CENTRAL NERVOUS SYSTEM (CNS)

Transcription

1 Wit JM, Ranke MB, Kelnar CJH (eds): ESPE classification of paediatric endocrine diagnosis. 6. Pituitary, hypothalamus, central nervous system (CNS). Horm Res 2007;68(suppl 2):31 34 ESPE Code Diagnosis OMIM ICD10 6 PITUITARY, HYPOTHALAMUS, CENTRAL NERVOUS SYSTEM (CNS) SECTION 1 FUNCTIONAL CLASSIFICATION 1 6A DEFICIENCIES OF ANTERIOR PITUITARY HORMONES 6A.0 Disorders classified elsewhere Growth hormone deficiency (1b.3) 6A.1 ACTH deficiency 6A.1a Congenital isolated ACTH deficiency 2 # A.1b Congenital ACTH deficiency in combination with other pituitary deficiencies 3 6A.1c Acquired hypothalamic-pituitary ACTH deficiency, e.g. by longterm glucocorticoid therapy 4 6A.2 TSH deficiency E03.9 6A.2a Congenital isolated TSH deficiency 5 6A.2a.1 Known genetic defect (TSH-beta, TRHR, TRH, other) 6 # A.2a.2 Unknown origin 6A.2b Congenital TSH deficiency in combination with other pituitary deficiencies 7 6A.2b.1 Secondary (pituitary) hypothyroidism 8 6A.2b.2 Tertiary (hypothalamic) hypothyroidism 9 6A.2c Acquired hypothalamic-pituitary hypothyroidism 10 6A.3 Gonadotrophin deficiency (hypogonadotrophic hypogonadism) 6A.3a X-linked inheritance 6A.3a.1 Isolated hypogonadotrophic hypogonadism and anosmia (X-linked form of Kallmann syndrome) (KAL1 mutation); [primary] [secondary 14B.16] Pituitary, Hypothalamus, Central Nervous System (CNS) 31

2 ESPE Code Diagnosis OMIM ICD10 6A.3a.2 Isolated hypogonadotrophic hypogonadism and adrenal hypoplasia congenita (DAX1 mutation) (also classified as 8A.2a.1) 12 6A.3b Autosomal inheritance: autosomal forms of Kallmann syndrome 6A.3b.1 Inactivating mutation of FGFR1 (KAL2) 13 # A.3b.2 Inactivating mutation of PROKR2 (KAL3) A.3b.3 Inactivating mutation of PROK2 (KAL4) A.3b.4 Inactivating mutation of GnRHR 15 * A.3b.5 GPR54 mutation 16 * A.3b.6 KISS mutation 17 * A.3b.7 Prohormone convertase 1 mutation A.3b.8 Leptin 1 or leptin receptor mutation 19 * * A.3b.9 LHR mutation (fertile eunuch syndrome) # A.3b.10 Isolated LH deficiency A.3b.11 Isolated FSH deficiency 21 # A.3b.88 Other specified gene mutations, including NELF, etc. * A.3c Hypogonadotrophic hypogonadism in combination with other pituitary deficiencies 22 6A.3c.1 Known genetic defect, e.g. PROP1, LHX3, HESX1 23 * * * A.3c.2 Unknown genetic defect 6A.3d Hypogonadotrophic hypogonadism in combination with dysmorphic syndromes, e.g. Prader-Willi-Labhart syndrome [primary 14B.25], Rieger syndrome [primary 14B.28] 6A.3z Hypogonadotrophic hypogonadism, isolated, unspecified 6A.4 Prolactin deficiency 6A.4a Isolated prolactin deficiency A.4b Prolactin deficiency in combination with other pituitary deficiencies 6A.4b.1 POU1F1 mutation A.4b.2 PROP1 mutation 26 * A.4b.8 Other specified gene mutations 6A.4b.9 Unknown origin ESPE Classification of Paediatric Endocrine Diagnoses 32

3 ESPE Code Diagnosis OMIM ICD10 6B OVERPRODUCTION OF ANTERIOR PITUITARY HORMONES 6B.0 Disorders classified elsewhere ACTH-producing adenoma (Cushing s disease) (8C.1) Growth hormone-producing adenoma (synonyms: acromegaly, pituitary gigantism) (2B.1) 6B.1 TSH-producing adenoma 27 E05.9 6B.2 Gonadotrophin-producing adenoma 28 6B.3 Prolactin overproduction 6A.3a Prolactinoma 29 M8271/0 6A.3b Hyperprolactinaemia of other cause (e.g. pituitary stalk lesion, E22.1 primary hypothyroidism) 30 6C CENTRAL DIABETES INSIPIDUS [primary 13A.1] 6D HYPOTHALAMIC DYSFUNCTION, NOT CLASSIFIED ELSEWHERE E23.3 6D.0 Disorders classified elsewhere Obesity (5D) 6D.8 Other specified functional changes 6D.9 Other functional changes, unspecified SECTION 2 AETIOLOGICAL CLASSIFICATION 1 6E CONGENITAL DISORDERS 6E.1 Congenital CNS malformations Q04 6E.1a Septo-optic dysplasia [primary] 31 # Q04.4 [secondary 14B.30] 6E.1b Other midline defects, e.g. cleft palate, central maxillary incisor syndrome, EEC syndrome (ectodactyly-ectodermal dysplasiaclefting syndrome) 32 Q04.8 Pituitary, Hypothalamus, Central Nervous System (CNS) 33

4 ESPE Code Diagnosis OMIM ICD10 Q04.8 6E.1c Ectopic neurohypophysis, absent infundibulum and hypoplastic adenohypophysis 33 6E.1d Hamartoma Q85.9 6E.1z Other congenital CNS malformations, unspecified Q04.9 6E.2 Congenital hypothalamic-pituitary disorders associated with syndromes 6E.2a Disorders classified elsewhere: Prader-Willi(-Labhart) syndrome (14B.25) Rieger syndrome (14B.28) 6E.2b Chromosomal disorders 35 6E.2c Chromosomal instability syndromes 36 6E.2d Empty sella syndrome 37 6E.2y Other specified syndromes 6E.2z Other syndromes, unspecified 6F ACQUIRED DISORDERS 6F.1 Neoplasms C71.9 6F.1a Tumours of the pituitary/hypothalamic region 6F.1a.1 Craniopharyngioma 38 6F.1a.2 Nonfunctional pituitary adenomas 39 6F.1a.3 Other benign structures 40 6F.1a.4 Isolated glioma 41 6F.1a.5 Glioma as part of neurofibromatosis I (von Recklinghausen s disease, 14B.27) 6F.1a.6 Germinoma, dysgerminoma 42 6F.1a.7 Leukaemia, lymphoma 43 6F.1a.8 Other neoplasms, specified 6F.1b Tumours outside the pituitary/hypothalamic region 6F.1b.1 Pinealoma 44 6F.1b.2 Isolated glioma 45 6F.1b.3 Glioma as part of neurofibromatosis I (von Recklinghausen s disease, 14B.27) 6F.1b.4 Germinoma, dysgerminoma 6F.1b.5 Medulloblastoma 46 6F.1b.6 Leukaemia, lymphoma 6F.1b.8 Other specified neoplasms 6F.2 Inflammatory/infiltrative 6F.2a Langerhans cell histiocytosis D76.0 D76.3 ESPE Classification of Paediatric Endocrine Diagnoses 34

5 ESPE Code Diagnosis OMIM ICD10 6F.2b Systemic lupus erythematodes 48 # # F.2c Neurosarcoidosis 49 # F.2d Lymphocytic neurohypophysitis 50 6F.2e Haemochromatosis 51 # F.3 Infectious 6F.3a Meningitis 52 G00 6F.3b Encephalitis G04, G05 6F.3c Abscess of pituitary 53 G06.0 6F.3d Congenital infection 54 G09 6F.4 Traumatic injury 6F.4a CNS surgery 55 G97 6F.4b Head trauma 56 S06 6F.4c Hypoxic injury 57 G97.8 6F.5 Iatrogenic 6F.5a Irradiation 58 T66 6F.5b Drugs, e.g. chemotherapy 59 E23.1 6F.6 Secondary to psychiatric disorders 6F.6a Anorexia nervosa 60 F50.0 6F.6b Emotional deprivation 61 6F.6c Other (specified) 6F.7 Idiopathic 1 Classification Comments: Diagnoses are classified according to function and aetiology. In many cases, therefore, two codes will be used for a patient with a CNS disorder. 2 Congenital isolated ACTH deficiency Phenotype: Rare inherited disorder which may cause hypoglycaemia, Addisonian crisis and death in neonates. In pregnant women isolated low oestriol levels may indicate the disease in the foetus. ACTH ( ), cortisol ( ). Comment: Autosomal-recessive inherited mutations in the TBX19 gene encoding a transcription factor important for differentiation of pituitary corticotroph cells is found in approximately 50%. 3 Congenital ACTH deficiency in combination with other pituitary deficiencies Phenotype: Congenital panhypopituitarism, mostly caused by hypoplasia or aplasia of the pituitary gland due to vascular damage. Neonatal symptoms of Addisonian crisis (hypoglycaemia, hypona- Pituitary, Hypothalamus, Central Nervous System (CNS) 35

6 traemia), hypothyroidism, growth retardation may occur in association with other brain malformations. ACTH ( ), cortisol ( ), TSH ( ), T4 ( ), GH ( ). Comments: Mutations in transcription factors responsible for pituitary development. In PROP1 mutations evolving ACTH (and cortisol) deficiency due to progressive pituitary degeneration. 4 Acquired hypothalamic-pituitary ACTH deficiency Phenotype: Fatigue, weakness, hypopigmentation, finally Addisonian crisis. Comments: Can occur in chronic infectious diseases (HIV). Side effect of oral, topical or inhaled longterm glucocorticoid therapy (negative feedback on ACTH). ACTH ( ), cortisol ( ). 5 Isolated TSH deficiency Phenotype: Relatively mild symptoms of hypothyroidism due to basal function of thyroid gland. Thyroid gland normal or hypoplastic. T4 and T3 ( ), basal TSH ( ), TRH-stimulated TSH ( ), Prl (+/N). Comments: Can be caused by hypophysitis, empty sella or Langerhans cell histiocytosis, or by mutations of TSH or TRHR. 6 Known genetic defect (TSH-beta, TRHR) Phenotype: Congenital secondary hypothyroidism may not be detected in neonatal screening in many countries, because TSH levels are not increased. T4 and T3 ( ), basal TSH ( ), TRH-stimulated TSH ( ), Prl (N or ). Comment: Different mutations in the coding region of the TSH-beta subunit gene and TRHR. 7 TSH deficiency in combination with other pituitary deficiencies Synonym: Hypopituitarism, combined pituitary hormone deficiency (CPHD). Phenotype: Hypoplastic or normal thyroid, symptoms of CH usually mild. Thyroid hormones ( ), TSH ( ), Tg ( ), GH ( ), Prl ( ) or gonadotrophins ( ). 8 Secondary (pituitary) hypothyroidism Phenotype: Due to pituitary TSH deficiency. TSH ( ), T4 ( ). Symptoms of hypothyroidism. Variable phenotype depending on other pituitary hormones affected. Comments: Mutations in POU1F1 or PROP1 and TRH receptor gene are coded elsewhere. Malformation syndromes (septo-optic dysplasia, midline defects) and mass lesions may affect pituitary TSH secretion. 9 Tertiary (hypothalamic) hypothyroidism Phenotype: Hypothyroidism due to hypothalamic TRH deficiency. Mostly other hypothalamic hormones are affected as well. TSH (N/ ), T4 ( ), prolonged TSH rise after TRH injection. 10 Acquired hypothalamic-pituitary hypothyroidism Phenotype: Consequence of pituitary surgery or lymphocytic adenohypophysitis. May occur in very low birth weight infants or critically ill children (non-thyroidal illness syndrome). 11 Isolated hypogonadotrophic hypogonadism and anosmia (Kallman syndrome) Phenotype: Clinically and genetically heterogeneous disorder with a wide spectrum of reproductive function and anosmia. Absence or severely delayed or slowly progressive or abortive puberty. ESPE Classification of Paediatric Endocrine Diagnoses 36

7 Histologically immature gonads. LH ( ), FSH ( ), T ( ), inhibin-b ( ). Hypoplasia of the bulbus olfactorius in MRI. In severe forms hypoplastic genitalia. Comments: Lack of GnRH neurones. X-linked mutations in KAL-1 gene (encodes anosmin-1, a protein involved in olfactory and neuronal migration). Autosomal-dominant loss of function mutations in FGFR-1 gene. Anosmia occurs in all KAL-1 mutations but only a small percentage of FGFR-1 mutations. 12 Isolated hypogonadotrophic hypogonadism and adrenal hypoplasia congenita (DAX1 mutation) Phenotype: X-linked congenital adrenal insufficiency in neonatal period, lack of pubertal development, abnormalities in spermatogenesis. Variable clinical presentation. In female carriers delayed puberty. Hypoplastic adrenals; inadequate testis development, decreased spermatogonia. LH ( ), FSH ( ), T ( ), especially at the time of puberty. Glucocorticoid and mineralocorticoid deficiency. Comments: Deletion or mutation of the NROB1 (DAX1) gene, encoding DAX1, an orphan nuclear receptor. DAX1 expression has been shown in regions of the hypothalamic/pituitary/adrenal/gonadal axis. 13 KAL2 (FGFR1 defect) Comment: Together with KAL mutations, FGR1 mutations are responsible for 20% of cases with Kallmann syndrome. 14 KAL3 and KAL4 Comments: PROKR and PROK2 defects may be responsible for 10% of cases with Kallmann syndrome. 15 Inactivating mutation of GnRHR Phenotype: Lack of pubertal development; wide spectrum of phenotypes. Patients are normosmic. LH ( ), FSH ( ), T ( ). Comment: Autosomal recessive. 16 GPR54 mutation Phenotype: Lack of pubertal development and fertility. LH ( ), FSH ( ), sex steroids ( ). Comments: GPR54 is a G protein-coupled receptor gene, expressed by GnRH neurons. Autosomal recessive. Patients respond to GnRH or Gn treatment. 17 KISS mutation Phenotype: Lack of pubertal development, infertility. Comment: Kisspeptins stimulate gonadotrophins by stimulating GnRH after activation of GPR Prohormone convertase 1 mutation Phenotype: Lack of pubertal development. LH ( ), FSH ( ), sex steroids ( ). Comment: Defects in prohormone processing. Pituitary, Hypothalamus, Central Nervous System (CNS) 37

8 19 Leptin 1 mutation Phenotype: Morbid obesity and hypogonadism. LH ( ), FSH ( ), sex steroids ( ). Comments: Sympathetic system dysfunction, thyroid dysfunction, type 2 DM and immune dysfunction may occur. Increased mortality in obese subjects. 20 Isolated LH deficiency Synonym: Fertile eunuch. Phenotype: Decreased virilisation and fertility. LH ( ), T ( ). 21 Isolated FSH deficiency Phenotype: Decreased fertility. Decreased number of germ cells. FSH ( ). 22 Hypogonadotrophic hypogonadism in combination with other pituitary deficiencies Synonym: Combined pituitary hormone deficiency (CPHD). 23 Known genetic defect, e.g. PROP1, LHX3, HESX1 Phenotype: Mutations in pituitary transcription factors result in combined pituitary hormone deficiency. In LHX3 mutation combination with rigid cervical spine. LH ( ), FSH ( ), sex steroids ( ); depending on the defect combination with other pituitary hormone deficits. PROP1: mutations in the PROP gene are associated with a highly variable phenotype. ACTH deficiency can occur late. HESX1: inactivating mutations in this gene were found in few patients with septo-optic dysplasia. LHX3: mutations in the LHX3 gene which encodes LIM transcription factors responsible for pituitary and nervous system development. 24 Isolated prolactin deficiency Phenotype: Pituitary Prl is synthesised by lactotrophs and mammosomatotrophs which release also GH. Prl is also synthesised in the decidua of the pregnant uterus. In adults, Prl is primarily involved with reproductive functions. In children no symptoms of isolated Prl deficiency. Prl ( ). Comments: Predominant negative hypothalamic control by dopamine. The main releasing factor is TRH. 25 POU1F1 mutation Phenotype: Symptoms related to congenital hypothyroidism and GH deficiency. Prl deficiency itself has no clinical sequelae in children. GH ( ). Basal and TRH-stimulated TSH ( ). Prl ( ). Variable phenotype. Comments: AD or AR. POU1F1 is expressed in lactotrophs, somatotrophs and thyrotrophs in which it is involved in the transcription of the GH, Prl and TSHbeta genes. 26 PROP1 mutation Phenotype: Short stature due to complete GH deficiency, congenital hypothyroidism, hypogonadism. Evolving ACTH deficiency in older patients (hyponatraemia, hypoglycaemia). Deficiency of anterior pituitary hormones. Progressive shrinking of the pituitary gland. Occasional pituitary enlargement imposing as adenoma, which can resolve spontaneously. Comments: PROP1 mutations were found in approximately 1/3 of patients with familial combined pituitary hormone deficiency; rare in sporadic cases. ESPE Classification of Paediatric Endocrine Diagnoses 38

9 27 TSH-producing adenoma Phenotype: TSH- (and Prl-) producing micro- and macroadenomas cause symptoms of hyperthyroidism (and hyperprolactinaemia). TSH (+), T4 (+), Prl (+). Comments: In most cases other pituitary hormones are involved as well. Carcinomas very rare. 28 Gonadotrophin-producing adenoma Phenotype: Functioning adenomas exhibit mainly FSH hypersecretion and ovarian overstimulation. FSH (+), E2 (+). Clinical symptoms of mass lesion (optic chiasm compression, deficiency of other pituitary hormones) may occur. LH-secreting adenoma may cause precocious puberty. LH (+), T (+). Comments: The majority of clinically nonfunctioning pituitary macroadenomas are of gonadotroph origin, LH and FSH are rarely increased. 29 Prolactinoma Phenotype: Prolactinomas may present with delayed puberty. Mostly girls affected: menstrual disorders and galactorrhoea. In large adenomas symptoms of intracranial mass lesion. Prl (+), pulsatile secretion, variable response to TRH stimulation. Comments: 40% of acromegalic patients have hyperprolactinaemia. The extent of Prl elevation may discriminate between nonfunctioning macroadenoma and macroprolactinoma. 30 Hyperprolactinaemia of other cause Phenotype: Pituitary stalk compression by a tumour may lead to hyperprolactinaemia by decreasing Prl inhibition by dopamine. In primary hypothyroidism the serum level of TRH, which is the primary Prl-releasing factor, is increased. 31 Septo-optic dysplasia (De Morsier syndrome) Phenotype: Growth retardation, visual impairment, nystagmus; hypothalamic dysfunction and pituitary failure may occur. Neonatal hypoglycaemia and seizures. Developmental anomalies of the midline structures of the brain like hypoplasia of optic nerves, agenesis of septum pellucidum and agenesis of corpus callosum. Variable pituitary hormone deficiencies. Very variable phenotype. Comment: HESX1 mutations were found only in few cases. 32 Other midline defects: cleft palate, central maxillary incisor syndrome, EEC syndrome (ectodactyly-ectodermal dysplasia-clefting syndrome) Phenotype: Developmental anomalies of the midline may affect the pituitary to a variable extent, mostly GH deficiency. Comments: Common development of palate/rathke pouch/pituitary. The central incisor syndrome may be associated with holoprosencephaly and various other congenital anomalies. 33 Ectopic neurohypophysis, absent infundibulum and hypoplastic adenohypophysis Phenotype: Short stature due to GH deficiency and other symptoms due to TSH, ACTH and gonadotrophin deficiency, mostly panhypopituitarism. MRI shows hypoplastic adenohypophysis and small sella, hypoplastic or absent infundibulum and ectopic neurohypophysis at the median eminence. Basal and stimulated GH ( ), TSH ( ), Gn ( ), ACTH ( ). Comments: This condition is likely to be the end result of perinatal disruption of the hypophyseal portal system. The ectopic neurohypophysis functions normally. Pituitary, Hypothalamus, Central Nervous System (CNS) 39

10 34 Hamartoma Phenotype: Precocious puberty of central type, psychomotor delay, seizures. Benign tumours composed of neurons, astrocytes and oligodendroncytes; appears attached to the tuber cinereum or the floor of the 3rd ventricle. The tumour may express GnRH. 35 Chromosomal disorders Phenotype: Turner syndrome, 18p deletion syndrome, XXXXY syndrome. Brain malformations and pituitary hormone deficiencies (mainly GH deficiency) were found in a variable degree. 36 Chromosomal instability syndromes Phenotype: Fanconi syndrome, Bloom syndrome, Nijmegen breakage syndrome. GH deficiency has been described. GH treatment in these cases may cause increased susceptibility to malignancies. 37 Empty sella syndrome Phenotype: In most cases asymptomatic; rarely clinical manifestation with headache, rhinorrhoea, impaired visual field and benign intracranial hypertension. Rarely with pituitary deficiencies. GH ( ), TSH ( ), LH ( ), FSH ( ), Prl (+). Comments: Disorder of the anlage of the diaphragm of the sella. Enlarged pituitary fossa by herniated arachnoid content. In unselected autopsies up to 20%. 38 Craniopharyngioma Phenotype: Symptoms depend on the relationship to the pituitary, hypothalamus or optic chiasma. Hypopituitarism by compression of the adenohypophysis. Compression of the hypophyseal stalk causes hyperprolactinaemia. Visual field disturbance, intracranial pressure, headache, vomiting, papilloedema, somnolence. After surgery virtually all patients show hypopituitarism. Derives from remnant of Rathke pouch, supra- or intrasellar, calcifications. Comment: Approximately 10% of childhood tumours. 39 Nonfunctional pituitary adenomas Phenotype: A mass lesion impinging on the pituitary or hypothalamus may cause local neurological effects on the optic tract, the cavernous sinus, temporal and frontal lobe and may cause symptoms of increased intracranial pressure. Involvement of the hypothalamus (temperature dysregulation, appetite and thirst disorders, etc.) and pituitary (hormone deficiencies). 40 Other benign structures Phenotype: May cause the same phenotype as in non-functional pituitary adenomas (6F.1a.2). 41 Isolated glioma Phenotype: Brain tumours originating from neuroglia. Symptoms depend on impingement on local structures (chiasmatic/hypothalamic area), hydrocephalus. Variable pituitary hormone deficits. 42 Germinoma, dysgerminoma Phenotype: Germinomas arise near the base of the hypothalamus and affect vasopressin axons thereby causing neurohormonal diabetes insipidus. Can be very small (pituitary stalk thickening) and undetectable for several years following the onset of polyuria. hcg (+), hcg in CSF, diabetes insipidus. Dysgerminoma may produce gonadotrophins and give rise to precocious puberty. ESPE Classification of Paediatric Endocrine Diagnoses 40

11 43 Leukaemia, lymphoma Phenotype: Most frequent causes of CNS-affecting malignant diseases. May affect hypothalamicpituitary axis by leukaemic infiltration (leukaemic meningitis) or as a consequence of treatment. Comments: Normal growth may be maintained despite biochemical GH deficiency due to hypothalamic hyperphagia in children with hypothalamic disorder. 44 Pinealoma Phenotype: Pineal parenchymal tumours (pineocytoma, pineoblastoma) or pure pineal germinomas (occur mainly in boys). Symptoms of mass lesion, obstructive hypertension. Melatonin has no diagnostic significance. 45 Isolated glioma Phenotype: Tumours outside the hypothalamo-pituitary region may cause symptoms of mass lesion and obstructive hypertension and thereby affect pituitary hormone secretion. 46 Medulloblastoma Phenotype: Embryonal tumour of the cerebellum, metastases into the CSF. Most common malignant brain tumour in children. Affection of the hypothalamus-pituitary axis as consequence of treatment (surgery, high dose irradiation, chemotherapy). Comment: Mutations of genes encoding proteins involved in embryonic growth factors or mutations of growth factor receptors are frequently found. 47 Langerhans cell histiocytosis (LCH) Phenotype: Can occur as an isolated lesion, as multifocal or as widespread systemic disease. Focal proliferation/accumulation of Langerhans cells. Class I, II and III histiocytosis based on histopathologic findings. Single or multiple lesions of the bone, skin involvement, exophthalmos, pulmonary infiltrates, pituitary involvement or hypothalamic dysfunction. Diabetes insipidus in approximately 25%, variable deficiencies of the anterior pituitary. LCH has an extremely variable clinical presentation. 48 Systemic lupus erythematodes (SLE) Phenotype: SLE is a multisystem autoimmune disorder which can present with neurological complications. Brain lesions on MRI. The pituitary-thyroid and pituitary-gonadal axis may be affected in newly diagnosed, untreated patients. Comments: Genetic predisposition, female preference. 49 Neurosarcoidosis Phenotype: Infiltrative granulomatous disease which may involve hypothalamic-pituitary area. Central diabetes insipidus, hypogonadism, GH deficiency, hyperprolactinaemia. Thickening of the pituitary stalk. Difficult differentiation from lymphocytic hypophysitis (biopsy). 50 Lymphocytic neurohypophysitis Phenotype: Recent pregnancy or other autoimmune disease in 50% of cases, occasionally after pituitary surgery. Diffuse destruction of pituitary and infundibulum. Affection of anterior and posterior pituitary hormone axis. Central diabetes insipidus, LH ( ), FSH ( ), T/E2 ( ), TSH ( ), T4 ( ), ACTH ( ), cortisol ( ), GH ( ). Pituitary, Hypothalamus, Central Nervous System (CNS) 41

12 51 Haemochromatosis Phenotype: May lead to pituitary infiltration, deposits in pituitary cells. Idiopathic or secondary (thalassaemia or sickle cell disease). Correlation with serum ferritin levels; MRI shows decreased signal intensity. Mainly gonadotrophic axis affected, delayed puberty. LH ( ), FSH ( ), T or E2 ( ). 52 Meningitis Phenotype: Viral or bacterial meningoencephalitis can be associated with anterior and posterior pituitary insufficiency which may resolve after cure of the disease. Central diabetes insipidus is frequently seen in congenital meningitis of various aetiology. 53 Abscess of pituitary Phenotype: Intrasellar infection presenting with headache, visual changes, fever, meningismus and endocrine abnormalities. Imaging demonstrates pituitary mass. Correct diagnosis mostly only after (surgical) treatment. Generally pituitary dysfunction does not recover after treatment. 54 Congenital infection Phenotype: Prenatal rubella infection in the first trimester causes dysmorphic stigmata (microphthalmos, microcephaly), cardiac anomalies, dystrophia, GH deficiency has been described. Hypothyroidism was described in congenital immunodeficiency syndromes. Neurohormonal diabetes insipidus was found in congenital cytomegalovirus infection. GH deficiency was found in Schwachmann-Diamond syndrome (pancreatic insufficiency, recurrent infections, metaphyseal anomalies). 55 CNS surgery Phenotype: Tumours in the sella or hypothalamus region are mostly associated with hypothalamic-pituitary hormone deficits; after surgery deficits will usually get worse, rarely recovery. Usually multiple pituitary hormone deficits. Brain surgery outside the hypothalamo-pituitary region may affect hormone production and secretion by pressure, blood circulatory disturbance or haemorrhage. Trans-sphenoidal surgery frequently followed by SIADH (hyponatraemia, elevated vasopressin). 56 Head trauma (traumatic brain injury, TBI) Phenotype: Up to 25 50% of patients have been reported to develop anterior pituitary deficiency, in particular GH deficiency. Can evolve over years. Systematic screening of pituitary function in all patients after head trauma and TBI appears warranted. 57 Hypoxic injury Phenotype: Hypoxic brain injury, especially in the neonate, can produce irreversible tissue damage. Predominantly diabetes insipidus as a sign of severe brain damage. Anterior pituitary hormone deficits may develop with some delay. 58 Irradiation Phenotype: Cranial irradiation for prophylaxis or treatment of leukaemic meningitis or for treatment of various brain tumours. Radiotherapy has a dose-dependent effect on hypothalamic-pituitary hormone secretion, GH secreting cells being most sensitive. Hormone deficits occur years after treatment. Comment: May also affect cartilage plates and bone growth. ESPE Classification of Paediatric Endocrine Diagnoses 42

13 59 Drugs, e.g. chemotherapy, alcohol Phenotype: Chemotherapy affects growth mainly by a catabolic condition and by direct effects on bone, possible effects on hypothalamus. Foetal alcohol syndrome results from maternal alcohol use during pregnancy (facial abnormalities, impairment in neurodevelopment and growth). Cases with GH deficiency have been reported. 60 Anorexia nervosa Phenotype: Amenorrhoea, weight loss, behavioural changes (fear of gaining weight, disturbance of self-evaluation of body shape, hyperactivity, sleep disturbance). Endocrine abnormalities represent an adaptation to starvation. LH ( ), FSH ( ), E2 ( ), T4 ( ), TSH (N), Prl (N), basal GH (+), IGF1 ( ). Generally in young women under age 25. Female:male ratio 9:1. 61 Emotional deprivation (psychosocial dwarfism, deprivational dwarfism) Phenotype: Short stature, abnormal behaviour patterns (perverted or voracious appetite, enuresis, encopresis, insomnia), occurs in children with a disturbed social environment. GH ( ), IGF1 ( ), occasional TSH and ACTH deficiency. Reversible if placed in a favourable psychosocial environment. Pituitary, Hypothalamus, Central Nervous System (CNS) 43