Child's Nervous System https://doi.org/10.1007/s00381-020-04894-y CASE REPORT Description of a giant hypothalamic hamartoma associated with an immature ruptured giant sacrococcygeal teratoma: a case report Nicolas Serratrice 1 2 3 4 5 & Alice Faure & Andre Maues de Paula & Nadine Girard & Nicolas André & Didier Scavarda 1,6 Received: 12 May 2020 / Accepted: 22 September 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020 Abstract Giant hypothalamic hamartomas (GHH) are rare neonatal intracerebral congenital malformations responsible for gelastic epilepsy and/or endocrine disturbances. Sacrococcygeal teratomas (SCT) are fetal neoplasms associated with perinatal morbidity and mortality, especially hemorrhagic complications in giant examples (GSCT). Here, we describe an immature ruptured GSCT complicated by hemorrhagic shock at 32-week gestation boy requiring an emergency delivery, followed immediately by urgent surgical removal. A brain lesion resembling a GHH was also present on the antenatal MRI. In order to exclude metastatic immature teratoma or glioma, a biopsy was performed by a retro-sigmoidal approach, which confirmed the nature of the hamartoma. Here, we describe for the first time the association of a ruptured immature GSCT associated with a GHH. Keywords Sacrococcygeal teratoma . Hypothalamic hamartoma . Giant . Epilepsy . Endocrine . Pediatric neurosurgery Introduction Giant hypothalamic hamartomas (GHH) are extremely rare neonatal intracerebral congenital malformations [1, 2]. They generally exceed 30–40 mm and can be responsible for hydrocephalus due to their associated mass effect [1, 3]. They are usually diagnosed in infants with magnetic resonance imaging (MRI) [1, 4]. The main differential diagnosis is hypothalamic glioma that should be systematically suspected when there is * Nicolas Serratrice nicolas.serratrice@ap-hm.fr; nico.serratrice@orange.fr Alice Faure alice.faure@ap-hm.fr contrast enhancement [2] or growing tumor. The mechanism of development of GHH is largely unclear [2]. GHH are intrinsically epileptogenic [5, 6], have a lower frequency of central precocious puberty (CPP) [1, 7], and can be associated with other midline brain and facial malformations (but they genetically differ from the lesions of Pallister-Hall syndrome) [8]. Sacrococcygeal teratomas larger than 10 cm are considered as giant (GSCT) and are at risk for significant perinatal 2 Department of Pediatric Surgery, La Timone Children Hospital, Assistance Publique - Hôpitaux de Marseille, Marseille, Provence-Alpes-Côte d’Azur, France 3 Department of Pathology, La Timone Hospital, Assistance Publique Hôpitaux de Marseille, Marseille, Provence-Alpes-Côte d’Azur, France 4 Department of Neuroradiology, La Timone Hospital, Assistance Publique - Hôpitaux de Marseille, Marseille, Provence-Alpes-Côte d’Azur, France 5 Department of Pediatric oncology, La Timone Children Hospital, Assistance Publique - Hôpitaux de Marseille, Marseille, Provence-Alpes-Côte d’Azur, France 6 Institut de Neurosciences des Systèmes, Aix-Marseille Université, Marseille, France Andre Maues de Paula andre.mauesdepaula@ap-hm.fr Nadine Girard nadine.girard@ap-hm.fr Nicolas André nicolas.andre@ap-hm.fr Didier Scavarda didier.scavarda@ap-hm.fr 1 Department of Pediatric Neurosurgery, La Timone Children Hospital, Assistance Publique - Hôpitaux de Marseille, Marseille, Provence-Alpes-Côte d’Azur, France Childs Nerv Syst morbidity and mortality [9]. Diagnosis is often made at an early gestational age, and this, plus development of fetal hydrops, and premature delivery all predict a poor prognosis [10]. It is recommended that whenever possible, delivery should be delayed to allow for maximal fetal development [10]. Stabilization of the infant should be attempted before resection of the GSCT; amnioreduction, cyst aspiration, and surgical debulking are potentially lifesaving interventions [11]. In the absence of fulminant hydrops or tumor rupture in utero, preemptive early delivery can be associated with favorable outcomes [10, 11]. Genetic causes for GSCT are unknown; however, they may be associated with other abnormalities [12]. Here, we describe for the first time the association of a GHH with an immature ruptured GSCT. Case report A large sacrococcygeal mass associated with significant polyhydramnios was discovered at 28 weeks of gestation (WG) by prenatal ultrasound (US). A fetal MRI showed a 12 × 13 × 11 cm mass arising from the coccyx suspicious for a GSCT (Fig. 1a–f). The imaging also revealed an associated 3.7 × 1.5 × 3.1 cm lesion at the base of the brain, suspicious for a GHH (Fig. 1d and e, red arrows). The subsequent onset of anasarca precipitated an emergency delivery via Caesarian section at 32 WG, with delivery of a 3.250 kg boy, who from birth had respiratory distress requiring intubation with transient assisted ventilation and surfactant supplementation. Then, the GSCT spontaneously ruptured (Fig. 2a), causing hemorrhagic shock requiring multiple transfusions, blood pressure support with norepinephrine, and leading to emergency surgical resection. At surgery, the mass was seen to be attached to the coccyx but was not invading the gluteal muscles, allowing for repositioning of the rectum and for gross total excision. The child was 1.80 kg following surgery. Histopathologically, the tumor consisted of multiple different tissue types including multiple foci with immature neuroepithelial tubules (Fig. 2b). The final diagnosis was WHO Grade 3 immature teratoma. The boy progressively developed axial hypotonia and feeding difficulties. EEG revealed bilateral temporo-occipital rhythmic discharges compatible with subclinical seizures. Phenobarbital was introduced. Trans-anterior fontanel US (Fig. 3a) and MRI performed at 1 month of life revealed progression of the 3.7 × 1.9 × 3.1 cm brain lesion, extending from the suprasellar region to the left cerebellopontine angle with a wide mass effect on the brainstem and with stretching of the pituitary stalk. The lesion did not enhance after contrast administration, and there was no abnormality of the spinal cord. Given the high alpha-fetoprotein (AFP) serum level, a diagnosis of metastatic immature GSCT was first considered. The child improved neurologically with better psychomotor status: he was able to track visually, and he had improved swallowing, but his axial hypotonia persisted. Primitive reflexes were still not present. The giant suprasellar mass continued to enlarge, reaching 4.6 × 3.2 × 3.9 cm and causing mass effect on the third ventricle with dilatation of the lateral ventricles (Fig. 3b–i). While the lesion’s MR signal characteristics were similar to those of normal brain, we decided to confirm its nature by a brain biopsy through a left retrosigmoidal open approach (Fig. 3j and l). The histology was hamartoma (Fig. 3k). The post-operative period was marked by a meningocele and a CSF leak (Fig. 3m) requiring the placement of a ventriculo-peritoneal shunt (Fig. 3n). Psychomotor development further improved, and the boy acquired walking at 2 years old, and he began the association of words to make sentences. In the same period, his anti-epileptic drug was stopped. The follow-up of the child now consists of an annual evaluation by pediatric epileptologists and endocrinologists with MRI and blood samples. Discussion Although different theories have been proposed, the exact etiology of hypothalamic hamartomas and sacrococcygeal teratomas, whether that differs for, and any potential link between these two kinds of lesions are unclear [1, 13, 14]. The classic model of teratoma formation is based on the misplacement of primordial germ cells from the primitive yolk sac causing abnormal m igration and differentiation. Environmental factors could directly interact with their migration and differentiation properties, hence generating teratomas [14]. On the other hand, the underlying cause for hypothalamic hamartomas is less unclear. A defect in factors that regulate fetal development of the hypothalamus is most likely. Over 95% of cases are sporadic, but hypothalamic hamartomas can also occur in patients with identified genetic disorders, such Pallister-Hall syndrome associated with mutations in the GLI3 gene, which acts as a transcription factor in the sonic hedgehog intracellular signaling pathway known to play a major role in the first month of the brain development [15]. The development of multiple lesions in a neonate and their timing of outcome might suggest a genetic predisposition [16, 17]. However, the familial pedigree was not in favor of any cancer predisposition, and hamartomas are not neoplasms, much less cancers. Moreover, a genetic evaluation and a germline testing were offered to the child and his parents but declined by them. GHH are intrinsically epileptogenic, with a similar frequency of seizures compared with non-giant hypothalamic hamartomas [5, 6]. Persistent seizures can be debilitating and result in significant cognitive and behavioral impairment Childs Nerv Syst Fig. 1 (a–f) Antenatal (in utero) MRI: (a–b) localizer images demonstrate a solid and cystic mass (white arrows) protruding behind the fetus. (c) TRU-FISP sequences also readily demonstrate the large teratoma. (d–f) HASTE images also reveal the mass; in d the intracranial giant hypothalamic hamartoma is also apparent (red arrows). (e) is a magnification of d in children. Early recognition and treatment are crucial to control seizures and to prevent further cognitive deterioration. Several minimally invasive procedures have been devised, but without conclusive results in giant forms [18]. Luckily, the child described in our report has not developed epilepsy to date. He is now 3 years old and has a relatively normal psychomotor development. Subsequent EEGs also showed no sign of subclinical seizures, and anti-epileptic drugs were progressively reduced and eventually stopped with no subsequent adverse effects. Fig. 2 (a) Picture of the giant teratoma rupturing spontaneously after the birth. (b) Histological section from the teratoma, demonstrating a highly cellular neoplasm with immature tissues including neuroepithelial tubules (red arrows). Hematoxylin & eosin, scale bar = 500 μm Childs Nerv Syst suspected mechanism of CPP is related to ectopic generation and pulsatile release of gonadotropin-releasing hormone (GnRH) [18]. Possible regulators could be glial factors (such as TGFα) and the GABA-mediated excitation pathway [18]. Both are known to be present in surgically resected hamartomatous tissues but are present in such tissues from patients with and without CPP, suggesting that the symptoms related to hamartomas might be more directly associated with their implantation site in the hypothalamus [19, 20]. Moreover, GnRH agonists are widely available and effective, while surgery is mainly reserved for patients with intractable epilepsy [6]. Conclusion For the moment, we have no link between these two rare forms of giant lesions. However, the occurrence of these two uncommon midline abnormalities suggests this is more than coincidence although the combination has not previously been recognized as part of any syndrome. However, one might be established by future genetic studies. Acknowledgments We are grateful to the co-authors for the rereading of the article. Compliance with ethical standards Conflict of interest The authors have nothing to disclose. References 1. Fig. 3 Giant hypothalamic hamartoma in trans-anterior fontanel US (a), in CT scan without (b) and with contrast (c) in axial planes, and in MRI respectively in sagittal (d), and coronal (e) T1-weighted images, coronal T2-weighted images (f), and sagittal (g), axial (h), and coronal (i) T1weighted images after gadolinium administration. (j) Per-operative view of the hamartoma shows signal characteristics similar to those of normal brain parenchyma (white asterisk). (k) Histology showing a tissue also comparable with normal brain parenchyma (hematoxylin/eosin, magnification × 200). Scale bar = 100 μm. (l) Post-biopsy CT scan shows pneumocephaly at the site of the biopsy (white arrow). (m) Postsurgical meningocele (white arrow) requiring an intraventricular shunt (n), positioning on a CT scan axial plane Patients with GHH have a lower frequency of central precocious puberty (CPP) than non-giant forms [1, 7]. The Alves C, Barbosa V, Machado M (2013) Giant hypothalamic hamartoma: case report and literature review. Childs Nerv Syst 29(3):513–516. https://doi.org/10.1007/s00381-013-2022-y Review 2. Kandregula S, Savardekar AR, Nandeesh BN, Arivazhagan A, Rao MB (2017) Giant hypothalamic hamartoma in an infant: a case report and review of the literature. Pediatr Neurosurg 52(1):55–61 3. Dorfer C, Kasprian G, Mühlebner A, Czech T (2011) Giant solidcystic hypothalamic hamartoma. Case report. Neurosurg Focus 30(2):E7. https://doi.org/10.3171/2011.1.FOCUS10240 4. Guibaud L, Rode V, Saint-Pierre G, Pracros JP, Foray P, TranMinh VA (1995) Giant hypothalamic hamartoma: an unusual neonatal tumor. Pediatr Radiol 25(1):17–18. https://doi.org/10.1007/ bf02020833 5. Razzaq AA, Chishti MK (2001) Giant hypothalamic hamartoma and associated seizure types. J Pak Med Assoc 51(8):296–298 6. Scholly J, Staack AM, Kahane P, Scavarda D, Régis J, Hirsch E, Bartolomei F (2017) Hypothalamic hamartoma: epileptogenesis beyond the lesion? Epilepsia 58(Suppl 2):32–40. https://doi.org/ 10.1111/epi.13755 7. Zúñiga OF, Tanner SM, Wild WO, Mosier HD Jr (1983) Hamartoma of CNS associated with precocious puberty. Am J Dis Child 137(2):127–133 8. Guimiot F, Marcorelles P, Aboura A, Bonyhay G, Patrier S, Menez F, Drouin-Garraud V, Icowick V, Eurin D, Garel C, Moirot H, Childs Nerv Syst Verspyck E, Saugier-Veber P, Attie-Bitach T, Picone O, Oury JF, Verloes A, Delezoide AL, Laquerrière A (2009) Giant diencephalic harmartoma and related anomalies: a newly recognized entity distinct from the Pallister-Hall syndrome. Am J Med Genet A 149A(6):1108–1115. https://doi.org/10.1002/ajmg.a.32859 9. Peiró JL, Sbragia L, Scorletti F, Lim FY, Shaaban A (2016) Management of fetal teratomas. Pediatr Surg Int 32(7):635–647. https://doi.org/10.1007/s00383-016-3892-3 10. Aktepe Keskin E, Arikan Onaran Y, Derbent A, Ayrim A, Kafali H (2011) Prenatal diagnosis and follow-up of giant sacrococcygeal teratoma. Taiwan J Obstet Gynecol 50(2):242–244. https://doi. org/10.1016/j.tjog.2011.01.023 11. Alani MA (2017) Successful postnatal management of ruptured giant sacrococcygeal teratoma. J Neonatal Surg 6(2):37. https:// doi.org/10.21699/jns.v6i2.471 eCollection 2017 Apr-Jun 12. Kremer MEB, Althof JF, Derikx JPM, van Baren R, Heij HA, Wijnen MHWA, Wijnen RMH, van der Zee DC, van Heurn LWE (2018) The incidence of associated abnormalities in patients with sacrococcygeal teratoma. J Pediatr Surg. https://doi.org/10. 1016/j.jpedsurg.2018.01.013 13. Freeman JL (2003) The anatomy and embryology of the hypothalamus in relation to hypothalamic hamartomas. Epileptic Disord 5(4):177–186 14. Shahjouei S, Hanaei S, Nejat F, Monajemzadeh M, Khashab ME (2015) Sacrococcygeal teratoma with intradural extension: case report. J Neurosurg Pediatr 15(4):380–383. https://doi.org/10.3171/ 2014.10.PEDS1445 15. Hildebrand MS, Griffin NG, Damiano JA, Cops EJ, Burgess R, Ozturk E, Jones NC, Leventer RJ, Freeman JL, Harvey AS, Sadleir LG, Scheffer IE, Major H, Darbro BW, Allen AS, Goldstein DB, Kerrigan JF, Berkovic SF, Heinzen EL (2016) Mutations of the sonic hedgehog pathway underlie hypothalamic hamartoma with gelastic epilepsy. Am J Hum Genet 99(2):423– 429. https://doi.org/10.1016/j.ajhg.2016.05.031 16. Orbach D, Sarnacki S, Brisse HJ, Gauthier-Villars M, Jarreau PH, Tsatsaris V, Baruchel A, Zerah M, Seigneur E, Peuchmaur M, Doz F (2013) Neonatal cancer. Lancet Oncol 14:e609–e620. https://doi. org/10.1016/S1470-2045(13)70236-5 17. Alfaar AS, Hassan WM, Bakry MS, Qaddoumi I (2017) Neonates with cancer and causes of death; lessons from 615 cases in the SEER databases. Cancer Med 6:1817–1826. https://doi.org/10. 1002/cam4.1122 18. Khawaja AM, Pati S, Ng YT (2017) Management of epilepsy due to hypothalamic hamartomas. Pediatr Neurol 75:29–42. https://doi. org/10.1016/j.pediatrneurol.2017.07.001 19. Harrison VS, Oatman O, Kerrigan JF (2017) Hypothalamic hamartoma with epilepsy: review of endocrine comorbidity. Epilepsia 58(Suppl 2):50–59. https://doi.org/10.1111/epi.13756 20. Prasad S, Shah J, Patkar D, Gala B, Patankar T (2000) Giant hypothalamic hamartoma with cystic change: report of two cases and review of the literature. Neuroradiology 42(9):648–650. https://doi. org/10.1007/s002340000350 Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.