Central Precocious Puberty in a Child With Metachromatic Leukodystrophy

Abstract

Metachromatic leucodystrophy (MLD) is a rare inherited lysosomal disorder caused by reduced activity of the enzyme arylsulfatase A with accumulation of sulfatides in the nervous system. We report a female child affected by MLD who developed central precocious puberty (CPP). This association has not been described so far. The proposita, after normal growth and psychomotor development, at age of 30 months presented with a rapidly progressive gait disturbance with frequent falls and with loss of acquired language skills. Magnetic resonance imaging showed leukoencephalopathy. Biochemical blood essays showed a 91% reduction in the arylsulfatase A activity and genetic analysis revealed compound heterozygous mutations of the Arylsulfatase A gene, enabling diagnosis of MLD. Subsequently, the patient had further rapid deterioration of motor and cognitive functions and developed drug-resistant epilepsy. At 4 years and 7 months of age bilateral thelarche occurred. Magnetic resonance imaging showed a small pituitary gland, extensive signal changes of the brain white matter, increased choline, decreased N-acetyl-aspartate and presence of lactate on 1HMR spectroscopy. Pelvic ultrasound demonstrated a slightly augmented uterine longitudinal diameter (42 mm). The gonadotropin-releasing hormone stimulation test revealed a pubertal LH peak of 12.9 UI/l. A diagnosis of CPP was made and treatment with gonadotropin-releasing hormone agonists was initiated, with good response. In conclusion, a CPP may occur in MLD as in other metabolic diseases with white matter involvement. We hypothesize that brain accumulation of sulfatides could have interfered with the complex network regulating with the hypothalamic-pituitary axis and thus triggering CPP in our patient.

Precocious puberty in a girl with 3-methylglutaconic aciduria type 1 (3-MGA-I) due to a novel AUH gene mutation

“…There are anecdotic reports of patients with precocious puberty in association with various inborn errors of metabolism (IEM) inducing accumulation of toxic substances in the central nervous system. Recently, a case of a girl with metachromatic leukodystrophy with puberty starting at 4 years, similar to our case, was reported [ 19 ]. CPP was also reported in a 4 year old girl with Tay-Sachs disease, in whom GM2 gangliosides storage was described in the hypothalamus post-mortem [ 20 ], in a few patients with mucopolysaccharidosis type IIIA [ 21 , 22 ] and in a patient with mucopolysaccharidosis type IH [ 23 ].…”

Rasmussen’s encephalitis and central precocious puberty. Neuroendocrinological characterization of three cases

“…Cases of CPP have been documented in neurodegenerative diseases such as mucopolysaccharidosis type I [23] and type III [24], neuronal ceroid lipofuscinosis [12], metachromatic leukodystrophy late infantile form [25] and Beta-propeller protein-associated neurodegeneration (BPAN) [26], where accumulation of toxic metabolites in blood and brain is hypothesized as a triggering event for CPP. It is possible that CPP in these entities is coincidental, but the number of cases from different neurodegenerative diseases, some being very rare disorders, could indicate a causal relationship.…”

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

“…2 Accumulation of sulfatide in oligodendrocytes, Schwann cells, phagocytes, astrocytes, and lysosomes of neurons in cases of CPP in MDL causes demyelination and inflammatory changes that lead to apoptosis in the central and peripheral nerves, and in the white matter, thalamus, and basal ganglia of the brain. 4 Accumulation of autofluorescent storage material in lysosomes may have induced CPP in this case, although pathological evaluation was not done. Further investigation of the sites of accumulation and clinical symptoms of this disease is required.…”

“…2 There are many possible causes of such lesions, including tumors, hypothalamic malformations, brain malformations, and trauma. 2 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 1,[3][4] (Table S1). A literature review revealed 12 cases of LSD associated with CPP, including this case (seven boys, four girls, one unknown).…”

“…Distortion or compression of the hypothalamic pathway, which regulates Gn‐RH secretion, may also induce CPP 2 . Accumulation of sulfatide in oligodendrocytes, Schwann cells, phagocytes, astrocytes, and lysosomes of neurons in cases of CPP in MDL causes demyelination and inflammatory changes that lead to apoptosis in the central and peripheral nerves, and in the white matter, thalamus, and basal ganglia of the brain 4 …”