Ghai Essential Pediatrics8th

Adrenal tumors in children are usually large and identifiable on ultrasound. Magnetic resonance imaging of the hypothalamic-pituitary region shouldbe performed in children with ACTH-dependent Cushing syndrome. Inferior petrosal sinus sampling is the test for identifying the source of ACTH production and should be performed in children with ACTH-dependent Cushing syndrome with normal neuroimaging.

Management

Resection of adrenal lesion is recommended for adrenal adenoma and carcinoma. Prolonged cortisol excess causes suppression of the normal contralateral adrenal gland. This mandates close monitoring for adrenal insufficiency in the perioperative period. Adrenal carcinoma is highly malignant and has a high rate of recurrence. Pigmented nodular hyperplasia should be treated with bilateral adrenalectomy. Trans-sphenoidal resection of pituitary adenoma is recommended for Cushing disease.

Medical management of Cushing syndrome with inhibitors of steroidogenesis (ketoconazole, amino­ glutethimide, cyproheptadine, metyrapone and mitotane) has been tried with variable results.

Aldosterone Excess

Hyperaldosteronism is associated with fluid and sodium retention along with increased urinary loss of potassium. The most commonclinical features of primary hyperaldos­ teronism are hypertension and hypokalemic alkalosis. Primary hyperaldosteronism due to increased adrenal aldosterone production is extremely rare. Secondary hyperaldosteronism results from factors that activate renin-angiotensin system.

Primary hyperaldosteronism may be caused by diffuse hyperplasia or adenoma. Glucocorticoid-remediable aldo­ steronism (GRA), a genetic disorder involving chimeric fusion of the promoter of CYPllBl and the coding region of CYP11B2 genes, resulting in regulation of aldosterone secretion by ACTH and therefore, hyperaldosteronism. Primary hyperaldosteronism should be differentiated from secondary hyperaldosteronism (renal failure, congestive cardiac failure, liver disease and nephrotic syn­ drome and other states of minerolocorticoid excess, and apparent mineralocorticoid excess (Table 17.18).

Hypokalemic alkalosis in a child with low renin hyper­ tension should prompt evaluation for true or apparent aldosterone excess. High aldosterone level in this setting is suggestive of primary hyperaldosteronism or GRA. Decrease in aldosterone levels and resolution of clinical andlaboratoryfeaturesafterdexamethasonesuppression suggests GRA; no effect is seen in primary hyper­ aldosteronism. Diagnosis of primary hyperaldosteronism should be confirmed by adrenal imaging.

Hyperaldosteronism should be managed with salt restriction and aldosterone antagonist such as, spiro-

Endocrine and Metabolic Disorders -

Table 1 7.18: Etiology of hyperaldosteronism

Primary hyperaldosteronism

Adenoma, hyperplasia

Glucocorticoid remediable hyperaldosteronism

Secondary hyperaldosteronism

Renal artery stenosis, renin secreting tumor

Cardiac failure, nephrotic syndrome, liver disease

Other causes of excessive mineralocorticoid action

Apparent mineralocorticoid excess (deficiency of llP­ hydroxysteroid dehydrogenase)

Liddle syndrome

Congenital adrenal hyperplasia due to deficiency of 17a­ hydroxylase or llP-hydroxylase

nolactone or eplerenone. Physiological hydrocortisone replacementsuppresses ACTHsecretioninglucocorticoid remediable aldosteronism resulting in resolution of hyperaldosteronism and hypertension. Surgery is the treatment of choice for adrenal adenoma.

Pheochromocytoma

Pheochromocytoma is a catecholamine-secreting tumor, arising from the chromaffin cells of adrenal medulla. It can also arise from the abdominal sympathetic chain, peri­ adrenal area, or in the thoracic cavity. The condition is rare in children and coexists with other syndromes such as neurofibromatosis, von Hippel Lindau disease and multipleendocrineneoplasiatypeIL Compared to adults, pheochromocytoma is more likely to be bilateral and associated with underlying genetic anomaly in children.

Excessive secretion of catecholamines results in hyper­ tension, which is usually sustained and occasionally paroxysmal. The clinical symptoms include headache, palpitation, pallor, sweating, nausea, vomiting, visual disturbances and occasionally convulsions. The diagnosis should be considered only after other common causes of childhood hypertension likerenalparenchymal disorders, renal artery stenosis and coarctation of aorta have been excluded. Diagnosis is established by demonstration of increased urinary excretion of catecholamines and their derivatives. Ultrasound, CT scan, MRI scan and 1231 metaiodobenzylguanidine (MIBG) scintigraphy are used for localization. Often the tumors are multiple.

Surgery is the treatment of choice. Transabdominal exploration of all the sites with removal of tumors is advocated. Preoperative alpha blockade is needed using phenoxybenzamine and prazosin. Recently, calcium channel blocking agents have been used successfully.

Adrenal Insufficiency

Adrenal insufficiency may be related to adrenal defects (primary adrenal insufficiency; autoimmune destruction, infection, steroidogenic defect, hemorrhage), decreased ACTH production (secondary adrenal insufficiency) or ACTH resistance.

Autoimmune adrenal dysfunction is the commonest cause of primary adrenal failure (Addison disease) beyond infancy. Autoimmune adrenal failure is often associated with autoimmune polyendocrinopathy type 1 and 2. Infections like tuberculosis and HIV can result in primary adrenal failure. Adrenal hemorrhage in the setting of meningococcalandother bacterialinfections (Waterhouse­ Friderichsen syndrome) is an important cause of insufficiency. Congenital adrenal hyperplasia (CAH) due to deficiency of 21-hydroxylase or 3-P hydroxysteroid dehydrogenase and deficient steroidogenesis due to defective steroidogenic acute regulatory protein (StAR; causing lipoid CAH) are the commonest causes in the neonatal period.

Secondary adrenal insufficiencyis caused by congenital malformations (holoprosencephaly, midline defects), genetic defects or acquired insults (neurosurgery, tumor, radiation). This is usually associated with other anterior pituitary hormone deficiencies as well. In secondary adrenal insufficiency, mineralocorticoid function is preserved as aldosterone isnotregulated by ACTH. Thus, salt wasting is not observed. Prolonged steroid treatment is associated with suppression of the hypothalamic­ pituitary axis resulting in adrenal insufficiency after discontinuation of medications. Again, mineralocorticoid activity is preserved in these patients.

Clinical Features

Adrenal insufficiency presents with slowly progressive lethargy, vomiting, salt craving, fatigue, postural hypo­ tension,hypoglycemiaandepisodesofshockduringsevere illness. The concomitant presence of shock, hyponatremia, hyperkalemia and hemoconcentration is characteristic of acuteadrenalinsufficiencyandwarrantsimmediatesteroid replacement.Primaryadrenalinsufficiencyischaracterized byhyperpigmentationdueto elevated levels of melanoyte stimulatinghormone. Hyperpigmentationispresentinsun­ exposedareassuchaselbowsandpalmarcreasesandareas that are normally hyperpigmented such as areola and genitalia.Pigmentationisabsentinchildrenwithsecondary adrenal insufficiency.

Evaluation

Allpatientssuspectedtohaveadrenalinsufficiencyshould undergo urgent testing for serum electrolytes and blood sugar. Basal levels of cortisol are low but can be in the normal range. Elevated plasma renin activity indicates mineralocorticoid deficiency. ACTH stimulation test (cortisol estimation 60 minutes after 0.25 mg of intra­ muscular or intravenous ACTH injection) is the best test foradrenocorticalreserve. Serumcortisollevelslowerthan 18 µg/dl are suggestive of adrenal insufficiency.

The next step in evaluation of adrenal insufficiency is estimation of ACTHlevels.ElevatedACTHlevels suggest primary adrenal pathology while low levels points towards pituitary defect. Further evaluation of primary

adrenal insufficiency includes abdominal CT scan and workup for tuberculosis.

Management

The initial management of salt wasting crisis includes correction of shock by fluid boluses. Hydrocortisone is given immediately at a dose of 50 mg/m2 followed by 100 mg/m2/day in four divided doses. Frequent monito­ ring ofhemodynamicparameters, urine output andserum electrolytes are required. Once the child is hemo­ dynamically stable, hydrocortisone can be tapered to the physiological dose (10 mg/m2/ day). Fludrocortisone acetate (0.1 mg/day) should be added once the hydro­ cortisone dose is less than 50 mg/m2/day.

Longtermmanagementof adrenalinsufficiency requires lifelong replacement of glucocorticoids and mineralo­ corticoids. Parents should be educated about the need of increasing dose during periods of stress. The dose of glucocorticoid should be increased2-3timesin conditions of minor stress (fever and mildinfection) and 4-5 times in severe stress (severe infection or surgery). These doses should continue throughout the period of stress. Patients with secondary adrenal insufficiency require lower dose of glucocorticoids (6-10 mg/m2/day); mineralocorticoid replacement is not necessary.

CongenitalAdrenal Hyperplasai

Congenital adrenal hyperplasia (CAH), a group of auto­ somal recessive defects in steroid synthesis, is char­ acterized bydeficiencyofadrenocorticalhormonesonone hand and excess of steroid precursors on the other (Fig. 17.11). CAH is the commonest adrenal disorder in childhood.

21-hydroxylase Deficiency

21-hydroxylasedeficiencyis the commonest form of CAH accounting for over 90% of all cases. This disorder is associated with diminished synthesis of the cortisol and aldosterone. Low cortisol levels stimulate ACTH synthesis. Elevated ACTH level causes accumulation of steroid precursors (dehydroepiandrosterone), androstene­ dione and 17-hydroxyprogesterone). Depending on the severity of enzyme deficiency the disease forms a spectrum of presentation as highlighted below.

Salt wasting form. These patients are the most severely affected and present in the neonatal period with virilizationandsalt wasting. Abnormal genitalappearance should prompt the diagnosis in girls. Diagnosis is often missed in boys as they lack specific clinical features. They present after second week of life with failure to thrive, polyuria, hyperpigmentation and shock. Early diagnosis is mandatory to prevent mortality. 21-hydroxylase deficiency should be suspected in neonates with ambiguous genitalia, polyuria, shock, recurrent vomiting and features of sepsis with negative septic screen. The

diagnosis should be confirmed immediately by measure­ ment of blood levels of 17-hydroxyprogesterone. If these are not available, the child should be managed empirically in the lines of adrenal insufficiency.

Simple virilizingform. A subset of patients with 21hydroxylase deficiency (25%) synthesizes enough aldo­ sterone to prevent adrenal crises. These patients have features of androgen excess in the form of virilization in girlsandperipheral precociouspubertyinboys (Fig.17.12).

Nonclassic form. This disorder is associated with partial 21-hydroxylase deficiency. Clinical manifestations are related to mild hyperandrogenism which presents with hirsutism, acne and menstrual irregularity.

Diagnosis

Diagnosis of salt wasting form is established by demons­ tration of extreme elevation of 17-hydroxyprogesterone levels (10000-20000 ng/dl, normal <90 ng/dl) in presence of clinical and laboratory featuresof adrenalinsufficiency. 17-hydroxyprogesterone levels are elevated to a lesser extent in those with simple virilizing and non classic forms. The best method of diagnosing these patients is the estimation of 17-hydroxyprogesterone levels before and 60 minutes after an intramuscular injection of ACTH (0.25 mg).

Management

These patients require lifelong treatment. Patients with salt wasting and virilizing forms should be treated with hydrocortisone (10-15 mg/m2/day) and fludrocortisone (0.1 mg/day). After completion of growth, synthetic glucocorticoid preparations (dexamethasone, predni­ solone) can be used (Table 17.19).

Fig. 17.12: Congenital adrenal hyperplasia secondary to 21- hydroxylase deficiency, Note the clitoral hypertrophy, hyper- pigmentation and increased rugosity of the labial folds giving a male appearance to the female genitalia

Table 17.19: Comparison of commonly used steroid preparations

Other Variants

Enzymedeficienciesother than 21-hydroxylase deficiency account for less than 10% of cases of CAH. Patients with 11 -hydroxylasedeficiencyand17a-hydroxylasedeficiency present with hypertension and should be managed with hydrocortisone alone. Deficiencies of StAR and 3a­ hydroxysteroid dehydrogenase manifest as salt wasting crisis and require addition of mineralocorticoid.

Suggested Reading

Amaldi G, Angeli A, Atkinson AB, et al. Diagnosis and classifica­ tionofCushingsyndrome: aconsensusstatement./Clin EndocrinolMetab 2003;88:5593-02

Etiology

In most children with obesity, environmental and here­ ditary factors play the major role. Underlying etiology is identified invery fewcases (<1%). The causes of childhood obesity are classified in Table 17.20.

Constitutional obesity. Most children with obesity do not have an organic cause. This is caused by imbalance in energy intake and expenditure. These children are tall for age, a factor that differentiates them from pathological obesity. They have proportional obesity and normal development. It is important to identify this subgroup of children to avoid unnecessary investigations.

Perry R, Kecha 0, Paquette J, et al. Primary adrenal insufficiency in children: Twenty years' experience at the Sainte-Justine Hospital, Montreal./ Clin Endocrinol Metab 2005;90:3243-50

Shulman DI, Palmert MR, Kemp SF for the Lawson Wilkins Drug and Therapeutics Committee. Adrenal insufficiency: Still a cause of morbidity and death in childhood.Pediatrics 2007;119: e484-94

Storr HL, Chan LF, Grossman AB, Savage MO. Pediatric Cushing syndrome: epidemiology, investigation and therapeutic advances.

Trends Endocrinol Metab 2007;18:167-74

OBESITY

The incidence of childhood obesity has increased rapidly in the last decade. Childhood obesity has serious short and longterm medical consequences.

Criteria for Obesity

Obesityimpliesexcessivefat and not merelyexcessweight. As methods of measuring body fat are cumbersome and expensive, several clinicaland anthropometric parameters are used as markers of obesity.

Body mass index. Body mass index (BMI) is the most widely used parameter to define obesity. It takes into account weight as wellas theheight. It is calculated by theformula:

BMI = Weight (kg) 7 height (m)2

Children with BMI more than 85th percentile for age are consideredoverweightwhilethosemorethan95th per­ centile for age are obese. BMI is a good indicator of body fat but is unreliable in short muscular individuals.

Weight for height. This compares the child's weight to the expected weight forhis/herheight (see Chapter 2). Weight for height more than 120% is diagnosed as obesity.

Skin fold thickness. Skin fold thickness measured over the subscapular, triceps or biceps regions is an indicator for subcutaneous fat. Age specific percentile cut-offs should be used with values more than 85 percentile being abnormal.

Waist circumference. This is a marker of abdominal adiposity, a key risk factor for metabolic and cardio­ vascular effects of obesity.

Endocrine causes. Growth failure in an obese child indicates an endocrine etiology. Cushing syndrome is characterized by central obesity, hypertension, striae and retarded skeletal maturation. Hypothyroidism is an extremely rare cause of isolated obesity and other features like develop­ mental delay and coarse skin are always present. In GH deficiency and pseudohypoparathyroidism, growth retardation and hypocalcemia are dominant clinical features and obesity is a less prominent manifestation.

Genetic syndromes. A variety of genetic syndromes have obesity as their major clinical feature. Many of these syndromes are associated with hypogonadism or hypotonia (Prader-Willi, Carpenter and Laurence Moon Bardet Biedl syndromes).

Hypothalamicobesity. CNSinsults duetosurgery, radiation, tumors and trauma results in rapid onset obesity. These disorders are associated with excessive appetite, signs and symptoms of CNS involvement and other hypothalamic­ pituitary defects.

Monogenic obesity. Monogenic obesity represents a very small proportion of children with obesity. They are more likely in the presence of early onset of obesity, morbid obesity and strong family history. Leptin deficiency was the first monogenic cause of obesity identified. Inefficient leptin action (deficiency or resistance) results in uncon­ trolled appetite and obesity. Abnormalities in mineral-

Table 17.20: Etiology of obesity

Constitutional

Environmental factors (95% cases)

Pathological

Endocrine: Cushing syndrome, deficiency of growth hormone, hypothyroidism, pseudohypoparathyroidism Hypothalamic: Head injury, infection, brain tumor, radiation, after neurosurgery

Drugs: Antiepileptic drugs, steroids, estrogen

Genetic syndromes: Prader-Willi, Laurence Moon Bardet Biedl, Beckwith Weidemann, Carpenter

Monogenic disorders: Leptin deficiency, or resistance, abnor­ malities of melanocortin-4 receptor and proconvertase

ocorticoid receptor and proconvertase have also been associated with obesity.

Evaluation

Initial evaluation is guided to differentiate constitutional from pathological obesity (Table 17.21). Normal growth, generalized pattern and lack of developmental delay or dysmorphismsuggestsconstitutional obesity and against the need for extensive investigations.

Clinical. Family history of obesity and its complications should be recorded. Detailed history of physical activity, dietaryrecallandperiods ofinactivity should be assessed.

Increased appetiteinachild with recentonsetobesity may indicate the possibility of a hypothalamic lesion. Features ofraisedintracranialtensionalongwithhistoryofneurologic infection, head trauma or neurosurgery suggests the diagnosis of neurologic cause of obesity. Intake of drugs linked with development of obesity like steroids and antiepileptics should be enquired. Examination should be performed for features of endocrinopathies, dysmorphic syndromes and complications such as hypertension and acanthosis nigricans. Special emphasis should be given to sexual maturity and ocular examination. Hypogonadism is an important feature of obese children with Laurence MoonBartletBiedlsyndromeandPrader-Willisyndromes (Figs 17.13, 17.14 and Table 17.22).

Table 17.21: Comparison of constitutional and pathological obesity

Fig. 17.13: Laurence Moon Bardet Biedl syndrome. Note the central obesity and hypoplastic genitalia

Endocrine and Metabolic Disorders -

l

Fig. 17.14: Laurence Moon Bardet Biedl syndrome. Note the polydactyly

Investigations. Investigations are decided based on the degree ofobesity andassociated complications. Endocrine investigations are done only in the presence of pointers to diagnosis such as growth failure, clinical features, developmental delay and dysmorphism. Screening for complications is indicated in obese children (BMI >95th percentile). Investigations are also recommended for overweight children in the presence of family history of cardiovascular complications or type 2 diabetes mellitus or rapidincreaseinobesity.This evaluationshouldinclude oral glucose tolerance test, serum cholesterol and liver function tests.

Complications

Childhood obesity is associated with significant compli­ cations (Table 17.23).

Cardiovascular. Obesity has been linked with hyper­ lipidemia, hypertension and coronary artery disease.

Endocrine. Most important endocrine complication of obesity is insulin resistance. This presents as a spectrum of changes ranging from elevated insulin levels to impaired glucose tolerance to type 2 diabetes mellitus. A

Table 17.22: Pointers to diagnosis of obesity

Table 17.23: Complications of obesity

characteristic clinical feature is acanthosis nigricans, dark and rough areas on the exposed areas of skin including back of neck, axilla and thigh (Fig. 17.15). Ovarian hyperandrogenism leading to premature adrenarche and polycystic ovarian syndrome is an important feature of obesity.

Respiratory. Obesity is associated with restrictive lung disease (decreased respiratory movements due to chest wall obesity) as well as obstructive airway disease (airway fat deposition). The most severe complication is the obesity-hypoventilation syndrome associated with hypoxia and features of cor pulmonale. Milder forms are associated with snoring, irritability, hyperactivity and daytime somnolence.

Orthopedic. Obese children are prone to slipped femoral epiphyses, flat feet, Blount disease (tibia vara) and early onset osteoarthritis.

Hepatobiliary. Insulin resistance in obesity is associated with fatty infiltration in liver. This may vary from mild infiltration with no effect to steatohepatitis and chronic liver disease. The incidence of cholelithiasis is increased

Management

Management of childhood obesity is challenging with major impetus on lifestyle measures (Fig. 17.16.) Specific management is available for only a few conditions. Diet,

Fig. 17.15: Acanthosis nigricans on the back of neck in a girl with obesity

Body mass Index

indicated orlistal

Fig. 17.16: Approach to management of obesity

activity and behavioral measures are the cornerstones of therapy, and intensive measures like drug therapy and surgery are reserved for morbid cases.

Dietary measures. Initial measures include mild caloric restriction and alteration in dietary habits. Intake of 1200-1800 Calories, depending upon the age of the individual, along with 30-40% restriction is recom­ mended. Over-aggressive dietary restriction is associated with poor compliance and growth faltering. Apart from restricting calorie intake, efforts should be directed towards improving the nutritive value of the diet. Reduction in consumption of junk foods, carbonated drinks and saturated fat should accompany an increase in fiber, fruits and vegetable intake. Regular meal consumption with fixed portion sizes is an effective strategy in inducing weight gain.

Lifestyle modification. Increase in physical activity along with reduction in sedentary lifestyle is an useful component of obesity management. Swimming, running and playing outdoor games should be encouraged. Physical activity for at least 30-45 minutes per day is recommended. Activities like television viewing, videogames and internet surfing should be restricted.

Drugs. Pharmacotherapy is reserved only for severe cases of obesity. The only drug approved in children is orlistat, a gastric lipase inhibitor. Metformin is indicated for children with insulin resistance. Leptin (for those with leptin deficiency) and octreotide (for hypothalamic obesity) may be used in a subgroup of children with obesity. The efficacy of pharmacological therapy for obesity is modest compared to surgery.

Surgery. Surgery for obesity is the last resort in treatment. It is indicated for morbid obesity (BMI more than 40 kg/ m2 with complications) when other measures have failed, but only after completion of statural growth. Laparoscopic gastric banding is the procedure of choice and is directed at reducing gastric capacity.

Suggested Reading

Alemzadeh R, Rising R, Cedillo M, Lifshitz F. Obesity in children. In: PediatricEndocrinology,4thedn. Ed: Lifshitz F. Marcel Dekker, New York, 2003;823-58

Hochberg I, Hochberg Z. Expanding the definition of hypothalamic obesity. Obes Rev 2010;11:709-21

Speiser PW, Rudolf MCJ, Anhalt H, et al on behalf of the Obesity Consensus Working Group. Consensus statement: Childhood obesity. J Clin Endocrinol Metab 2005;90:1871-87

DISORDERS OF THE GONADAL HORMONES

Puberty

Puberty is the phase of life when secondary sexual char­ acteristics appear and mature and capability of repro­ duction is attained. Deviations from the normal pattern of puberty have significant diagnostic and therapeutic implications.

Physiology

Puberty involves development of primary (testicular and penile growth in boys and breast and uterine growth in girls) and secondary sexual characteristics (pubic and axillary hair growth, change of voice in boys, acne and axillary odor). Sex hormones (estrogen in girls and testosterone in boys) play an important role in the devel­ opment of primary sexual characteristics, while adrenal androgens are involved in the development of secondary sexual characteristics in girls.

Kisspeptin, a hypothalamic peptide, is thekey regulator of puberty. Acting as the 'on-off switch' of puberty, kisspeptin initiates GnRH pulses. Initially GnRH pulses occur only during nights followed by secretion during both day and night. This results in increase in the levels of gonadotropins, and thereby, sex hormones. LH is a better indicator of pubertal status compared to FSH. Pulsatile secretion of GnRH makes basal gonadotropin levels an unreliable indicator of pubertal status. The hypothalamic-pituitary-gonadal axis is under feedback control. Thus secretion of LH is inhibited by testosterone and estrogen producedby the Leydig cells and theca cells, respectively. Inhibin produced by the Sertoli and granulosa cells inhibits FSH production.

Patterns of Pubertal Development

The pattern of pubertal development is different in girls and boys. Puberty starts at around the age of 10 yr in girls (range 8-12 yr) and is completed over 5 yr. Breast enlarge­ ment (thelarche) is the first event followed by the development of pubic hair (pubarche) and onset of mens­ trual cycles (menarche). Breast development may be asymmetricalin the initialphase.Menarcheusuallyoccurs two years after thelarche usually during stage III and IV. Discordant pubertal development (menarche within one year of thelarche) suggests hyperestrogenic states with withdrawal bleeding.

Endocrine and Metabolic Disorders -

In boys, puberty starts with testicular enlargement at 11.5 yr (range 9 yr to 14 yr). This is followed by penile enlargement and pubarche. Spermarche occurs by the age of 14 yr.

Assessment of Puberty

The stage of pubertal assessment is assessed using Tanner staging system (see Figs 3.1 and 3.2). Breast development beyond Tanner II in girls and testicular volume greater than 4 mL indicates onset of puberty. Maximum growth spurt occurs during early puberty in girls (Tanner II-III) compared to boys where it occurs later (Tanner III-IV) (Table 17.24). Menstrual periods are irregular in the first few years before attainment of regular ovulatory cycles. It is important to differentiate adrenarche (pilosebaceous development related to increase in adrenal steroids) from gonadarche (genital development related to increase in GnRH) in girls.

Precocious Puberty

Pubertal onset before the age of 8 yr in girls and 9.5 yr in boys is suggestive of precocious puberty. Precocious puberty may be due to stimulation of the hypothalamic­ pituitary axis (gonadotropin-dependent precocious puberty) or autonomous sex hormone production (gonadotropin-independent).

Precocious Puberty in Girls

Precocious puberty is common in girls and may represent normal variation in the age at onset of puberty. In most cases, puberty is slowly progressive with no longterm adverse effect. Endocrine workup should be restricted to girls with progressive forms of puberty.

Gonadotropin-dependent precocious puberty or central precocious puberty is much more common than gonadotro­ pin-independentprecociouspuberty (Table 17.25). Inmore than 90% of these cases, no underlying cause is identified. It may be caused by a variety of pathologies of the central nervous system as listed in Table 17.25. Hypothalamic hamartoma, a neuronal migration defect, is the commonest cause of organic central precocious puberty (Figs 17.17 and 17.18). The disorder presents with early onset and rapid progression of puberty, seizures and uncontrolled laughter episodes (gelastic epilepsy).

Table 17.24: Comparison of pattern of pubertal development in boys and girls

Idiopathic

Tumors: Hamartoma, pituitary adenoma, craniopharyngioma, glioma

Infections: Neurotuberculosis, meningitis

Injury: Head trauma, neurosurgery, cranial irradiation Malformation: Arachnoid cyst, hydrocephalus, septo-optic dysplasia

Gonadotropin-independent or peripheral precocious puberty

Hypothyroidism

Ovarian estrogen: McCune Albright syndrome, cyst, tumor, arornatase excess

Adrenal estrogen: Estrogenic adrenal adenoma Exogenous estrogen exposure

Incomplete variants

Isolated thelarche

Isolated pubarche (adrenarche)

Isolated menarche

Fig. 17.17: Central precocious puberty secondary to hypothalamic hamartoma

Gonadotropin-independent precocious puberty or peripheral precocious puberty is rare and usually caused by estrogenic ovarian cysts. Fluctuating pubertal development and early vaginal bleeding (due to hyperestrogenic state) is common. The condition is usually self-resolving and there is no need for treatment. Recurrent ovarian cysts should raisethe possibility ofMcCuneAlbrightsyndrome, a somatic activating mutation of stimulatory G protein. The condition presents with constellation of cutaneous (multiple dark brown cafe au lait spots), skeletal (multiple fibrous dysplasia) and endocrine abnormalities (hyper-

Fig. 17.18: MRI scan of brain showing an isodense mass suggestive of hypothalamic hamartoma

thyroidism, rickets and GH excess). Precocious puberty occurs at an early age and is rapidly progressive. Prolonged untreated primary hypothyroidism may induce early puberty due to action of TSH on FSH receptor. Delayed bone age and growth is characteristic.

Evaluation

Aims of evaluation include confirmation of diagnosis, identification of underlying etiology and determination of prognosis and treatment.

Clinical. History should include the onset, progression and extent of puberty. Exposure to steroids, estrogens and androgens should be enquired. Family history of precocious puberty and early menarche points towards

idiopathic central precocious puberty. Features of hypothyroidism should be assessed. Advanced growth is characteristic of precocious puberty; growth retardation indicates hypothyroidism or concomitant GH deficiency. Examination of vaginal mucosa for estrogen effect provides clues regarding the pubertal status ofthepatient. Red, glistening mucosa suggests lack of estrogens while pink mucosa with mucus is indicative of estrogen effect. Abdominal examination for adrenal or ovarian mass should be done. Features of McCune Albright syndrome include cafe au lait spots, polyostotic fibrous dysplasia, bony deformities and polyendocrinopathy.

Investigations. Assessment of pubertal status is based on basal or stimulated gonadotropin levels. Pooled gonado­ tropin levels are preferred due to their pulsatile secretion. LH is a better indicator compared to FSH as LH levels increase significantly during puberty. LH levels in the pubertal range with LH/FSH ratio more than 1 is sugges­ tive of development of puberty. Ultrasound of abdomen and pelvishelps in diagnosingfollicularcysts and ovarian and adrenal mass. Thyroid function should be assessed to rule out hypothyroidism. Bone age helps in assessing

the heightcompromiseand in predictingfinal height. MRI of brain should be done in girls with onset of puberty before 6 yr of age, rapid progression and associated neurological features. Pituitary functions should be assessed in girls with organic GPP.

Advanced bone age (more than two years ahead of chronological age) is suggestive of progressiveprecocious puberty, while normal bone age indicates slowly pro­ gressive puberty. Retarded growth and skeletal matu­ ration is diagnostic of hypothyroidism. Pubertal LH levels are suggestive of gonadotropin dependent precocious puberty and should be followed with an MRI of brain. Girls with prepubertal LH levels should undergo ultrasound of ovary and adrenals (for ovarian cyst and adrenal tumor) and skeletal survey (for fibrous dysplasia in McCune Albright syndrome).

Management

Aims of treatment includetreatmentof underlying cause, management of associations, puberty suppression and achievement of target height potential. The significant longterm consequence of precocious puberty is short stature. Growth is accelerated at presentation. This is associated with disproportionately advanced bone age resulting in premature epiphyseal fusion culminating in compromised final height.

Gonadotropin-dependent precocious puberty. Drugs used for pubertal suppression include medroxyprogesterone acetate (MPA),cyproterone and GnRH analogs. MPA does not improve height outcome and may be considered in girls with intellectual disability where final height is not important. Long acting GnRH analogs are the only agents effective in improving height outcome. They cause sustained stimulation and desensitization of pituitary leading to reversing of pubertal changes. GnRH analogs should be considered in girls with early onset (before 6 yr of age) rapidly progressive puberty and height compro­ mise (bone age to chronological age difference more than two years). The treatment is discontinued at the chrono­ logical ageof 11yr andbone age of 12.5 yr. This isfollowed by gradual reappearance of secondary sexual characters. Menarche is attained around 12-18 months following discontinuation of treatment.

Gonadotropin-independent precocious puberty. Thyroxine replacement results in reversal of pubertal changes in hypothyroidism. Treatment for McCune Albright syn­ drome is directedtowards inhibiting estrogen production (aromatase inhibitors like anastrazole or letrozole) or estrogen action (tamoxifen).Treatment of ovarian cysts is guided by size and morphological features.

Incomplete Variants of Precocious Puberty

These disorders represent normal variants and do not require specific treatmsent. Their identification helps in restricting the extent of diagnosticworkupandcounseling.

Endocrine and Metabolic Disorders -

Isolated thelarche. Isolated breast development may represent isolated thelarcheorfirst manifestationofcentral precocious puberty. Bone age, gonadotropin levels and pelvic ultrasound helps in differentiating the two condi­ tions. Normal growth, prepubertal LH, age appropriate bone age and smalluterine size suggest isolated thelarche.

Isolated adrenarche. Premature adrenarche refers to development of pubic hair and acne in the absence of breast development or menarche. Most cases are physi­ ological variants. Rarely, androgen excess due to adrenal (CAH due to 21-hydroxylase deficiency, llP-hydroxylase deficiency or adrenal tumor) or ovarian (tumor or polycystic ovarian disease) causes may be identified. Normal bone age and absence of virilization suggest premature adrenarche and no treatment.

Isolated menarche. Vaginal bleeding in the absence of thelarche is against the diagnosis of gonadotropin­ dependent precocious puberty. Vaginal bleeding may occur early in course of estrogen excess stateslike ovarian cysts, hypothyroidism and McCune Albright syndrome. Vaginal bleeding without breast development should prompt evaluation of local causes like infection, foreign body, sexual abuse and tumors.

Precocious Puberty in Boys

Precocious puberty is less common in boys, but when present is usually associated with significant pathology. This mandates prompt evaluation and treatment of all boys with precocious puberty.

Etiology

Gonadotropin-dependent and independent precocious puberty accounts for similar number of cases in boys (Table 17.26).

Gonadotropin-dependent precocious puberty. The etiology is similar to girls with the exception that organic etiology is more common. Hypothalamic hamartoma, cranio­ pharyngioma, hydrocephalus and tubercular meningitis are important causes. These disorders are associated with increase in testicular volume andelevatedbasaland GnRH stimulated LH.

Gonadotropin-independent precocious puberty. This is caused by increased androgen production by testis and adrenals in the setting of prepubertal LH levels. Adrenal over­ production due to congenital adrenal hyperplasia is the commonest causeofperipheral precocious puberty.Rarely adrenal tumors may present with precocious puberty.

Human chorionic gonadotropin (hCG) secreting germ cell tumors of theliver, mediastinum or brain maypresentwith precocious puberty. Testotoxicosis, a disorder associated with constitutional activation of LH receptor, presents with early onset gonadotropin-independent precocious puberty. Androgen secreting testicular tumors present with precocious puberty and unilateral testicular enlargement.

Table 17.26: Etiology of precocious puberty in boys

Gonadotropin-dependent or central precocious puberty

Idiopathic

Centralnervoustumors:Hamartoma, craniopharyngioma, glioma Infections: Tubercular meningitis

Injury: Head trauma, surgery, radiation Malformation: Arachnoid cyst, hydrocephalus

Gonadotropin-independent or peripheral precocious puberty

Congenital adrenal hyperplasia: 21-hydroxylase deficiency, 11P­ hydroxylase deficiency

Adrenal tumors: Adenoma, carcinoma Testicular tumors: Seminoma, germinoma Testotoxicosis: Activation of LH receptor

hCG secreting tumor: Germinoma, hepatoblastoma

Exogenous androgen exposure: Testosterone cream

Evaluation

Evaluation is directed towards confirming the diagnosis and establishing the underlying cause.

emphasizing the need for watchful monitoring and conservative approach.

Delayed Puberty n Grls i i

Delayed puberty is defined as lack of secondary sexual characteristics by the age of 14 yr. Absence of menarche by the age of 16 yr or 5 yr after pubertal onset also indicates pubertal delay.

Etiology

Delayed puberty may be caused by defects in the hypo­ thalamic-pituitary axis, ovaries or genital tract (Table 17.27). Patients with anatomical defects present with amenorrhea with normal breast development. Defects in the hypothalamic-pituitary axis are associated with low gonadotropin levels (hypogonadotropic hypo­ gonadism). This may be related to reversible causes like systemic diseases, malnutrition, eating disorders, hyper-

Table 17.27: Etiology of delayed puberty in girls

Hypogonadotropic hypogonadism

Clinical. History should include age at onset of pubertal development, progression of puberty, neurological features, family history of precocious puberty and andro­ gen exposure. Detailed anthropometric and neurological examination should be performed. Pointers to CAH (hyperpigmentation and hypertension) should be identi­ fied. Estimation of testicular volume forms an integral part of assessment. Prepubertal testicular volume (less than 4 ml) is characteristic of CAH and adrenal tumors, while unilateral enlargement is seen in testicular tumors. Pubertal testicular enlargement indicates GPP while lesser enlargement is observed in hCG secreting tumors and testotoxicosis.

Investigations. Initial investigations should include LH, FSH and testosterone levels and bone age. All patients with pubertal LH levels should undergo visual field examination and MRI of brain. In the presence of prepubertal LH levels, imaging for adrenals (preferably CT scan) and 17-hydroxyprogesterone levels should be done. hCG levels should be estimated if these investi­ gations are noncontributory.

Management

Management includes treatment of underlying neurologic pathology and GnRH analog therapy. GnRH analog should be continued till the age of 12 yr. CAH is managed with hydrocortisoneand fludrocortisone. Surgeryis thetreatment of choice for adrenal and testicular tumors, while radio­ therapy is effective in hCG secreting tumors. Aromatase inhibitorsand antiandrogens are indicated in testotoxicosis.

Delayed Puberty

Delayed puberty is more common in boys than girls. Most children with delayed puberty have constitutional delay

Transient

Systemic disorders: Renal failure, liver disease, celiac disease, renal tubular acidosis, cystic fibrosis

Nutritional disorders: Malnutrition, anorexia nervosa Endocrine disorders: Hypothyroidism, hyperprolactinemia,

type 1 diabetes

Permanent

Isolated hypogonadotropic hypogonadism

Genetic: KALl, GnRH receptor, LH, FSH, DAX1 mutations Dysmorphic syndromes: CHARGE, Prader-Willi, Laurence Moon Bartlet Biedl

Multiple pituitary hormone deficiency

Malformations: Holoprosencephaly, septo-optic dysplasia, midline defects

Genetic disorders: PROP1, LH gene deletions

Brain tumors: Craniopharyngioma, germinoma, glioma Brain injury: Surgery, infection, radiation, trauma Infiltrative disorders: Histiocytosis, autoimmune disorders

Hypergonadotropic hypogonadism

Gonadal dysgenesis: Turner syndrome, SRY deletion, trisomy 18, 13, 21

Steroidogenic defects: StAR, 17a.-hydroxylase, 17P-hydroxy­ steroid dehydrogenase or aromatase deficiency

Ovarian insults: Surgery, radiation, alkylating agents, infections

Autoimmuneovarianfailure: Autoimmunepolyendocrinopathy Gonadotropin resistance: LH and FSH receptor mutations

Isolated amenorrhea

Structural malformations: Mullerian agenesis, vaginal septum, imperforate hymen

Inefficient androgen action: Complete androgen insensitivity syndrome

DAXl dosage sensitive sex reversal; FSH follicle stimulating hormone; GnRH gonadotropin releasing hormone; LH Luteinizing hormone; KALl Kallman syndrome gene 1; StAR steroidogenic acute regulatory protein; SRY sex determining region on Y chromosome