Original Paper
HOR MON E RE SE ARCH I N PÆDIATRIC S
Horm Res Paediatr 2015;83:118–125 DOI: 10.1159/000370066
Received: August 25, 2014 Accepted: November 24, 2014 Published online: January 21, 2015
Thyroid Function in Rett Syndrome Stefano Stagi a Loredana Cavalli b Laura Congiu c Maria Flora Scusa c Alessandra Ferlini d Stefania Bigoni d Alberto Benincasa c Bruno Rossi b Giorgio Pini c a
Health Sciences Department, University of Florence, Anna Meyer Children’s University Hospital, Florence, Department of Neuroscience, Section of Neurorehabilitation, University of Pisa, Pisa, c Tuscany Rett Center, Versilia Hospital, Viareggio, and d Medical Genetic Section, Department of Medical Sciences, Ferrara University, Ferrara, Italy
b
Abstract Introduction: Thyroid function in Rett syndrome (RTT) has rarely been studied with unanimous results. However, this aspect is of great concern regarding the effect thyroid hormones (TH) have on proper mammalian brain development. Objective: To evaluate the prevalence of abnormalities of thyroid function in a cohort of children with RTT. Patients and Methods: Forty-five consecutive Caucasian girls (mean age: 8.6 ± 5.3 years, range: 2.0–26.1) meeting the clinical criteria for RTT were recruited. In all of the subjects, we evaluated the serum concentrations of free-T3 (FT3), free-T4 (FT4), thyroid-stimulating hormone (TSH), thyroperoxidase autoantibodies, thyroglobulin autoantibodies (TgA), and TSH receptor (TSHr) autoantibodies. The results were compared with a group of 146 age-matched healthy Caucasian children and adolescent girls (median age: 9.5 years, range: 1.8– 14.6) from the same geographical area. Results: Mean FT3 and TSH levels were not significantly different between the RTT patients and controls. Nevertheless, FT4 levels were significantly higher in RTT patients than in controls (p < 0.005). In particular, 17.7% showed FT4 levels higher than the upper reference limit (vs. 0.7% of controls, p < 0.0001), whereas 12
© 2015 S. Karger AG, Basel 1663–2818/15/0832–0118$39.50/0 E-Mail [email protected] www.karger.com/hrp
patients (26.7%) showed higher FT3 levels than the upper reference limit, significantly differing in respect to controls (2.0%, p < 0.0001). Finally, 5 patients (11.1%) showed higher levels of TSH, statistically differing from the control subjects (2.0%, p < 0.0001). However, evaluating the patients on the basis of different RTT genotype subgroups, patients with CDKL5 deletions showed significantly higher FT4 values than patients with MeCP2 deletions (p < 0.05). On the other hand, patients with other types of MeCP2 mutations also showed FT4 levels significantly higher than patients with MeCP2 deletions (p < 0.05). In fact, out of 8 patients with FT4 levels higher than the upper references limit, 3 of them presented with CDKL5 deletions (3 patients, 37.5%), 4 (50%) had MeCP2 mutations, and 1 (12.5%) belonged to the subgroup of MeCP2 deletions. However, when analyzing FT3 levels of the 12 patients showing higher FT3 levels than the upper references limit, 6 (50%) belonged to the subgroup with MeCP2 mutations, 4 (33.3%) to the subgroup with MeCP2 deletions, and 2 (16.7%) to the subgroups with CDKL5 deletions. Furthermore, no patient with RTT was positive for antithyroglobulin autoantibodies, antithyroid peroxidase, or antiTSHr, with no statistical differences in respect to the controls. L-thyroxine treatment was not necessary for any patient. Conclusions: Abnormalities of thyroid function are not rare in RTT. The possible relationship between these dis-
S.S. and L.C. contributed equally to the manuscript.
Dr. Loredana Cavalli Via Valfonda 7 IT–50123 Firenze (Italy) E-Mail cavallil.doc @ gmail.com
Downloaded by: University of Nebraska-Lincoln Libraries 129.93.16.3 - 4/3/2015 7:39:19 PM
Key Words Children · Rett syndrome · Thyroid function · Thyroid autoimmunity · Subclinical hypothyroidism · Hypothyroidism · Thyroid hormone
Introduction
Rett syndrome (RTT; OMIM 312750) is an X-linked neurodevelopmental disorder that affects almost exclusively girls [1]. It is characterized by loss of spoken language and hand use with the development of distinctive hand stereotypies, and was originally described by Andreas Rett in the 1960s [2, 3]. The prevalence of RTT ranges from 1:10,000 to 1:22,000 [4]. Typical RTT girls have an apparently normal development until the 6- to 1-month period, and then present a progressive deterioration or loss of acquired skills such as purposeful hand function and communication, deceleration of head growth, and later the appearance of stereotypic hand movements. This syndrome is associated to comorbidities including reduced somatic growth, gastrointestinal disease, osteopenia, gait apraxia, scoliosis, autonomic dysfunction, breathing disturbances, and commonly seizures [1, 3, 5–11]. In addition to typical or classical RTT, some individuals present with many, but not all, of the clinical features of RTT, thus there are ‘variant’ or ‘atypical’ RTT, which have been found to cluster in some distinct clinical groupings, such as the ‘preserved speech variant’, which is characterized by the recovery of some degree of speech [12], the ‘congenital variant’, which is recognized at birth and was recently identified with the mutation in FOXG1 gene [13], and the ‘early-onset seizure variant’, which is also known as the ‘Hanefeld variant’ [14]. In 90–95% of the cases with typical RTT, mutations in Methyl-CpG binding protein 2 gene (MeCP2; OMIM 300005) have been detected. On the other hand, patients with Rett phenotype and early-onset of epilepsy are known to be caused by mutations in the cyclin-dependent kinase-like 5 gene (CDKL5; OMIM 300203) [15]. In contrast, males, who are hemizygous for comparable mutations, generally do not survive [16]. Thyroid function has been rarely studied in RTT patients, but one study reported a higher prevalence of lower mean serum total thyroxine (TT4) [17], whereas another study did not disclose problems in free-T4 (FT4) and thyroid-stimulating hormone (TSH) levels in these patients [18]. However, this aspect is of great concern regarding the effect of thyroid hormones (TH) on proper mammalian RTT and Thyroid Function
Table 1. Demographic data and prevalence of thyroid dysfunction
and autoimmunity in patients with RTT and controls RTT
Controls
Patients, n 45 146 Age, years 8.60±5.3 9.0±5.8 Height, SDS –0.67±1.24 0.03±1.19 BMI, SDS –0.80±1.59 0.34±1.47 Tanner stage Prepubertal, n (%) 32 (71.1%) 99 (67.8%) Pubertal, n (%) 13 (28.9%) 47 (32.2%) Subjects, n MeCP2 mutations 29 – MeCP2 deletions 10 – CDKL5 mutations 6 – 17.15±4.43 14.52±4.12 FT4 levels, pmol/l 6.16±1.10 6.43±0.93 FT3 levels, pmol/l TSH levels, μIU/ml 2.41±1.45 2.77±1.31 Hyperthyroxinemia 17.7% 0.7% 26.7% 2.0% Increased FT3 levels Subclinical hypothyroidism 10.2% 2.0% Overt hypothyroidism 0.0% 0.0% Thyroid autoimmunity 0.0% 1.1%
p – –
HOR MON E RE SE ARCH I N PÆDIATRIC S
Horm Res Paediatr 2015;83:118–125 DOI: 10.1159/000370066
Received: August 25, 2014 Accepted: November 24, 2014 Published online: January 21, 2015
Thyroid Function in Rett Syndrome Stefano Stagi a Loredana Cavalli b Laura Congiu c Maria Flora Scusa c Alessandra Ferlini d Stefania Bigoni d Alberto Benincasa c Bruno Rossi b Giorgio Pini c a
Health Sciences Department, University of Florence, Anna Meyer Children’s University Hospital, Florence, Department of Neuroscience, Section of Neurorehabilitation, University of Pisa, Pisa, c Tuscany Rett Center, Versilia Hospital, Viareggio, and d Medical Genetic Section, Department of Medical Sciences, Ferrara University, Ferrara, Italy
b
Abstract Introduction: Thyroid function in Rett syndrome (RTT) has rarely been studied with unanimous results. However, this aspect is of great concern regarding the effect thyroid hormones (TH) have on proper mammalian brain development. Objective: To evaluate the prevalence of abnormalities of thyroid function in a cohort of children with RTT. Patients and Methods: Forty-five consecutive Caucasian girls (mean age: 8.6 ± 5.3 years, range: 2.0–26.1) meeting the clinical criteria for RTT were recruited. In all of the subjects, we evaluated the serum concentrations of free-T3 (FT3), free-T4 (FT4), thyroid-stimulating hormone (TSH), thyroperoxidase autoantibodies, thyroglobulin autoantibodies (TgA), and TSH receptor (TSHr) autoantibodies. The results were compared with a group of 146 age-matched healthy Caucasian children and adolescent girls (median age: 9.5 years, range: 1.8– 14.6) from the same geographical area. Results: Mean FT3 and TSH levels were not significantly different between the RTT patients and controls. Nevertheless, FT4 levels were significantly higher in RTT patients than in controls (p < 0.005). In particular, 17.7% showed FT4 levels higher than the upper reference limit (vs. 0.7% of controls, p < 0.0001), whereas 12
© 2015 S. Karger AG, Basel 1663–2818/15/0832–0118$39.50/0 E-Mail [email protected] www.karger.com/hrp
patients (26.7%) showed higher FT3 levels than the upper reference limit, significantly differing in respect to controls (2.0%, p < 0.0001). Finally, 5 patients (11.1%) showed higher levels of TSH, statistically differing from the control subjects (2.0%, p < 0.0001). However, evaluating the patients on the basis of different RTT genotype subgroups, patients with CDKL5 deletions showed significantly higher FT4 values than patients with MeCP2 deletions (p < 0.05). On the other hand, patients with other types of MeCP2 mutations also showed FT4 levels significantly higher than patients with MeCP2 deletions (p < 0.05). In fact, out of 8 patients with FT4 levels higher than the upper references limit, 3 of them presented with CDKL5 deletions (3 patients, 37.5%), 4 (50%) had MeCP2 mutations, and 1 (12.5%) belonged to the subgroup of MeCP2 deletions. However, when analyzing FT3 levels of the 12 patients showing higher FT3 levels than the upper references limit, 6 (50%) belonged to the subgroup with MeCP2 mutations, 4 (33.3%) to the subgroup with MeCP2 deletions, and 2 (16.7%) to the subgroups with CDKL5 deletions. Furthermore, no patient with RTT was positive for antithyroglobulin autoantibodies, antithyroid peroxidase, or antiTSHr, with no statistical differences in respect to the controls. L-thyroxine treatment was not necessary for any patient. Conclusions: Abnormalities of thyroid function are not rare in RTT. The possible relationship between these dis-
S.S. and L.C. contributed equally to the manuscript.
Dr. Loredana Cavalli Via Valfonda 7 IT–50123 Firenze (Italy) E-Mail cavallil.doc @ gmail.com
Downloaded by: University of Nebraska-Lincoln Libraries 129.93.16.3 - 4/3/2015 7:39:19 PM
Key Words Children · Rett syndrome · Thyroid function · Thyroid autoimmunity · Subclinical hypothyroidism · Hypothyroidism · Thyroid hormone
Introduction
Rett syndrome (RTT; OMIM 312750) is an X-linked neurodevelopmental disorder that affects almost exclusively girls [1]. It is characterized by loss of spoken language and hand use with the development of distinctive hand stereotypies, and was originally described by Andreas Rett in the 1960s [2, 3]. The prevalence of RTT ranges from 1:10,000 to 1:22,000 [4]. Typical RTT girls have an apparently normal development until the 6- to 1-month period, and then present a progressive deterioration or loss of acquired skills such as purposeful hand function and communication, deceleration of head growth, and later the appearance of stereotypic hand movements. This syndrome is associated to comorbidities including reduced somatic growth, gastrointestinal disease, osteopenia, gait apraxia, scoliosis, autonomic dysfunction, breathing disturbances, and commonly seizures [1, 3, 5–11]. In addition to typical or classical RTT, some individuals present with many, but not all, of the clinical features of RTT, thus there are ‘variant’ or ‘atypical’ RTT, which have been found to cluster in some distinct clinical groupings, such as the ‘preserved speech variant’, which is characterized by the recovery of some degree of speech [12], the ‘congenital variant’, which is recognized at birth and was recently identified with the mutation in FOXG1 gene [13], and the ‘early-onset seizure variant’, which is also known as the ‘Hanefeld variant’ [14]. In 90–95% of the cases with typical RTT, mutations in Methyl-CpG binding protein 2 gene (MeCP2; OMIM 300005) have been detected. On the other hand, patients with Rett phenotype and early-onset of epilepsy are known to be caused by mutations in the cyclin-dependent kinase-like 5 gene (CDKL5; OMIM 300203) [15]. In contrast, males, who are hemizygous for comparable mutations, generally do not survive [16]. Thyroid function has been rarely studied in RTT patients, but one study reported a higher prevalence of lower mean serum total thyroxine (TT4) [17], whereas another study did not disclose problems in free-T4 (FT4) and thyroid-stimulating hormone (TSH) levels in these patients [18]. However, this aspect is of great concern regarding the effect of thyroid hormones (TH) on proper mammalian RTT and Thyroid Function
Table 1. Demographic data and prevalence of thyroid dysfunction
and autoimmunity in patients with RTT and controls RTT
Controls
Patients, n 45 146 Age, years 8.60±5.3 9.0±5.8 Height, SDS –0.67±1.24 0.03±1.19 BMI, SDS –0.80±1.59 0.34±1.47 Tanner stage Prepubertal, n (%) 32 (71.1%) 99 (67.8%) Pubertal, n (%) 13 (28.9%) 47 (32.2%) Subjects, n MeCP2 mutations 29 – MeCP2 deletions 10 – CDKL5 mutations 6 – 17.15±4.43 14.52±4.12 FT4 levels, pmol/l 6.16±1.10 6.43±0.93 FT3 levels, pmol/l TSH levels, μIU/ml 2.41±1.45 2.77±1.31 Hyperthyroxinemia 17.7% 0.7% 26.7% 2.0% Increased FT3 levels Subclinical hypothyroidism 10.2% 2.0% Overt hypothyroidism 0.0% 0.0% Thyroid autoimmunity 0.0% 1.1%
p – –
