A familial syndrome of hypothalamic hamartomas, polydactyly, and SMO mutations: a clinical report of 2 cases

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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.

ABBREVIATIONS Dhh = 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.

Article Information

Correspondence Sebastian Rubino: Albany Medical Center, Albany, NY. rubinos@amc.edu.

INCLUDE WHEN CITING Published online October 12, 2018; DOI: 10.3171/2018.7.PEDS18292.

Disclosures The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

© AANS, except where prohibited by US copyright law.



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    Case 1. Axial (A) and sagittal (B) noncontrasted T1-weighted MRI sequence, and axial (C) and sagittal (D) contrasted T1-weighted MRI sequence. The thick arrows in each panel demonstrate the 12 × 11 × 16–mm nonenhancing suprasellar mass. In panel B, the thin arrow demonstrates the 4 × 8 × 5–mm nonenhancing pituitary cyst and the thick outlined arrow demonstrates the type I Chiari malformation coming into view.

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    Case 2. Axial (A) and sagittal (B) noncontrasted T1-weighted MRI sequence, and axial (C) and sagittal (D) contrasted T1-weighted MRI sequence. The arrows in each panel indicate the exophytic, nonenhancing 24 × 34 × 27–mm suprasellar mass.

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    Case 2. Endoscopic endonasal operative view of the pituitary gland, stalk, and hypothalamic hamartoma after entry through the sphenoid sinus and sella turcica. Figure is available in color online only.

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    Case 2. Photomicrographs of the hypothalamic hamartoma. Hematoxylin and eosin stain (A and B) demonstrates small foci of vague nodularity in the brain tissue at low power (A, circles), composed of medium-sized neurons with pericellular halo (B, thick arrows), further highlighted by nuclear stain for Neu-N (C). These cells are embedded in finely vacuolated neuropil with a few reactive astrocytes (B, thin arrows), further highlighted by GFAP staining (D). Magnifications ×2.5 (A, C, and D), ×20 (B, insets of C and D). Figure is available in color online only.

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    Hedgehog signaling pathway. Binding of a hedgehog ligand such as Shh inhibits the Patched receptor and allows intravesicular Smoothened to translocate to the cell membrane. There it is activated by GRK2, which ultimately leads to downstream disinhibition of GLIs, allowing them to enter the nucleus to affect gene expression. Adapted by permission from Springer Nature: Nature Publishing Group, Nature Reviews Cancer, G-protein-coupled receptors and cancer by Dorsam RT and Gutkind JS, 2007.9 Akt = serine/threonine protein kinase; cAMP = cyclic adenosine monophosphate; GSKβ = glycogen synthetase kinase 3β; GTP = guanosine triphosphate; PI3K = phosphatidylinositol 3-kinase; PKA = protein kinase A. Figure is available in color online only.



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