Non-idiopathic CPP is caused by acquired or congenital hypothalamic lesions visible on MRI or is associated with various complex genetic and/or syndromic disorders. This study investigated the different types and prevalence of non-isolated CPP phenotypes.
Design and Methods
This observational cohort study included all patients identified as having non-idiopathic CPP in the database of a single academic pediatric care center over a period of 11.5 years. Patients were classified on the basis of MRI findings for the CNS as having either hypothalamic lesions or complex syndromic phenotypes without structural lesions of the hypothalamus.
In total, 63 consecutive children (42 girls and 21 boys) with non-isolated CPP were identified. Diverse diseases were detected, and the hypothalamic lesions visible on MRI (n = 28, 45% of cases) included hamartomas (n = 17; either isolated or with an associated syndromic phenotype), optic gliomas (n = 8; with or without neurofibromatosis type 1), malformations (n = 3) with interhypothalamic adhesions (n = 2; isolated or associated with syndromic CNS midline abnormalities, such as optic nerve hypoplasia, ectopic posterior pituitary) or arachnoid cysts (n = 1). The patients with non-structural hypothalamic lesions (n = 35, 55% of cases) had narcolepsy (n = 9), RASopathies (n = 4), encephalopathy or autism spectrum disorders with or without chromosomal abnormalities (n = 15) and other complex syndromic disorders (n = 7).
Our findings suggest that a large proportion (55%) of patients with non-isolated probable non-idiopathic CPP may have complex disorders without structural hypothalamic lesions on MRI. Future studies should explore the pathophysiological relevance of the mechanisms underlying CPP in these disorders.
SilveiraLGNoelSDSilveira-NetoAPAbreuAPBritoVNSantosMGBiancoSDKuohungWXuSGryngartenMet al. Mutations of the KISS1 gene in disorders of puberty. Journal of Clinical Endocrinology and Metabolism2010952276–2280. (https://doi.org/10.1210/jc.2009-2421)
TelesMGBiancoSDBritoVNTrarbachEBKuohungWXuSSeminaraSBMendoncaBBKaiserUBLatronicoAC.A GPR54-activating mutation in a patient with central precocious puberty. New England Journal of Medicine2008358709–715. (https://doi.org/10.1056/NEJMoa073443)
DauberACunha-SilvaMMacedoDBBritoVNAbreuAPRobertsSAMontenegroLRAndrewMKirbyAWeirauchMTet al. Paternally inherited DLK1 deletion associated with familial central precocious puberty. Journal of Clinical Endocrinology and Metabolism20171021557–1567. (https://doi.org/10.1210/jc.2016-3677)
AbreuAPDauberAMacedoDBNoelSDBritoVNGillJCCukierPThompsonIRNavarroVMGagliardiPCet al. Central precocious puberty caused by mutations in the imprinted gene MKRN3. New England Journal of Medicine20133682467–2475. (https://doi.org/10.1056/NEJMoa1302160)
MogensenSSAksglaedeLMouritsenASorensenKMainKMGideonPJuulA.Diagnostic work-up of 449 consecutive girls who were referred to be evaluated for precocious puberty. Journal of Clinical Endocrinology and Metabolism2011961393–1401. (https://doi.org/10.1210/jc.2010-2745)
TrivinCCouto-SilvaACSainte-RoseCChemaitillyWKalifaCDozFZerahMBraunerR.Presentation and evolution of organic central precocious puberty according to the type of CNS lesion. Clinical Endocrinology200665239–245. (https://doi.org/10.1111/j.1365-2265.2006.02582.x)
MogensenSSAksglaedeLMouritsenASorensenKMainKMGideonPJuulA.Pathological and incidental findings on brain MRI in a single-center study of 229 consecutive girls with early or precocious puberty. PLoS ONE20127e29829. (https://doi.org/10.1371/journal.pone.0029829)
PedicelliSAlessioPScireGCappaMCianfaraniS.Routine screening by brain magnetic resonance imaging is not indicated in every girl with onset of puberty between the ages of 6 and 8 years. Journal of Clinical Endocrinology and Metabolism2014994455–4461. (https://doi.org/10.1210/jc.2014-2702)
De SanctisVCorriasARizzoVBertelloniSUrsoLGalluzziFPasquinoAMPozzanGGuarneriMPCisterninoMet al. Etiology of central precocious puberty in males: the results of the Italian Study Group for Physiopathology of Puberty. Journal of Pediatric Endocrinology and Metabolism200013 (Supplement 1) 687–693.
CisterninoMArrigoTPasquinoAMTinelliCAntoniazziFBeduschiLBindiGBorrelliPDe SanctisVFarelloGet al. Etiology and age incidence of precocious puberty in girls: a multicentric study. Journal of Pediatric Endocrinology and Metabolism200013 (Supplement 1) 695–701.
Soriano-GuillenLCorripioRLabartaJICaneteRCastro-FeijooLEspinoRArgenteJ.Central precocious puberty in children living in Spain: incidence, prevalence, and influence of adoption and immigration. Journal of Clinical Endocrinology and Metabolism2010954305–4313. (https://doi.org/10.1210/jc.2010-1025)
DharSURobbins-FurmanPLevyMLPatelAScagliaF. Tetrasomy 13q mosaicism associated with phylloid hypomelanosis and precocious puberty. American Journal of Medical Genetics Part A2009149A993–996. (https://doi.org/10.1002/ajmg.a.32758)
van der KaayDCLevineBSDoyleDMendoza-LondonoRPalmertMR.RASopathies are associated with delayed puberty; are they associated with precocious puberty too?Pediatrics2016138e20160182. (https://doi.org/10.1542/peds.2016-0182)
SimonDBaIMekhailNEcosseEPaulsenAZenatyDHouangMJesuran PerelroizenMde FilippoGPSalernoMet al. Mutations in the maternally imprinted gene MKRN3 are common in familial central precocious puberty. European Journal of Endocrinology20161741–8. (https://doi.org/10.1530/EJE-15-0488)
CacciariEFrejavilleECicognaniAPirazzoliPFrankGBalsamoATassinariDZappullaFBergamaschiRCristiGF.How many cases of true precocious puberty in girls are idiopathic?Journal of Pediatrics1983102357–360. (https://doi.org/10.1016/S0022-3476(83)80648-9)
JungHCarmelPSchwartzMSWitkinJWBenteleKHWestphalMPiattJHCostaMECorneaAMaYJet al. Some hypothalamic hamartomas contain transforming growth factor alpha, a puberty-inducing growth factor, but not luteinizing hormone-releasing hormone neurons. Journal of Clinical Endocrinology and Metabolism1999844695–4701.
ChanYMFenoglio-SimeoneKAParaschosSMuhammadLTroesterMMNgYTJohnsonbaughRECoonsSWPrengerECKerriganJFet al. Central precocious puberty due to hypothalamic hamartomas correlates with anatomic features but not with expression of GnRH, TGFalpha, or KISS1. Hormone Research in Paediatrics201073312–319. (https://doi.org/10.1159/000308162)
HusemanCAKelchRPHopwoodNJZipfWB.Sexual precocity in association with septo-optic dysplasia and hypothalamic hypopituitarism. Journal of Pediatrics197892748–753. (https://doi.org/10.1016/S0022-3476(78)80142-5)
BirkebaekNHPatelLWrightNBGriggJRSinhaSHallCMPriceDALloydICClaytonPE.Endocrine status in patients with optic nerve hypoplasia: relationship to midline central nervous system abnormalities and appearance of the hypothalamic-pituitary axis on magnetic resonance imaging. Journal of Clinical Endocrinology and Metabolism2003885281–5286. (https://doi.org/10.1210/jc.2003-030527)
LadjouzeASoskinSGarelCJullienMNaud-SaudreauCPintoGCzernichowPLegerJ.GH deficiency with central precocious puberty: a new rare disorder associated with a developmental defect of the hypothalamic-pituitary area. European Journal of Endocrinology2007156463–469. (https://doi.org/10.1530/EJE-06-0688)
SiddiqiSUVan DykeDCDonohouePMcBrienDM.Premature sexual development in individuals with neurodevelopmental disabilities. Developmental Medicine and Child Neurology199941392–395. (https://doi.org/10.1017/S0012162299000857)
BruzziPMessinaMFBartoliAPredieriBLucaccioniLMadeoSFVerrottiADe LucaFIughettiL.Central precocious puberty and response to GnRHa therapy in children with cerebral palsy and moderate to severe motor impairment: data from a Longitudinal, Case-Control, Multicentre, Italian Study. International Journal of Endocrinology201720174807163.
CelikNCinazPBideciAYuceOEmeksizHCDogerECamurdanO.Cardio-facio-cutaneous syndrome with precocious puberty, growth hormone deficiency and hyperprolactinemia. Journal of Clinical Research in Pediatric Endocrinology2014655–58. (https://doi.org/10.4274/Jcrpe.1151)
MartinRJArefiMSplittMRedfordLMossCRajanN.Phacomatosis pigmentokeratotica and precocious puberty associated with HRAS mutation. British Journal of Dermatology2018178289–291. (https://doi.org/10.1111/bjd.15643)
TayYKWestonWLGanongCAKlingensmithGJ.Epidermal nevus syndrome: association with central precocious puberty and woolly hair nevus. Journal of the American Academy of Dermatology199635839–842. (https://doi.org/10.1016/S0190-9622(96)90098-5)
PoliFPizzaFMignotEFerriRPagottoUTaheriSFinottiEBernardiFPirazzoliPCicognaniAet al. High prevalence of precocious puberty and obesity in childhood narcolepsy with cataplexy. Sleep201336175–181. (https://doi.org/10.5665/sleep.2366)
CisterninoMDella MinaELosaLMadeARossettiGBassiLAPieriGBayindirBMessaJZuffardiOet al. Idiopathic central precocious puberty associated with 11 mb de novo distal deletion of the chromosome 9 short arm. Case Reports in Genetics20132013978087.