BRAIN HISTIOCYTOSIS WITH PRECOCIOUS PUBERTY AND GROWTH HORMONE DEFICIENCY AT EARLY CHILDHOOD CASE REPORT HISTIOCITOZA MOŽDANOG TKIVA SA PRERANIM PUBERTETOM I DEFICITOM HORMONA RASTA U RANOM DETINJSTVU Authors: Dragan Katanić*, Jovanka Kolarović*, Danica Grujičić†, Milica Skender Gazibara,

Introduction. Langerhans Cell Histiocytosis (LCH) is a rare chronic granulomatous, usually multisystem disease of elusive etiology, with peak incidence in early childhood and slow progressing course. Isolated brain histiocytosis is a very rare condition and neurological finding does not correlate with the extent of space-occupying anatomical lesions and degenerative changes. Case report. A girl, age 2.5 years was presented with diabetes insipidus and nearly fatal full spectrum isolated brain histiocytosis. Brain magnetic resonance imaging (MRI) showed multiple nodules with perifocal edema, the most prominent in the projection of the hypothalamus/pituitary and the stalk and in the region of the pineal gland. Identical nodules were present in both caudate nucleus and putamen, left insular subcortex, both temporal lobes, tegmental area of the midbrain, central part of pons and medulla, both cerebellar hemispheres and leptomeningeal membranes. The pattern resembled snow balls and flakes. Biopsy showed positivity for vimentin, S-100, CD- 68 and CD1a markers. Treatment protocol LCH-III was not successful and a salvage treatment was refused by parents. She appeared again at the age of 7 with growth deceleration and fully developed precocious puberty. The control MRI of the brain revealed similar nodules in certain regression. Due to central precocious puberty, treatment with luteinizing hormone? releasing hormone (LH-RH) analogue was introduced. School performance was mediocre with cocktail-party effect behavior and slower speech. Conclusion. Brain histiocytosis is potentially fatal disease with chronic, variable, slowly progressive course and unpredictable responses to treatment protocols


Introduction
Langerhans Cell Histiocytosis is a rare chronic granulomatous, usually multisystem disease of elusive etiology, with peak incidence in early childhood and slow progressing course.
Isolated brain histiocytosis is a very rare condition and neurological finding does not correlate with the extent of space-occupying anatomical lesions and degenerative changes.

Case report
A girl age 2.5 years is presented with diabetes insipidus and nearly fatal full spectrum isolated brain histiocytosis.Brain magnetic resonance (MR) showed multiple nodules with perifocal edema, the most prominent in the projection of the hypothalamus / pituitary and the stalk and in the region of the pineal gland.Identical nodules were present in both caudate nucleus and putamen, left insular subcortex, both temporal lobes, tegmental area of the midbrain, central part of pons and medulla, both cerebellar hemispherae and leptomeningeal membranes.The pattern resembled snow balls and flakes.Biopsy showed positivity for vimentin, S-100, CD-68 and CD1a markers.Treatment protocol LCH-III was not successful longterm and a salvage treatment was refused by parents.She appeared again at the age of 7 years with growth deceleration and fully developed precocious puberty.The control MR of the brain revealed similar nodules in certain regression.Due to central precocious puberty, treatment with LH-RH analogue was introduced.School performance was mediocre with cocktail-party behavior and slower speech.

Conclusion:
Brain histiocytosis is potentially fatal disease with chronic varied slowly progressive course and unpredictable responses to treatment protocols.

Case report
A girl is presented with nearly fatal full spectrum isolated brain histiocytosis, growth deceleration and precocious puberty.She was admitted because of polyuriapolydypsia (urine volume more than 5l / 24h) at the age of 2.5 years in generally good condition, except somnolence, mild dehydration, signs of hypermobility syndrome (general laxity) and imperfect dentinogenesis.She was afebrile, heart rate 72/min, respiration rate 16/min, blood pressure 100/70 mmHg.BW 16 kg (90 percentile), BH 97.4 cm (97 percentile) which was congruent with familiar tall stature; BMI 17.02 kg/ m 2 (50 percentile).
Patient's perinatal history was unremarkable and psychomotor development uneventful.Four months ago she had varicella and afterwards was treated for pneumonia and pericarditis.Family history was not significant.
Previous head trauma or operation (anesthesia) were immediately ruled out as a possible cause of diabetes insipidus.Renal insufficiency and diabetes mellitus were excluded quickly.There were no bone involvement and no signs of Leterrer-Siwe or Hand-Schuller-Christian histiocytosis (without exophthalmos, skin rash or "geographic skull" on X-ray) (12).Ophthalmologist did not find papilledema at initial presentation.
Overnight water deprivation test was inconclusive between psychogenic polydypsia and partial diabetes insipidus -urine specific gravity was around 1,010 (400 mOsmol/kg) at the end of the test.Decision was made to introduce replacement treatment with intranasal DDAVP 5-10 mcg daily.The fluid intake was reduced to 1.5 l/24h, she was temporarily discharged but soon hospitalized at a local hospital for vomiting and somnolency (possible water intoxication due to DDAVP overdose since sodium was low 128 mmol/l).Upon cessation of DDAVP and fluid intake reduction, urine specific gravity raised to 1,030 (1200 mOsmol / kg), but 36 hours later polyuric-polydypsic syndrome developed again and DDAVP had to be given.MR angiography, imaging and spectroscopy of endocranium (sagittal T1-weighted, transversal and coronal T2-weighted tomograms), accompanied with triplanar postcontrast study and detailed examination of the pituitary revealed multiple axial and leptomeningeal soft tissue nodules with perifocal edema, the most prominent in the medial line -in the projection of the hypothalamus / pituitary and the stalk (maximum diameter of 20mm) and in the region of the pineal gland (15mm) without cystic component and without calcifications.Identical intraaxial nodules are present in both caudate nucleus and putamen (8-12mm), and in the left insular subcortex (17mm) and in both temporal lobes (predominantly left, generating intraaxial edema).In the midbrain one nodule in the left tegmental area was spotted, also one in the central part of pons and medulla with diameter of 3.5mm.
In both cerebellar hemispherae were multiple nodules with diameters of 2-12mm.At all leptomeningeal membranes (in the depths of sulci) multiple nodules of identical characteristics and genesis are found, corresponding to massive cerebrospinal fluid dissemination of the basic process; nodules generated parenchymal edema, both supra and infratentorial.In the displayed myelon C-segment there were three micronodules with consecutive edema.Bright spot signal of the posterior pituitary was lost.
In conclusion, MR showed multiple intraaxial and leptomeningeal nodules with  Appropriate treatment protocol LCH-III (prednisolone and vinblastine) was started (13) and the child was much better soon after.Since the longterm response to the protocol was not as expected (the condition of the child deteriorated gradually with seizures, respiratory arrest, anisocoria, cyanosis and papilledema), a salvage treatment with cladribine ( 14) was proposed but refused by parents.After discharge, the contact was lost for a few years (parents referred to a religious pilgrimage) and the child appeared again at the age of 7 years in better condition, with BH 119.5 cm (50 percentile) that suggested growth deceleration, but with signs of fully developed precocious puberty (breasts stage 4 and recently occurred menarche), advanced bone age of 11 years, low IGF-1 and predictive height 135 cm only.She complained of dry mouth (anti-Ro/SSA and anti-La/SSB antibodies for Sjögren syndrome were negative).
Ključne reči: histiocitoza, mozak, prerani pubertet Introduction Langerhans Cell Histiocytosis is a rare chronic granulomatous, usually multisystem disease of elusive etiology, most commonly affecting the bone (skull, longitudinal bones, spine), bone marrow, skin, liver, lungs and infrequently salivary glands (parotid), thyroid gland (1), gastrointestinal tract (colon, duodenum) and brain and can occur at any age, with peak incidence in early childhood.The annual incidence in children under 10-15 years is 0.2-2 per 100,000 children.Granulomas are composed of immature histiocytes, lymphocytes, giant cells and eosinophils.It has a slow progressing course.Isolated brain histiocytosis is a very rare condition and neurological finding does not correlate with the extent of space-occupying anatomical lesions and degenerative changes.Magnetic resonance (MR) imaging and pathohistology categorizes changes of brain histiocytosis into three patterns (2)infiltration of the hypothalamic-pituitary region (3), neurodegenerative changes (4,5) in cerebellum and basal ganglia and extraaxial lesions in the meninges, choriod plexus and pineal gland.Neurological deterioration includes reflex abnormalities, gait disturbance, ataxia, dysarthria, dysdiadochokinesis, nystagmus, seizures, spastic paresis or plegia, behavioral disturbances, poor concentration, memory and attention deficit, cognitive defects, mental retardation and psychiatric disorders.When the disease is detected at an early age, severe neurological consequences may occur in early adulthood, favoring its slow progression, possible arrests and the reactivations in the course and requirement of large devastation of axonal mass (threshold), that brain can not compensate.Endocrine disorder triad includes pituitary gland -diabetes insipidus (in 50% of cases), precocious puberty and growth hormone deficiency (6), although secondary hypothyroidism, hypogonadism and hyperprolactinemia can occur.Differential diagnosis of brain histiocytosis covers tuberculosis, sarcoidosis, Wegener's disease (granulomatosis with polyangiitis), cysticercosis, coccidiomycosis, cryptococcosis, cerebrotendinous xanthomatosis, Rosai-Dorfman disease (non-progressive and self-limited sinus histiocytosis with massive lymphadenopathy)(7), Erdheim-Chester disease (polyostotic sclerosing histiocytosis) and Machado-Joseph-Azorean disease (spinocerebellar ataxia).
perifocal soft tissue edema, most pronounced in the midline, and the projection of the hypothalamus, a tripod and the pineal gland.The presence of micronodules at all leptomeningas and in the projection of the displayed myelon C-segment may indicate cerebrospinal fluid dissemination of the underlying disease.The pattern resembled snow balls and flakes (Fig.1,2,3).