A case of neuronal ceroid lipofuscinosis type 8 associated with central precocious puberty

Abstract

Neuronal ceroid lipofuscinosis (NCL) is characterized by nerve inflammation and degeneration caused by intralysosomal autofluorescent storage material accumulation, and shows symptoms of progressive developmental regression, epilepsy, visual impairment, and ataxia. Its incidence in Japan is unknown but atypical cases have been reported with diagnosis made by comprehensive genetic testing, and there may be undiagnosed cases. Although various complications have been reported in NCL, precocious puberty (PP) is rare. Here, we report NCL type 8 associated with central precocious puberty (CPP). A 7-year-old boy born to non-consanguineous parents was referred due to pubic hair development and testicular volume increase. He initially developed gait disturbance and seizures at age 3 and remarkable developmental regression at age 4. Brain computed tomography revealed cerebral atrophy. Although testing for palmitoyl protein thioesterase 1 (PPT1) and tripeptidyl peptidase 1 (TPP1) yielded normal results, cultured skin fibroblasts showed curvilinear accumulation on electron microscopy. He was diagnosed with late-type infant NCL (non-classified) at 4 years of age. He was admitted to our department for signs of puberty without acceleration of growth at 8.3 years old. On admission, he was severely handicapped and bedridden. Physical examination indicated signs of puberty: testes enlargement (6 mL bilaterally measured with an orchidometer), genital stage 3, and pubic hair 3 according to the Tanner criteria. Abdominal ultrasonography was unremarkable but brain magnetic resonance imaging showed extensive atrophy. Bone age was estimated as 10.8 years according to the Tanner–Whitehouse 2 RUS method. Basal plasma luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels corresponded to high pubertal levels (3.3 mIU/ mL and 1.7 mIU/mL, respectively) with a high testosterone level (235 pg/mL). An exaggerated response to the gonadotropin-releasing hormone (GnRH) stimulation test indicated GnRH-dependent precocious puberty. The GnRH analog (60 lg/kg/month) treatment was begun at 8.5 years. At 12 years, whole-exome sequencing revealed heterozygous complex mutations with a maternal frameshift mutation (c.598_599delAT p.Met200Valfs*46) and a paternal missense mutation (c.620T> G p.Leu207Arg) in exon 3 of the CLN8 gene. He was diagnosed with NCL type 8. His seizures were predominantly myoclonus but could lead to generalized tonic seizures and he was hospitalized several times. Now 15 years old, he is receiving antiepileptic medication (perampanel hydrate, clobazam, and levetiracetam) at our hospital. Central precocious puberty is caused by premature activity of the hypothalamic-pituitary-gonadal axis. It is more common in girls and its cause is more idiopathic. Boys with CPP frequently have central nervous system lesions. There are many possible causes of such lesions, including tumors, hypothalamic malformations, brain malformations, and trauma. Lysosomal storage diseases (LSDs), such as mucopolysaccharidosis type III A, Hurler syndrome, Tay– Sachs disease, and heterozygous leukodystrophy (MDL) have also been reported as causes (Table S1). A literature review revealed 12 cases of LSD associated with CPP, including this case (seven boys, four girls, one unknown). As they showed autosomal recessive inheritance, there was no difference in the original disease between men and women. However, PP complications tend to be more common in boys, although the number of cases was small. Electrolytic lesions in the hypothalamus of immature female rats were reported to induce precocious sexual maturation, and a patient with Tay– Sachs disease complicated by CPP had pathological accumulation of GM2 gangliosides in the hypothalamus but not the pituitary gland. Thus, hypothalamic lesions may be responsible for CPP. Gn-RH is produced in the preoptic area of the hypothalamus and released from axon terminals in the median eminence. Chronic disruption of Gn-RH-containing nerve Correspondence: Maki Saito, MD, Department of Pediatrics, The Jikei University School of Medicine, 3-19-18, Nishishinbashi, Minato-ku, Tokyo 105-0003, Japan. Email: [email protected] Received 19 May 2020; revised 15 July 2020; accepted 28 July 2020. doi: 10.1111/ped.14421