correlation is not statistically significant (p = 0.318) (Table 2B). • Traditional body height classification (Ht) and hypothyroidism. Normal body height co-occurs more frequently with lack of hypothyroidism (68%), and less frequently with existing hypothyroidism (43%). Short stature more frequently co-occurs with hypothyroidism (57%), and less frequently with lack of hypothyroidism (28%). The correlation is not statistically significant (p = 0.065) (Table 5A). • In accordance with the traditional classification, normal body height was found in 67% of patients, short stature in 30%, and tall stature in 3% of patients. Assessment based on FDA criteria showed short stature at the rate of 28% (Table 2C). • The findings show more/less frequent (%) co-occurrence as well as statistically significant relations between: • Traditional body height classification (Ht) and NTDs. Short stature more frequently co-occurs with sasM-MC&HCP (59%). Normal body height is more common in sasMMC (100%). Tall stature occurs more frequently in isolated HCP (100%). The relation is statistically significant (p = 0.029) (Table 4A). • Traditional body height classification (Ht) and CP spastic type. Short stature more frequently co-occurs with tetraplegia (46%), and less frequently with hemiplegia (7%). Normal body height is more common in hemiplegia (88%), and less common in tetraplegia (51%). The relation is statistically significant (p < 0.001) (Table 4B). • Proposed body height classification (Ht) and type of spasticity. Short stature again more frequently co-occurs with tetraplegia (42%), and less frequently with hemiplegia (7%). Normal body height is more common in hemiplegia (93%), and less common in tetraplegia (57%). The relation is statistically significant (p < 0.001) ( Table 4C). The traditional classification is slightly more effective in differentiating this relationship (Cp = 0.328) compared to the proposed classification (Cp = 0.314) - Table 4B,C. • Traditional body height classification (Ht) and type of spasticity: tetraplegic and other (i.e. diplegic, hemiplegic). The relation is statistically significant (p < 0.001) (Table 4D). • Proposed body height classification (Ht) and type of spasticity: tetraplegic and other (i.e. diplegic, hemiplegic). In the group of children and adolescents with spastic CP, short stature frequently co-occurs with tetraplegia (Table 4E). Again, the traditional classification is slightly more effective in differentiating this relationship (Cp = 0.297) compared to the proposed classification (Cp = 0.288) - www.nature.com/scientificreports www.nature.com/scientificreports/ • Proposed body height classification (Ht) and hypothyroidism. Normal body height frequently co-occurs with a lack of hypothyroidism (74%), and is less common in the patients with hypothyroidism (43%). Short stature frequently co-occurs with hypothyroidism (57%), and is less common in the patients without hypothyroidism LGMD 6 (86%)   www.nature.com/scientificreports www.nature.com/scientificreports/ (26%). The relationship is statistically significant (p = 0.040). By using the FDA criterion for diagnosing short stature it was possible to show frequent co-occurrence of short stature and hypothyroidism in the group of children and adolescents with congenital disorders of the nervous system and/or neurological syndromes with symptoms manifesting from infancy (Table 5B).  www.nature.com/scientificreports www.nature.com/scientificreports/ In the remaining cases the findings showed no statistically significant relations. In the next stage the analyses examined relations between the quantitative independent variable, i.e. z-score Ht, and a dependent qualitative variable: distinctions within subgroups or presence of an additional diagnosis. Statistical significance was identified in two conditions, i.e. division of the spastic CP type subgroup into tetraplegia and other (i.e. diplegia, hemiplegia); as well as division of the whole group of patients relative to presence or lack of hypothyroidism. Tetraplegia co-occurs with lower values of z-score Ht (p < 0.001, OR = 0.689). Tetraplegia is more likely to have low z-scores Ht than other spastic CP types (Table 5C). Hypothyroidism also co-occurs with lower values of z-score Ht (p = 0.014, OR = 0.739). Hypothyroidism is more likely to have low z-score Ht than cases without hypothyroidism (Table 5D).   Table 4. Growth disorders and: NDTs (A-B), type of spasticity in CP (C-F). N -numbers of patients, % -percent, p -probability value calculated by chi-square test of independence, Cp -Pearson's Contingency Coefficient C,Cp ≥ 0, values distant from 0 reflect some relationship; values approaching 1 correspond to a perfect association, ASR -Adjusted Standardized Residuals, values > 1.96 reflect a greater number, and those below <−1.96 correspond to a smaller number than a random distribution.

Discussion
Low stature affects about 2% of the general population of children and adolescents and represents one of the more common developmental abnormalities and the reasons for consulting a pediatric endocrinologist 17 . In the studied group of children and adolescents hospitalized in the rehabilitation department due to neurodysfunction, a higher incidence of short stature was found to be 29.7% (traditional criterion) or 27.5% (criterion accepted by the FDA). Normal body height is an important measure of health and well-being in children while growth disorders may result from destabilized diet, environment or health of the child 19,20 . Dysfunctions in a child's nervous system may be caused by numerous factors: genetic, contagious physical, chemical or environmental. Prevalence of neurodysfunctions in pediatric populations is relatively high, compared to defects of other systems. This is linked with the fact that development of the specific structures of the nervous system occurs over a relatively long period of time, during which the processes are affected by harmful factors. It may be difficult to accurately identify the cause even in half of the children affected by the condition [21][22][23] . Research has shown that dysfunctions of the nervous system may impact body height. In fact literature review shows that there are some publications focusing on growth disorders in children with CP 19,[24][25][26][27] , with NTDs 28 , with SD 29 or with hypothyroidism 8,30 , however there are no studies reporting cumulative analyses of relationships between co-occurring growth disorders and syndromes as well as diseases associated with neurodysfunction. Hence, this article presents the first scientific report related to this area. Coexistence of short stature and major diagnoses was examined, however no statistical significance was obtained. Short stature was observed in patients with: NBIA-MPAN, sasMMC&HCP, ACM, DS, ES, DGS, CdLS, FAS, CP, HMSN, LGMD, DMD, AMC&N, CM, and SMA. Therefore, subgroups were distinguished among the patients studied. The coexistence of short stature and separated subgroups as well as short stature and diagnoses in subgroups was studied.
The current study shows more frequent co-occurrence of, and statistically significant relationships between short stature (based on the traditional classification as well as on FDA criteria) and tetraplegia in subgroup with spastic CP. It was also shown that tetraplegia co-occurs with the lower z-score Ht. Growth disorder is a common secondary impairment in children with CP 19 . Likewise, children with CP grow more slowly than children with no   25 . These findings have been confirmed in the present study which shows statistically significant relationship between growth and tetraplegia. An important finding of the current study is the higher prevalence of short stature (traditional classification) in the children with sasMMC&HCP among patients with NTDs. The problem of short stature in children with neural tube defects has been widely known for a long time. Short stature in this group of patients is attributed to smaller lower limbs, spinal deformities and scoliosis 28 .
As it is known, hypothyroidism is one of many causes of short stature 17 . Besides the main diagnoses, we took into consideration additional diagnoses such as hypothyroidism. In Poland, thyroid disease problems are very rarely investigated 32 . In fact, hypothyroidism is the most common thyroid disease. It is estimated that about 2-5% of people in Poland suffer from it. The incidence of hypothyroidism increases with age 32,33 . In the group of children and adolescents examined, hypothyroidism was as common as in the general population -with a rate of 4.3%. It has been shown that, similarly to the general population, in children and adolescents with neurodysfunction, short stature and hypothyroidism occur together. It was also demonstrated that hypothyroidism co-occurs with lower values of z-score Ht. Hypothyroidism may mask other concomitant causes of short stature. In the absence of a satisfactory growth effect during levothyroxine therapy, other possible causes of short height should be investigated 17 . It is noteworthy that all the patients were treated for hypothyroidism. It should be mentioned that hypothyroidism by itself cannot explain such frequent incidence of short stature in the relevant group of children.
Hypothyroidism in children and adolescents is a frequent problem in developing parts of the world and the condition leads to short stature 30 . Gutch et al. in their study assessed the prevalence of short stature in adolescents with hypothyroidism. Out of 900 patients with hypothyroidism, 87 subjects aged 6-18 years were enrolled for the study; they were newly diagnosed with hyperthyroidism or had been treated in an endocrine clinic for up to 1.5 years. The mean age for hypothyroidism diagnosis in the adolescents was 11.2 years. Short stature was observed in 45%, and delayed bone age was found in 72% of the subjects. The authors point out that prompt diagnosis of hypothyroidism may lead to early and effective treatment, and consequently to improvements related to skeletal defects and short stature 30 . Hussein et al. assessed frequency of etiological factors leading to short stature in a group of 637 children (354 boys and 283 girls). Hypothyroidism was the second most common endocrine factor for short stature, preceded only by growth hormone deficiency 8 .
The present study shows that among children and adolescents with neurodysfunction there are relationships between short stature and NTDs, as well as between short stature and spastic CP. Furthermore, short stature in the study group co-occurs with hypothyroidism. It is necessary to carry out endocrinological diagnostics in children and adolescents who have neurodysfunction. Short stature cannot be explained by just "innervation disorders" linked to abnormalities in the central and peripheral nervous system.

conclusions
Children and adolescents with neurodysfunction present growth defects.
Short stature in children and adolescents with neurodysfunction co-occurs with hypothyroidism over the whole group studied, tetraplegia in the subgroup with spastic CP, and in patients operated on due to myelomeningocele with hydrocephalus belonging to the NTDs.