BALANCE 13 DISORDERS OF WATER DISORDERS CHARACTERISED BY POLYDIPSIA AND POLYURIA. (vasopressin deficiency) 1 [primary] [secondary 6C] insipidus

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1 Wit JM, Ranke MB, Kelnar CJH (eds): ESPE classification of paediatric endocrine diagnosis. 13. Disorders of water balance. Horm Res 2007;68(suppl 2):96 97 ESPE Code Diagnosis OMIM ICD10 13 DISORDERS OF WATER BALANCE 13A DISORDERS CHARACTERISED BY POLYDIPSIA AND POLYURIA 13A.1 Central diabetes insipidus (vasopressin deficiency) 1 [primary] [secondary 6C] 13A.1a Genetic causes 13A.1a.1 Mutations in the AVP-NPII gene 2 # A.1a.1a Familial autosomal-dominant neurohypophyseal diabetes insipidus 13A.1a.1b Autosomal-recessive neurohypophyseal diabetes insipidus 13A.1a.2 Wolfram syndrome/didmoad 3 [primary 14B.38] [other # secondary 11A.3h.4] 13A.1b Congenital intracranial anatomic defects 13A.1b.1 Septo-optic dysplasia 4 # [primary 6E.1a] [other secondary 14B.30] 13a.1b.2 Midline craniofacial defects 13a.1b.3 Holoprosencephalic syndromes 5 % a.1b.4 Agenesis of the pituitary 13A.1c Acquired causes (for detailed classification use codes in 6E and 6F) 13A.1c.1 Neoplasms 13A.1c.2 Inflammatory/infiltrative 13A.1c.3 Infectious 13A.1c.4 Traumatic injury 13A.1c.9 Idiopathic 13A.1d Adipsic diabetes insipidus 6 E A.2 Nephrogenic diabetes insipidus N A.2a Genetic 13A.2a.1 X-linked recessive (AVP-V2 receptor) 7 # A.2a.2 Autosomal recessive (aquaporin-2) 8 # A.2a.3 Autosomal dominant (aquaporin-2) # A.2b Acquired 13A.2b.1 Drugs, e.g. lithium, foscarnet, demeclocycline 13A.2b.2 Metabolic, e.g. hyperglycaemia, hypercalcaemia, hypokalaemia, protein malnutrition 13A.2b.3 Renal 96

2 ESPE Code Diagnosis OMIM ICD10 13A.3 Primary polydipsia 9 R A.3a Psychogenic 10 13A.3b Dipsogenic 11 13A.3c Iatrogenic 12 13B DISORDERS CHARACTERISED BY HYPERNATRAEMIA E B.1 Disorders classified elsewhere Central diabetes insipidus (13A.1) Nephrogenic diabetes insipidus (13A.2) 13B.2 Adipsic hypernatraemia 13 13B.3 Physical obstacles to drinking 13B.4 Excessive free water loss (other than diabetes insipidus) e.g. after gastroenteritis with prolonged vomiting and diarrhoea 13B.5 Excessive sodium intake 13B.5a Salt poisoning (child abuse) 13B.5b Other causes 13C DISORDERS CHARACTERISED BY HYPONATRAEMIA E C.1 Inappropriate AVP secretion (syndrome of inappropriate antidiuretic hormone, SIADH) 14 E C.1a Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) 15 # C.1b Tumours 13C.1c Drugs 13C.1d CNS disorders 13C.1e Non-malignant pulmonary disorders 13C.1f Post-operative hyponatraemia 13C.1g Adrenal insufficiency [primary 8A] 13C.1h Hypothyroidism [primary 7A] 13C.2 Appropriately increased secretion of vasopressin E C.2a Hypovolaemic hyponatraemia from salt and water depletion 13C.2a.1 Salt and water depletion Disorders of Water Balance 97

3 ESPE Code Diagnosis OMIM ICD10 13C.2a.2 13C.2b Primary sodium deficiency Hypervolemic hyponatraemia 13C.3 Water intoxication E C.4 Cerebral salt wasting 16 E Central diabetes insipidus Synonyms: Hypothalamic, neurogenic, pituitary, neurohypophyseal diabetes insipidus. Phenotype: Polyuria (exceeding 2 litres/m 2 /day), nocturia, enuresis, thirst, increased fluid intake, especially water. If water is restricted hypernatraemia occurs. 2 Familial central diabetes insipidus Phenotype: Polyuria and polydipsia usually after the first year of life. Undetectable AVP. Comments: Defect in the arginine vasopressin gene (AVP-neurophysin II gene). An X-linked form of neurohypophyseal diabetes insipidus has been suggested, but the evidence is weak. 3 Wolfram syndrome (DIDMOAD) Phenotype: (Partial) diabetes insipidus, gradual onset of diabetes mellitus, optic atrophy, deafness. In addition, neurogenic bladder, ataxia, psychiatric disorders. Signs outside the nervous system: hypogonadism, pigmented retinopathy, cardiomyopathy, sideroblastic anaemia, thrombocytopenia. Frequently, insulin dependence, no autoimmune phenomena. Serum AVP ( ). DNA: heterogeneous with mitochondrial and nuclear mutations. Comments: Caused by mutation in the gene encoding wolframin (WFS1). Another locus for the disorder has been mapped to 4q (WFS2). 4 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 have been found in only a few cases. 5 Holoprosencephalic syndromes Phenotype: Etiologically heterogeneous entity which varies widely from cyclopia to almost no manifestation except perhaps a single middle incisor. Comments: Frequency of about 1 in 16,000 live births and about 1 in 200 spontaneous abortions. There are teratogenic causes, maternal diabetes being the most significant, giving a 200-fold increased risk. Genetic factors are indicated by familial occurrence, the occurrence of holoprosencephaly in some mendelian genetic syndromes, and the association with non-random chromosomal aberrations. One of the genetic syndromes that includes holoprosencephaly as a feature is 98

4 Smith-Lemli-Opitz syndrome. Several loci for holoprosencephaly have been mapped to specific chromosomal sites and the molecular defects in some cases of HPE have been identified. Holoprosencephaly-1 (HPE1) maps to 21q22.3, HPE2 is caused by a mutation in the SIX3 gene, HPE3 is caused by a mutation in the sonic hedgehog gene (SHH), HPE4 is caused by a mutation in the TGIF gene, HPE5 is caused by a mutation in the ZIC2 gene, HPE6 maps to 2q37.1, HPE7 is caused by a mutation in the PTCH1 gene, HPE8 maps to 14q13, and HPE9 is caused by a mutation in the GLI2 gene. 6 Adipsic diabetes insipidus Phenotype: Diabetes insipidus in combination with absent thirst. This can manifest itself as adipsic hypernatraemia in case of insufficient water intake (see 13B.2). 7 X-linked recessive nephrogenic diabetes insipidus Synonym: Renal diabetes insipidus. Phenotype: Polyuria, polydipsia, nocturia, compulsive drinking. In infants: failure to thrive, fever, weight loss, irritability. High serum ADH, activation of the renin-angiotensin-aldosterone system (RAAS). Comments: Nephrogenic diabetes insipidus is caused by the inability of the renal collecting ducts to absorb water in response to antidiuretic hormone (ADH), also known as arginine vasopression (AVP). Approximately 90% of patients are males with the X-linked recessive form, type I, which is caused by a mutation in the gene encoding the vasopressin V2 receptor (AVPR2). 8 Autosomal-recessive nephrogenic diabetes insipidus Synonym: Renal diabetes insipidus. Phenotype: Polyuria, polydipsia, nocturia, compulsive drinking. In infants: failure to thrive, weight loss, fever. High serum ADH, activation of the renin-angiotensin-aldosterone system (RAAS). Comments: Nephrogenic diabetes insipidus is caused by the inability of the renal collecting ducts to absorb water in response to antidiuretic hormone (ADH), also known as arginine vasopressin (AVP). 10% of patients have the autosomal form, type II, caused by mutation in the AQP2 gene. Both autosomal dominant and autosomal recessive forms have been reported. 9 Primary polydipsia Synonym: Primary polyuria. Phenotype: Excessive water drinking, resulting in decrease of plasma osmolality. Normalisation of renal concentrating capacity by stepwise reduction of water intake. Hypernatraemia is never seen. Therapy with ddavp may cause water intoxication to develop rapidly. 10 Psychogenic polydipsia Phenotype: Can occur as part of a general cognitive defect associated with schizophrenia or other psychiatric disorder or compulsive water drinking. 11 Dipsogenic polydipsia Phenotype: Increased water consumption is due to an increase in thirst, e.g. in diseases involving the hypothalamus.. 12 Iatrogenic polydipsia Phenotype: Primary polydipsia can also be prompted by incorrect advice or incorrect understanding of advice offered by physicians, etc. Disorders of Water Balance 99

5 13 Adipsic hypernatraemia Phenotype: Primary adipsia is usually caused by lesions in the anterior hypothalamus. The water intake associated with a normal diet is insufficient to match obligate renal, bowel, and insensible water losses, and absent thirst can lead to hypernatraemic dehydration. 14 Inappropriate AVP secretion (syndrome of inappropriate antidiuretic hormone, SIADH) Phenotype: Euvolaemic hyponatraemia, concentrated urine, sodium concentration >20 mmol/l, low serum uric acid and urea concentration. Can be caused by ADH-producing tumours, pulmonary and CNS disorders of different origin, drugs, and others. Inappropriately high serum ADH, elevated serum ANF. Comments: The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a common cause of hyponatraemia. The syndrome manifests as an inability to excrete a free water load, with inappropriately concentrated urine and resultant hyponatraemia, hypo-osmolality, and natriuresis. SIADH occurs in a setting of normal blood volume, without evidence of renal disease or deficiency of thyroxine or cortisol. Although usually transient, SIADH may be chronic; it is often associated with drug use or a lesion in the central nervous system or lung. 15 Nephrogenic syndrome of inappropriate diuresis (NSIAD) Comments: Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is characterised by a clinical picture similar to SIADH, but is associated with undetectable levels of AVP. The disorder is caused by gain-of-function mutations in the gene encoding the vasopression V2 receptor (AVPR2). Constitutive activation of the receptor results in antidiuresis. 16 Cerebral salt wasting Comment: Following CNS injury, a syndrome of hyponatraemia associated with increased urine sodium concentration, increased urine volume, and volume depletion known as salt wasting can develop. 100