Hypothalamic hamartomas are benign tumors known to cause gelastic or dacrystic seizures, precocious puberty, developmental delay, and medically refractory epilepsy. These tumors are most often sporadic but rarely can be associated with Pallister-Hall syndrome, an autosomal dominant familial syndrome caused by truncation of glioblastoma transcription factor 3, a downstream effector in the sonic hedgehog pathway. In this clinical report, the authors describe two brothers with a different familial syndrome. To the best of the authors’ knowledge, this is the first report in the literature describing a familial syndrome caused by germline mutations in the Smoothened (SMO) gene and the first familial syndrome associated with hypothalamic hamartomas other than Pallister-Hall syndrome. The authors discuss the endoscopic endonasal biopsy and subtotal resection of a large hypothalamic hamartoma in one of the patients as well as the histopathological findings encountered. Integral to this discussion is the understanding of the hedgehog pathway; therefore, the underpinnings of this pathway and its clinical associations to date are also reviewed.
ABBREVIATIONSDhh = desert hedgehog; DI = diabetes insipidus; GFAP = glial fibrillary acidic protein; GLI = glioblastoma transcription factor; GRK2 = G protein–coupled receptor kinase 2; Hh = hedgehog; Ihh = Indian hedgehog; PTCH = Patched; Shh = sonic hedgehog; SUFU = Suppressor of Fused.
BerkovicSFAndermannFMelansonDEthierREFeindelWGloorP: Hypothalamic hamartomas and ictal laughter: evolution of a characteristic epileptic syndrome and diagnostic value of magnetic resonance imaging. Ann Neurol23:429–4391988
DyerMAFarringtonSMMohnDMundayJRBaronMH: Indian hedgehog activates hematopoiesis and vasculogenesis and can respecify prospective neurectodermal cell fate in the mouse embryo. Development128:1717–17302001
HallJGPallisterPDClarrenSKBeckwithJBWiglesworthFWFraserFC: Congenital hypothalamic hamartoblastoma, hypopituitarism, imperforate anus and postaxial polydactyly—a new syndrome? Part I: clinical, causal, and pathogenetic considerations. Am J Med Genet7:47–741980
LewisPMDunnMPMcMahonJALoganMMartinJFSt-JacquesB: Cholesterol modification of sonic hedgehog is required for long-range signaling activity and effective modulation of signaling by Ptc1. Cell105:599–6122001
NishimakiHKasaiKKozakiKiTakeoTIkedaHSagaS: A role of activated Sonic hedgehog signaling for the cellular proliferation of oral squamous cell carcinoma cell line. Biochem Biophys Res Commun314:313–3202004
SasakiHNishizakiYHuiCNakafukuMKondohH: Regulation of Gli2 and Gli3 activities by an amino-terminal repression domain: implication of Gli2 and Gli3 as primary mediators of Shh signaling. Development126:3915–39241999
VorechovskýIUndénABSandstedtBToftgårdRStåhle-BäckdahlM: Trichoepitheliomas contain somatic mutations in the overexpressed PTCH gene: support for a gatekeeper mechanism in skin tumorigenesis. Cancer Res57:4677–46811997
WijgerdeMOomsMHoogerbruggeJWGrootegoedJA: Hedgehog signaling in mouse ovary: Indian hedgehog and desert hedgehog from granulosa cells induce target gene expression in developing theca cells. Endocrinology146:3558–35662005
YangYDrossopoulouGChuangPTDuprezDMartiEBumcrotD: Relationship between dose, distance and time in Sonic Hedgehog-mediated regulation of anteroposterior polarity in the chick limb. Development124:4393–44041997