Central Precocious Puberty due to Hypothalamic Hamartomas Correlates with Anatomic Features but Not with Expression of GnRH, TGFα, or <i>KISS1</i>

Abstract

Background/Aims: Hypothalamic hamartomas are the most common identifiable cause of central precocious puberty (CPP). Hamartoma characteristics proposed to be associated with CPP include specific anatomic features and expression of molecules such as gonadotropin-releasing hormone (GnRH), transforming growth factor α (TGFα), and GRM1A, which encodes the type 1 metabotropic glutamate receptor α isoform. We sought to determine whether hamartomas that cause CPP could be distinguished by anatomic features, expression of these molecules, or expression of KISS1, whose products signal through the receptor GPR54 to stimulate GnRH release. Methods: Clinical records and radiologic images were reviewed for 18 patients who underwent hamartoma resection for intractable seizures; 7 had precocious puberty. Resected tissue was examined for expression of GnRH, GnRH receptor (GnRHR), TGFα, KISS1, GPR54, and GRM1A. Results: Hypothalamic hamartomas associated with CPP were more likely to contact the infundibulum or tuber cinereum and were larger than hamartomas not associated with CPP. GnRH, TGFα, and GnRHR were expressed by all hamartomas studied. Expression of KISS1, GPR54, and GRM1A did not differ significantly between hamartomas associated and not associated with CPP. Conclusion: Anatomic features rather than expression patterns of candidate molecules distinguish hypothalamic hamartomas that are associated with CPP from those that are not.

Gender-related differences in etiology of organic central precocious puberty

“…15 Neurofibromatosis and optic glioma were more common in that study in comparison to ours, while prevalence of hamartomas were similar (6%). Although idiopathic CPP was more common than organic CPP in boys in our study, still, organic CPP was 3.5 times more common in boys compared to 17,[19][20][21][22][23] In a study including one boy and 20 girls with CPP, hypothalamic hamartomas were present in 14%, and all showed pubertal signs in the first two years of life. 20 In the current study, pubertal signs were observed before two years of age in two girls with hamartoma, whereas onset of puberty was before three years of age in four boys, and between three and seven years of age in the remaining two.…”

Gender-related differences in etiology of organic central precocious puberty

“…15 Neurofibromatosis and optic glioma were more common in that study in comparison to ours, while prevalence of hamartomas were similar (6%). Although idiopathic CPP was more common than organic CPP in boys in our study, still, organic CPP was 3.5 times more common in boys compared to 17,[19][20][21][22][23] In a study including one boy and 20 girls with CPP, hypothalamic hamartomas were present in 14%, and all showed pubertal signs in the first two years of life. 20 In the current study, pubertal signs were observed before two years of age in two girls with hamartoma, whereas onset of puberty was before three years of age in four boys, and between three and seven years of age in the remaining two.…”

High prevalence of syndromic disorders in patients with non-isolated central precocious puberty

“…As previously reported, patients with hypothalamic hamartoma developed CPP at a younger age and displayed faster growth, leading to greater height, more advanced bone maturation and slightly stronger gonadotropin responses after the administration of exogenous GnRH than were observed in other children with CPP (12,23). Hamartomas are noninvasive heterotopic structures that can trigger an increase in GnRH levels through undetermined mechanisms (24,25). Optic gliomas with or without NF1, and arachnoid cysts have also frequently been described in association with CPP (9,10).…”

Hypothalamic hamartomas. Part 1. Clinical, neuroimaging, and neurophysiological characteristics

“…104 However, size is probably not the only feature responsible for these clinical phenotypes. 55 As noted earlier, Chan and colleagues 27 found that HHs associated with CPP were larger and more likely to contact the infundibulum or tuber cinereum than hamartomas not associated with CPP. Figure 4 outlines the common topographical classifications of HHs based on MRI findings described by various investigators.…”

Gender-related differences in etiology of organic central precocious puberty

“…15 Neurofibromatosis and optic glioma were more common in that study in comparison to ours, while prevalence of hamartomas were similar (6%). Although idiopathic CPP was more common than organic CPP in boys in our study, still, organic CPP was 3.5 times more common in boys compared to 17,[19][20][21][22][23] In a study including one boy and 20 girls with CPP, hypothalamic hamartomas were present in 14%, and all showed pubertal signs in the first two years of life. 20 In the current study, pubertal signs were observed before two years of age in two girls with hamartoma, whereas onset of puberty was before three years of age in four boys, and between three and seven years of age in the remaining two.…”

High prevalence of syndromic disorders in patients with non-isolated central precocious puberty

“…As previously reported, patients with hypothalamic hamartoma developed CPP at a younger age and displayed faster growth, leading to greater height, more advanced bone maturation and slightly stronger gonadotropin responses after the administration of exogenous GnRH than were observed in other children with CPP (12,23). Hamartomas are noninvasive heterotopic structures that can trigger an increase in GnRH levels through undetermined mechanisms (24,25). Optic gliomas with or without NF1, and arachnoid cysts have also frequently been described in association with CPP (9,10).…”

Hypothalamic hamartomas. Part 1. Clinical, neuroimaging, and neurophysiological characteristics

“…104 However, size is probably not the only feature responsible for these clinical phenotypes. 55 As noted earlier, Chan and colleagues 27 found that HHs associated with CPP were larger and more likely to contact the infundibulum or tuber cinereum than hamartomas not associated with CPP. Figure 4 outlines the common topographical classifications of HHs based on MRI findings described by various investigators.…”

Gender-related differences in etiology of organic central precocious puberty

“…15 Neurofibromatosis and optic glioma were more common in that study in comparison to ours, while prevalence of hamartomas were similar (6%). Although idiopathic CPP was more common than organic CPP in boys in our study, still, organic CPP was 3.5 times more common in boys compared to 17,[19][20][21][22][23] In a study including one boy and 20 girls with CPP, hypothalamic hamartomas were present in 14%, and all showed pubertal signs in the first two years of life. 20 In the current study, pubertal signs were observed before two years of age in two girls with hamartoma, whereas onset of puberty was before three years of age in four boys, and between three and seven years of age in the remaining two.…”

High prevalence of syndromic disorders in patients with non-isolated central precocious puberty

“…As previously reported, patients with hypothalamic hamartoma developed CPP at a younger age and displayed faster growth, leading to greater height, more advanced bone maturation and slightly stronger gonadotropin responses after the administration of exogenous GnRH than were observed in other children with CPP (12,23). Hamartomas are noninvasive heterotopic structures that can trigger an increase in GnRH levels through undetermined mechanisms (24,25). Optic gliomas with or without NF1, and arachnoid cysts have also frequently been described in association with CPP (9,10).…”

Hypothalamic hamartomas. Part 1. Clinical, neuroimaging, and neurophysiological characteristics

“…104 However, size is probably not the only feature responsible for these clinical phenotypes. 55 As noted earlier, Chan and colleagues 27 found that HHs associated with CPP were larger and more likely to contact the infundibulum or tuber cinereum than hamartomas not associated with CPP. Figure 4 outlines the common topographical classifications of HHs based on MRI findings described by various investigators.…”