Ghai Essential Pediatrics8th

the morning, 40% in the afternoon and 20% in the evening is recommended.

The first line of treatment is usually non-pharma­ cological, comprising motivational therapy and use of alarm devices. Motivational therapy alone is successful in curing enuresis in 25% patients. The child is reassured and provided emotional support. Every attempt is made to remove any feeling of guilt. The benign nature of the disorder is explained to the child and parents using diagrams, if required, to explain theprobablebasis of the disorder. The child is encouraged to assume active responsibility, including keeping a dry night diary, voiding urine before going to bed and changing wet clothes and bedding. Dry nights should be credited with praise and encouraging words from the parents. Punish­ ments and angry parental responses should be avoided.

Behavioral modification is encouraged to achieve good bladder and bowel habits. The child is encouraged both to void frequently enough to avoid urgency and daytime incontinence and tohave a dailybowelmovement. A stool softener such as polyethylene glycol helps children with constipation.Bladdertrainingexerciseshavenotbeenshown to be useful in improving the functional bladder capacity.

Alarm therapy involves the use of a device to elicit a conditioned response of awakening to the sensation of a full bladder. Gradually, the association with bladder distention evokes micturition. The alarm device consists of a small sensor attached to the child's underwear, or a mat under the bed-sheet and an alarm attached to the child'scollarorplacedat thebedside. When thechildstarts wetting the bed, the sensors are activated causing the alarm to ring. The child should awaken to the alarm, void in the toilet and reattach the alarm; a parent should attend the child each time to ensure the child does not merely wake to switch off the alarm. The alarm is best used after seven years of age and is successful in about two-thirds of children; a third of children may relapse afterwards. Alarm systems are now available in India; however, the ordinary alarm clock may be used to wake the child up, to void in the toilet at a critical time when the bladder is full and the child is still dry. The combination of moti­ vationaland alarmtherapyissuccessfulin up to 60-70% of children.

Plwrmacotherapy is considered if enuresis persists despite institution of alarm, regular voiding habits, exclusion or treatment ofconstipationandexclusionofpostvoidresidual urine, dysfunctional voiding or low voiding frequency. Imipramineworksbyalteringthearousal-sleepmechanism. It gives a satisfactory initial response at a dose of 1-2.5 mg/ kg/day, but relapse rate after discontinuation of therapy is high. Cardiac arrhythmias are a serious adverse event effect. Anticholinergic drugs reduce uninhibited bladder contractionsand are usefulin children who have significant daytime urge incontinence besides nocturnal enuresis. The usual dose is 5 mg for oxybutynin, 2 mg for tolterodine or

Disorders of Kidney and Urinary Tract -

0.4 mg/kg for propiverine at bedtime, given above 6 yr of age. Desmopressin (ODAVP, 10 µg orally or intranasally) works by reducing the volume of urine. However, its the relapse rate is high after stopping the medication. Its rapid onset of action makes it a satisfactory choice for special occasions like staying out for the night.

Suggested Reading

Lottmann HB, Alova I. Primary monosymptomatic nocturnal

enuresis in children and adolescents. Int J Clin Pract (suppl) 2007;155:

8-16

Weaver A, Dobson P. Nocturnal enuresis in children. J Fam Health Care 2007;17:159-ol

CONGENITAL ABNORMALITIES OF KIDNEY AND

URINARY TRACT

Congenital abnormalities of kidney and urinary tract (CAKUT) are common and account for about 25% cases of CKD in children.

Single Kidney

Unilateral renal agenesis is present when one kidney fails to form while the other kidney is normal in size, position and function. Agenesis may occur due to primary failure of formation of the ureteric bud or its inability to engage with the renal mesenchyme. The condition may occur sporadically or as part of syndromes such as branchio­ otorenal,DiGeorge, Fanconianemia,Fraseror nail-patella syndromes. Renal agenesis is asymptomatic, usually detectedincidentallyonultrasonography. Ultrasoundalso confirms compensatory hypertrophy of the normal single kidney. A DMSA scan helps in ruling out scarring due to associated vesicoureteric reflux or an ectopic kidney. Children with single kidney should avoid contact sports. Whileaffectedpatients areexpectedto maintainglomeru­ lar function, they require annual monitoring for hyper­ tension and proteinuria.

Fetuses with bilateral renal agenesis or hypoplasia rarelysurvive toterm.Lackof fetal urineproductionleads to oligohydramnios and limb anomalies. Neonates show low set ears, flat nose, prominent epicanthic folds and small chin (Potter facies). Pulmonary hypoplasia is the usual cause of death.

Renal Dysplasia

Renal dysplasia implies abnormal development of renal parenchyma. Primitive ducts surrounded by connective tissue, metaplastic cartilage, poorly differentiated glomeruli and dilated tubules are present. Bilateral total renal dysplasia is fatal in the neonatal period.

Multicystic dysplastic kidney. A multicystic dysplastic kidney (MCDK) is an enlarged nonfunctioning kidney with cysts of varying sizes resulting from abnormal differentiation of the metanephros. Affecting 1 in 2400 to 4300 live births, it is the most common cystic renal malformation in children. Ultrasonography shows

characteristic findings, including multiple thin-walled noncommunicating cysts of varying size, in an enlarged kidney without identifiable parenchyma or renal pelvis (Fig. 16.22).

Fig. 16.22: Multicystic dysplastic kidney. Multiple, thin-walled and noncommunicating cysts are seen to involve the left kidney on postnatal ultrasound at one month age

Most patients with MCDK have a normal contralateral kidney showing compensatory hypertrophy. However, 20-40% cases may show associated abnormalities of the contralateral genitourinary tract, such as vesicoureteric refluxorpelviuretericjunction obstruction. A DMSA scan confirms that the affected kidney is nonfunctional and rules out reflux-associated scarring of the contralateral kidney. Children with MCDK require regular monitoring byultrasoundto ensurecompensatoryhypertrophy of the normal kidney and progressive involution of the affected kidney, which is undetectable by 5-7 yr of age in most cases. Progressive renal impairment is seen only if other abnormalities are associated. The risk of malignant transformation (Wilms' tumor) and hypertension are negligible. Nephrectomy is not indicated except in presence of severe hypertension, suspected malignancy, or a large kidney that fails to involute.

Obstructive Uropathy

Obstructiveanomalies of the urinarytract are an important cause of irreversible renal damage in childhood. The common lesions include pelviuretericjunction obstruction, vesicoureteric junction obstruction and posterior urethral valves. Diagnosis is suspected on antenatal ultrasono­ graphy or following presentations withdribblingof urine, poor urinary stream, fever and/or urinary tract infections. Chronic obstruction results in dysfunction ofdistal tubules with impaired urinary concentration and acidification, leading topolyuria,polydipsia, failme tothrive,refractory rickets and systemic acidosis.

Pelvlureterlc Junction (PW) obstruct/on Stenosis of the PUJ may be unilateral or bilateral. Obstruction is more

common in boys and in presence of ectopic, malrotated or horseshoekidney. Itmaypresent asanasymptomatic flank mass, or with upper abdominal pain, UTI or hematuria. Ultrasonography shows a dilated renal pelvis without uretericdilatation. Radionuclide(DTPA)renalscanshows impaired drainage of the affected kidney which does not improve despite administration of a diuretic. Where scintigraphy is not available, intravenous pyelography is performed, which shows renal pelvis dilatation with an abrupt cut-off at thePUJ. Mildcases are followed up with ultrasound. Surgical treatment bypyeloplasty is indicated if the relative function of the affected kidney is impaired. Nephrectomy may be required for a kidney in which extremely poor function does not improve despite temporary nephrostomy and severe hypertension or recurrent urinary infections are present.

Posterior urethral valves These constitute an important cause of distal urinary tract obstruction in boys. The usual presenting features are dribbling, abnormal urinary stream, palpable bladder andrecurrentUTI. Thepresence of severe obstructionin the urinary tract in utero maylead to renal dysplasia, with mild to moderate renal dys­ function at birth. Antenatal ultrasound shows bilateral hydroureteronephrosis with or without a thick-walled bladder and oligohydramnios. Thediagnosisis confirmed on MCU, which shows dilated posterior urethra and valves at itsjunction with the anterior urethra. The bladder is enlarged and may show diverticuli and trabeculations; secondary vesicoureteric reflux is common.

Endoscopic fulguration of the valves is performed as early as possible. Alternatively, temporary urinary diver­ sion by vesicostomy or bilateral ureterostomies is necessary. Longterm followup after surgery is necessary since a significant proportion of patients may show pro­ gressive kidney disease. Additionally, bladder dysfunc­ tion is common, with delayed continence or incontinence, poor bladder sensation and a poorly compliant low capacity bladder. If pharmacotherapy fails, patients may requireclean intermittent catheterization and occasionally bladder augmentation.

Meatal stenosls Significantnarrowing of urethralmeatus is rarely a cause ofurinary tract obstruction. The treatment consists of meatal dilatation, failing which meatoplasty may be needed.

Phimos/s Phimosis may predispose to recurrent UTI in infants. However, up to the age of 2 yr, the prepuce cannot be fully retracted because of its congenital adhesions with the glans. Therefore, the diagnosis of phimosis should be made with caution in young children.

VUJ obstruction This condition is caused by an aperistaltic segment of the ureter near VU junction. Primary VUJ obstruction is more common in males and on the left side, and may be associated with ureterocele or VUR.

Ureterocele This is a congenital condition in which the terminal part of the ureter distends within the bladder to form a sac, due to an abnormality of the submucosal part of the ureter and stenosis of the ureteric orifice. Uretero­ celes are commonly associated with duplex systems, particularly in girls. Endoscopic deroofing isthetreatment of choice.

Miscellaneous

Renal ectopia, renal fusion An ectopic kidney may lie in thepelvis or theiliac fossa. It maybestructurallynormal or hypoplastic. The patient may be asymptomatic, or have abdominal discomfort or dysuria. A horseshoe kidney results from fusion of identical poles of both kidneys. Patientswithhorseshoekidney show vesicoureteric reflux in 30% cases.

Renal duplication A duplex (duplicated) system is a kidney with two pyelocalyceal systems. In patients with partial or incomplete duplication, either a single or bifid ureter is present; in those with complete duplication, two ureters from the affected side empty separately into the bladder. Evaluation consists of imaging of the upper tract (ultrasonography, DTPA renal scan, intravenous pyelo­ graphy) to evaluate for obstruction and lower tract (MCU) for vesicoureteric reflux.

ANTENATAL HYDRONEPHROSIS

Extensive use of antenatal ultrasonography has lead to increasing detection of CAKUT. On antenatal ultrasound, hydronephrosis is identified in 4-5% pregnancies. However, the majority of cases of antenatal hydro­ nephrosis resolvewithout sequelae, representing transient physiological obstruction or stasis. These children require monitoring by ultrasound during the antenatal period for progressive worsening and association with oligo­ hydramnios, which suggests severe lower urinary tract obstruction. A postnatal ultrasound is recommended during the first week of life and on day 1 in severe cases. Neonates with posterior urethral valve, solitary kidney or bilateral hydronephrosis and impaired renal function require prompt management. Neonates showing signi­ ficant unilateral or bilateral dilatation should undergo a MCU at 4-6 weeks of life to detect vesicoureteric reflux; if reflux is ruled out, a diuretic renal dynamic (DTPA) scan is done to detect significant PUJ or VUJ obstruction and evaluate differential renal function. Most cases with mild to moderate hydronephrosis require only ultrasound monitoring and show spontaneous resolution by 2-5 yr of age. Surgery is indicated in presence of obstructive drainagepatternassociated with low differentialfunction, and/or recurrent UTI. Infants with vesicoureteric reflux should receive continuous antibiotic prophylaxis.

Figure 16.23 shows a proposed algorithm for postnatal evaluation and management of antenatally detected

Disorders of Kidney and Urinary Tract -

hydronephrosis. Parents of all infants with antenatal hydronephrosis should be counseled regarding increased risk of urinary tract infections and their prompt manage­ ment.

Suggested Reading

Nguyen HT, Herndon CD, Cooper C, et al. The Society for Fetal Urology consensus statement on the evaluation and management of antenatal hydronephrosis. J Pediatr Ural 2010;6:212-31

Sinha A, Bagga A, Krishna A, et al. Revised guidelines on the man­ agement of antenatally detected hydronephrosis. Indian Pediatr 2013;50:215-32

CYSTIC KIDNEY DISEASES

Polycystic kidney disease and nephronophthisis are relatively common and glomerulocystic kidney disease is increasingly diagnosed. Better delineation using high resolution ultrasonography or MRI and identification of geneticlocihaveenabled accuratediagnosisandimproved management for these conditions.

Polycystic Kidneys

Polycystic kidneys are inherited in either the autosomal dominant or autosomal recessive form, with distinctive features. Autosomal recessive polycystic kidney disease (ARPKD), caused by mutations in PKHD1 gene encoding fibrocystin or polyductin, is characterized by fusiform dilation of collecting tubules which are arranged radially from the cortex to medulla. Affected children usually present in the neonatal period with oliguria, respiratory insufficiency and palpable kidneys. ARPKD is sometimes diagnosed in young children presenting with hyper­ tension, renal insufficiency and enlarged kidneys, or with portal hypertension due to associated congenital hepatic fibrosis. Ultrasonography shows enlarged 'bright' kidneys, usually without visible cysts (Fig. 16.24A). Contrast enhanced computerized tomography (CT) reveals a characteristic striatepattern of contrast excretion on delayed films.

The autosomal dominant form of polycystic kidneys

(ADPKD) is caused by mutations in the ADPKD1 (chromosome 16) or ADPKD2 (chromosome 4) genes

encoding polycystins 1 and 2, respectively, membrane proteins called that regulate tubular and vascular development in various tissues. This condition usually presents beyond the third decade of life with episodic hematuria, hypertension, palpable kidneys and gradual decline in renal function, but may bedetected incidentally inchildhood.Associatedfindingsincludecysts in theliver, spleen and pancreas, mitral valve prolapse and berry aneurysms of the cerebral arteries. Ultrasonography reveals cysts in the kidneys (Fig. 16.24B) in one affected parent unless they are younger than 30 yr, in which case grandparentsshould be screened; rare cases are due to de nova mutations. Therapy with angiotensin converting enzyme inhibitors helps control hypertension and limits

hyperfiltration and proteinuria. The role of inhibitors of the mTOR pathway such as sirolirnus and everolirnus is being explored.

Glomerulocystci Kdneyi Dseasei

The predominant finding in glomerulocystic kidney disease (GCKD) is cysts involving glomeruli, diagnosed most definitely on renal biopsy. Ultrasonography shows

small subcortical cysts with increased kidney echogenicity and loss of cortical medullary differentiation. The condition may occur sporadically, with autosomal dominant inheritance, as a part of known syndromes (tuberous sclerosis, trisomy 13) or in association with other renal diseases such as dysplasia, ADPKD or ARPKD. Mutations in the hepatocyte nuclear factor gene lead to the renal cysts and diabetes syndrome, characterized by

GCKD, maturity onset diabetes and genitourinary abnormalities.

Nephronophthisis Medullary

Cystic Disease Complex

This group includes recessively inherited cystic disorders

_

causedbymutations ingenes,namedNPHP 1-9, encoding

cytosolic proteins called nephrocystins. Patients with

_

nephronophthisis present during t e first decade of 1fe with polydipsia, polyuria or enuresis, growth retardation and nonspecific signs of renal insufficiency, ac d? is d anemia. Extrarenal features may include rehmhs p1g­ mentosa; ocular motor apraxia, hypotonia and cerebellar or midbrain abnormalities Goubert syndrome); skeletal chondodysplasia Geune syndrome); and hepatic fibrosis with pancreatic dysplasia.

The diagnosis of nephronophthisis is supported by the ultrasound or CT finding of small kidneys with corti­ comedullary cysts and poor corticomedullary differ­ entiation. Renal histology shows cysts involving the collecting ducts, interstitial fibrosisand tubular dilatation with atrophy. While medullary cystic kidney disease is

Disorders of Kidney and Urinary Tract

histologically indistinguishable from nephronophthisis, the disease is inheritedinan autosomaldominantmanner, and presentation is delayed to adulthood.

Renal Cysts in other Syndromes

Cystic dysplastic kidneys may be seen as a part of syndromes such as Bartlet Biedl, Beckwith-Wiedemann, Meckel Gruber, Zellweger and brachiootorenal syn­ dromes. Sincetheaffected genesarecontinguous, ADPKD may beassociatedwithtuberoussclerosis,presentingwith characteristic skin lesions, periungual fibromas and seizures. The presence of retinal and central nervous system hemangioblastomas, pheochromocytoma and pancreatic cysts with cystic renal tumors suggests von Hippel-Lindau syndrome.

Suggested Reading

Avni FE, Hall M. Renal cystic diseases in children: new concepts. Pediatr Radio! 2010;40:939-46

Guay-Woodford LM. Renal cystic diseases: diverse phenotypes con­ verge on the ciliurn/centrosome complex. Pediatr Nephrol 2006;21: 1369-76

GENERAL PRINCIPLES

Endocrine glands play a crucial role in maintenance of body physiology and homeostasis. The hypothalamic­ pituitary axis regulates most endocrine organs including thyroid, adrenals and gonads, and processes like growth and water regulation.

Structure and Mechanism of Action

Hormones are derivatives of amino acids (e.g. peptide hormones, glycoproteins, thyroxine and epinephrine) or cholesterol (e.g. steroid hormones, vitamin D, adrenal and gonadal steroids). The peptide hormones (e.g. parathyroid hormone or PTH, growth hormone or GH and insulin) do not bind to circulating bindingproteins resulting in rapid elimination and a short half-life. They do not cross the plasma membrane, but act on membrane receptors. The steroid hormones, on the other hand, bind to circulating proteins resulting in prolonged half-life. They traverse the cell membranes and act on intracellular receptors.

Hormone receptors may be extracellular (e.g. peptide hormones) or intracellular (e.g. steroid and thyroid hormones). Binding of hormones to extracellular receptors activates a catalytic process resulting in production of second messengers that induce structural changes in intracellular proteins, culminating in the hormone effect (Fig. 17.1). Steroids and thyroxine act on intracellular receptors (Fig. 17.2). The resulting hormone-receptor complex then binds to the hormone response elements in the target gene resulting in regulation of transcription. The effect of these hormones is therefore slower than those acting through extracellular receptors.

Regulation and Metabolism

Hormone secretion is regulated by a feedback system that includes regulatory hormones, hormone levels and hormone effects. The feedback operates at the level of the

Fig.17.1: Mechanism of action of extracellular G protein coupled adrenocorticotropic hormone (ACTH) receptor. Note that ACTH has a small extracellular receptor (R). Activation of the ACTH receptor stimulates G protein Gsa subunit by hydrolysing guanosine triphosphate (GTP) to guanosine diphosphate (GDP), resulting in increased intracellular cyclic AMP that stimulate steroidogenesis by activating cyclicAMPdependent kinases. ATPadenosine triphosphate

Fig. 17.2: Mechanism of action of intracellular cortisol receptor. HRE hormone response element

endocrineglandaswellasthe hypothalamic-pituitaryaxis. Peptide hormones are rapidly inactivated by plasma enzymes resulting in a short duration of action. Steroid hormonesare slowly metabolized by the liverandexcreted in the urine. Hormone metabolism is an important part of their regulation. Activation of hormones (e.g. androgen to estrogen, testosterone to dihydrotestosterone and calcidiol to calcitriol) is vitalfortheir actions. Inactivation of hormones at the site of action prevents their excess effects (e.g. inactivation of cortisol by 11 -hydroxysteroid dehydrogenase prevents its action on mineralocorticoid receptor). Peripheral conversion also plays an important role in hormone function (e.g. conversion of T4 to T3).

Assessment

Endocrine assessment relies on the assessment of basal hormone levels (thyroid disorders), their metabolites (urine products in adrenal disorders), hormone effects (insulin-like growth factor-1 levels in GH deficiency and urinary osmolality for diabetes insipidus), stimulation tests in deficiency states (GH deficiency and adrenal insufficiency) and suppression tests in excess states (GH excess and Cushing syndrome). Pulsatile secretionof most hormones makes the assessment of endocrine status with a single blood test difficult.

The feedback mechanism guides assessment of endo­ crine disorders. In primary organ failure, pituitary hor­ mones are compensatorily elevated, e.g. thyroid stimu­ lating hormone or TSH in congenital hypothyroidism luteinizinghormone (LH)andfolliclestimulatinghormone (FSH) with delayed puberty and adrenocorticotropic hormone (ACTH) with adrenal insufficiency, while low levels suggest hypothalamic or pituitary dysfunction. The feedback mechanism also provides the basis for dynamic endocrine tests for diagnosis of hormone excess states (dexamethasone suppression test for Cushing syndrome and glucose suppression test for GH excess).

DISORDERS OF PITUITARY GLAND

Physiology

The anterior and posterior parts of pituitary gland are distinct both in embryology and function. The anterior pituitary develops from the Rathke's pouch. Posterior pituitary originates from the infundibulum, which is a downgrowth from the floor of the diencephalon.

The principal hormones produced by the anterior pitu­ itary are TSH, ACTH, FSH, LH, GH and prolactin (PRL). These hormones regulate actions of adrenals (by ACTH), thyroid (by TSH) and gonads (by LH and FSH). The secretionofanteriorpituitaryhormonesisin turn regulated by hypothalamic peptides (growth hormone releasing hormone or GHRH, somatostatin, dopamine, gonado­ tropinreleasinghormoneorGnRH,corticotropinreleasing hormone or CRH and thyrotropin releasing hormone or TRH)andalsobyhormonesproducedbythetargetglands.

Endocrine and Metabolic Disorders -

Posterior pituitary hormones (arginine vasopressin or AVP, and oxytocin) are secreted by neurons located in the hypothalamic nuclei. AVP, also known as the antidiuretic hormone (ADH), is the key regulator of body water and osmolality.

Growth Hormone Deficiency

Growth hormone deficiency (GHD) may be caused by congenital CNS malformations,geneticdefectsor acquired neurological insults (Table 17.1.) These children have normal growth at birth. Growth retardation becomes apparent around one year of age. Midfacial crowding, round facies, mild obesity, depressed nasal bridge, single central incisor tooth and micropenis are common (Fig. 17.3). Bodyproportionsare normal.The development of teeth is delayed. The facial appearance is 'doll like' and these children look much younger than their actual age. Bone age is delayed. Newborns may present with severe hypoglycemic seizures due to concomitant ACTH deficiency. Associated gonadotropin deficiency causes

delay in sexual development and small genitalia. Resistance to growth hormone action (growth hormone

insensitivity or Laron syndrome) presentswith almostsimilar features with severe growth retardation and elevated baseline GH levels.

Short Stature

Growth failure may occur as part of any long-standing systemic illness. Chronic systemic disorders and nutritional causes of growth retardation (including malabsorption)havepredominanteffectonweight.Height is secondarily affected. Thus weight age is substantially lowerthanheightage intheseconditions. Onthe contrary,

Table 17.1: Etiology of growth hormone deficiency

Congenital

Genetic defects

Isolated GH deficiency

Type I: Autosomal recessive Type II: Autosomal dominant Type Ill: X-linked recessive

Multiple pituitary deficiencies Type I: Autosomal recessive Type II: X-linked

Idiopathic CH releasing i1or111011e deficiency

Develop111e11tal defects: Pituitary aplasia or hypoplasia, anencephaly, holoprosencephaly, midfacial anomalies, septo­ optic dysplasia

Acquired

Tu111ors: Hypothalamic, pituitary or other intracranial tumors

Irradiation

Infections: Encephalitis, meningitis,tuberculosis, toxoplasmosis Infiltration: Histiocytosis, hemochromatosis, sarcoidosis Injury: Perinatal insult (breech), head injury, surgery Vascular: Aneurysm, infarction

Fig. 17.3: A 6-yr-old girl with short stature due to growth hormone deficiency. Note the immature facies, midfacial hypoplasia and cherubic appearance

endocrine causes like GHD, hypothyroidism and pseudo­ hypoparathyroidism mainly affect height resulting in disproportionately low height age (see Chapter 2).

Evaluation

History. Perinatal history, birth weight and length should berecorded.History of birthasphyxia,breech presentation, neonatal hypoglycemia, micropenis and prolonged jaun­ dice are early indicators of GHD. Features of chronic infections, cardiopulmonary disorders, malabsorption and raised intracranial tension should be looked for. Presence of polyuria and polydipsia suggests diabetes insipidus, diabetes mellitus and/or renal tubular acidosis. Consti­ pation, delayed milestones, lethargy and cold intolerance indicate hypothyroidism. Family history of short stature and/or delayed puberty suggests the possibility of familial short stature orconstitutionaldelay of puberty and growth.

Examination. Anthropometric assessments (weight, height, weight for height and head circumference) are required. Compromised weight suggests a nutritional etiology (malnutrition, systemic illness or malabsorption) while weight is preserved in most endocrine disorders.

Body proportions are helpful in identifying skeletal dysplasia. Lower segment (LS) is measured from the pubic symphysis to the feet. Upper segment (US) is obtained by subtracting it from height. The US:LS ratio is 1.7:1 at birth and decreases by 0.07-0.1 each year to reach 1:1 by 7-10 yr of age. Increased US:LS ratio suggests hypothyroidism, achondroplasia (Fig. 17.4) or Turner syndrome while reduced US:LS ratio is seen in disorders such as Morquio syndrome and spondyloepiphyseal dysplasia. Body proportions are normal in GHD.

The clinician should look for specific features of an underlying etiology such as GHD, hypothyroidism, Turner syndrome and rickets (Table 17.2). Evaluation for dysmorphism, skeletal deformities and sexual maturity rating are essential.

Fig. 17.4: Achondroplasia: Note the abnormal body proportions and facies

Table 17.2: Pointers to the etiology of short stature

Investigations. Laboratory evaluation of short stature involves stepwise application of diagnostic tests to determine the etiology (Fig. 17.5).

Step 1. The first step in investigation is to rule out common causes. This involves exclusion of malnutrition, chronic systemic illnesses and recurrent infections using complete

Corrected height SOS

Fig. 17.5: Approach to a child with short stature.

GH growth hormone; IGF-1 insulin-like growth factor-1, IGFBP-3 IGF binding protein 3; LFT liver function tests; RFT renal function tests; SDS standard deviation score

blood counts, erythrocyte sedimentation rate, chest X-ray, serum electrolytes and liver and renal function tests. Tissue transglutaminase antibody (celiac disease) and venous blood gas (renal tubular acidosis) should be performed if these screening tests are normal.

Estimation of skeletal maturation forms an important aspect of evaluation of short stature. This is done by comparing theX-ray of left wrist with age specific norms.

Step 2. The next step in evaluation involves evaluation for hypothyroidism (free T4 and TSH) and Turner syndrome (karyotype) in all girls.

Step 3. Evaluationfor GH-IGF axis is performed only after other common causes of growth retardation have been excluded. This is important as systemic illness and hypo­ thyroidism influence the CH-insulin-like growth factor (IGF) axis. Random or fasting blood GH level measure­ ments do not confirm the diagnosis of GHD as hormone secretion is pulsatile. The diagnosis of GHD thus requires pharmacologic stimulation tests. GHD is suspected when the peak level of GH is <10 ng/rnl following stimulation. The common provocative agents used are insulin, glu­ cagon and clonidine. Levels of IGF-1 and IGF binding protein 3 are helpful to diagnose GHD and Laron syn­ drome. GHD may be associated with other pituitary

Endocrine and Metabolic Disorders -

hormone deficiencies and appropriate investigations should be carried out to detect deficiency of these hormones if GHD is present. CT or MRI scans of hypothalamic and pituitary regions are essential to rule out developmental or acquired neurological lesions.

Management

Management of short stature involves correction of underlying cause and provision of adequate nutrition intake.

Patients should be advised diet rich in protein andcaloriecontent. They should beencouraged to increase their physical activity. Iron and vitamin deficiencies should be corrected. Zinc supplementation (10 mg/day for 3-6 months) may help in improving growth in patients with idiopathic short stature.

Initiation of specific treatment is effective in restoring growth in hypothyroidism (thyroxine), celiac disease (gluten free diet) and renal tubular acidosis (bicarbonate supplements). A short course of testosterone may be given to boys with constitutional delay of puberty and growth. Treatment of genetic syndromes and skeletal dysplasias is extremely difficult. Some of them do respond to GH therapy. Bone lengthening (Ilizarov technique) has been used with variable success in some forms of skeletal dysplasia.

Growth hormone GH is highly effective patients with GHD. This can result in an increase in height by 20-30 cm. The treatment is given as daily night time injections (25-50 µg/kg/day) till epiphyseal closure. The treatment is expensive and hence should be started only if it can be given regularly for at least 2 yr. The role of GH is expan­ ding with increasing use in Turner syndrome, chronic renal failure, small for gestational age infants who fail to catchup, Russel-Silver syndrome, Prader-Willi syndrome and idiopathic short stature.

Suggested Reading

Bajpai A, Kabra M, Gupta AK, Menon PSN. Growth pattern and skeletal maturation following growth hormone therapy in growth hor­ mone deficiency: Factors influencing outcome. Indian Pediatr 2006;43:593-9

Bajpai A, Menon PSN. Insulin like growth factors axis and growth disorders. Indian J Pediatr 2006;73:67-71

Cohen P, Rogol AD, Deal CL, et al. Consensus statement on the di­ agnosis and treatmentof children withidiopathic short stature. Lawson Wilkins Pediatric Endocrine Society and the European Society for Short Stature. J Clin Endocrinol Metab 2008;93:4210-17

Patel L, Clayton PE. Normal and disordered growth. In: Clinical Pediatric Endocrinology, 5th edn. Eds: Brook CGD, Clayton PE, Brown RS. Blackwell Publishers, London, 2005;90-112

Growth Hormone Excess

Excess of GH during childhood results in somatic overgrowth or gigantism. Increased GH secretion after the

fusion of skeletal epiphyses causes features of acromegaly. Coarsefeatureswith prominent jaw, broadnose, enlarged tongue, bushy eyebrows, thick skin and dorsal kyphosis are characteristic. Headache and visual field defects (bitemporal hemianopia and enlargement of the blind spot) are common.

The diagnosis is based on clinical examination, serial photographs of the child, growth assessment and investi­ gations. SkullX-rayfilmsshow enlarged sella witherosion ofthemargins. Tuftingofthephalangesandincreasedheel pad thickness may be present. MRI helps to confirm and determine the extent of the tumor. GH levels are elevated and are not suppressed by a glucose tolerance test.

Pituitary gigantism is rare in children. It may be the only clue to an underlying pituitary adenoma, which may be associated with isolated or multiple endocrine involve­ ments in the setting of multiple endocrine neoplasia or McCune Albright syndrome.

GH excess should be differentiated from Sotos syndrome (cerebral gigantism) characterized by large size at birth, excessive growth in early childhood, and advanced height, weight and bone ages. The skull is large with prominent forehead and jaw, high arched palate, hypertelorism and antimongoloidslantof thepalpebralfissure.Hereditarytall stature,obesity,precociouspuberty, Marfansyndromeand lipodystrophy should be ruled out by appropriate tests.

Medical management involves the use of long-acting somatostatin analogs such as octreotide. The GH receptor antagonist pegvisomant is also useful in treatment. Partial or complete resection of pituitary adenoma is indicated if there is evidence of raised intracranial tension.

Diabeteslnsipidus

Polyuria (urine output >5 ml/kg/hr or 2 L/m2/day) is an important pediatric problem and may be the only manifestation of a serious disease such as diabetes insipidus, diabetes mellitus, brain tumorandrenaltubular acidosis. Polyuria may result from increased solute load or impaired renal concentrating capacity (Table 17.3).

Diabetes insipidus (DI) is an important cause of poly­

uria. DIpresentswith low urine osmolality in association with high plasma osmolality. DImay be due to decreased produc­ tion ofvasopressin (central DI) or action (nephrogenic DI). Dehydration is unusual unless there is an abnormality of thirst mechanism. However, infants are at a high risk of developing hypernatrernic dehydration.

Central DI is commonly associated with an intracranial pathology (Table 17.3.) Craniopharyngiomapresents with DI, growthretardationand skullcalcification.Germinoma located in the pituitary stalk may be missed on neuro­ imaging, emphasizing the need to repeat neuroimaging if no cause is found. Malformations of the central nervous system such as septo-optic dysplasia and holoprosence­ phaly display central DI and deficiency of anterior pituitary hormones. Histiocytosis is the commonest

Table 17.3: Causes of polyuria

Increased fluid load

Iatrogenic

Compulsive water drinking

Increased solute load

Osmotic diuresis: Diabetes mellitus, mannitol treatment

Salt loss: Adrenal insufficiency, diuretics, cerebral salt wasting, aldosterone resistance

Impaired urinary concentration

Inefficient ADH action (Diabetes insipidus, DI)

Central DI (Neurogenic DI) Genetic defects

Malformations: Septo-optic dysplasia, holoprosencephaly, anencephaly

CNS insults: Head trauma, neurosurgery, infection, brain death

Infiltrative disorders: Sarcoidosis, histiocytosis

Space occupying lesions: Craniopharyngioma, germinoma Nephrogenic DI

Genetic: X linked (V2 receptor), AR, AD (aquaporin defect) Acquired: Hypokalemia, hypercalcemia, obstructive

uropathy, nephrocalcinosis

Tubulopathy

Renal tubular acidosis Bartter syndrome Gitelman syndrome

infiltrative disorderassociatedwithcentralDI. Neurological infections including tuberculosis may cause central DI.

Nephrogenic DI. This condition results from inherited or acquired resistance to vasopressin. Hypokalemia and hypercalcernia are important causes of nephrogenic DI.

Water Balance and Polyuria

Maintenance of water balanceinvolves regulation of urine output and thirst. Thirst is controlled by the hypothala­ mus. Urine output is determinedby solute load, hydration status and urine concentration capacity. Fluidhomeostasis involves close interaction of arginine vasopressin, renin­ angiotensin-aldosterone system and atrial natriuretic peptide. Vasopressin is secreted by the hypothalamus in response to osmotic signals and acts on the V2 receptors in collecting duct to increase free water resorption. The renin-angiotensin-aldosterone system is central to the regulation of sodium, fluid and blood pressure.

Differential Diagnosis of Polyuria

Diabetes mellitus. Diabetes mellitus presents with poly­ dipsia, polyphagia, recurrent infections and weight loss in addition to polyuria.

Renal disorders. Polyuria is common in obstructive uropathy. It is often the presenting feature of tubular disorderslikerenal tubular acidosis, Bartter syndromeand Gitelman syndrome. These conditions are associated with severe failure to thrive and rickets.