Ghai Essential Pediatrics8th

prolactinemia and hypothyroidism. Irreversible defects include destruction of the hypothalamic-pituitary axis by infection,surgery,radiation or tumor. Kallmann syndrome, a neuronal migrationdefectduetomutationof KALI gene, is characterized by defective smell sensation, low GnRH levels and hypogonadotropic hypogonadism. Hyper­ gonadotropic hypogonadism is associated with defective estrogen production by ovaries and elevated gonado­ tropin levels.Turnersyndrome, ovarianfailureand enzy­ matic defects in estrogen synthesis production are important causes of this condition.

Evaluation

Goals of evaluation includeidentification of constitutional delay, organic etiology requiring neuroimaging and decision regarding treatment.

Clinical. Family historyof delayedpuberty provides a clue to constitutional delay in puberty. Features of chronic systemic diseasesshouldbeinquired.Poorsmellsensation is indicative of Kallmann syndrome. Amenorrhea with normalsecondarysexualcharacteristicsindicatesanatomical defectsandshouldbeevaluatedaccordingly.Neurological examination including that for olfactory sensation should be performed. Features of Turner syndrome and hypo­ thyroidism should be looked into. Galactorrhea points towards hypothyroidism or hyperprolactinemia.

Investigations. Initialworkupis directedtowards excluding systemic disorders such as liver disease, renal disease and malabsorption.Thisshouldbe followedbymeasurementof FSH levels. Karyotypeshouldbedoneif FSHlevelsarehigh. Steroidogenic defects are likely, if karyotype and pelvic ultrasound are normal. In patients with low/normal FSH levels,prolactinandthyroidprofileshould bemeasuredto exclude reversible causes. Neuroimaging and pituitary function tests should bedoneif these levels arenormal.

Management

All patients with hypergonadotropic hypogonadism and irreversible hypogonadotropic hypogonadism need hormone replacement. Hormone replacement should be deferred till the bone age of 12 yr to avoid deleterious effects on height. The goal of treatment is to initiate and maintain sexual characteristics and to prevent osteo­ porosis. Treatment should be started with low dose estro­ gens (5 µg ethinyl estradiol or 0.3 mg conjugated estrogen every day) and gradually increased every 3 months till adult doses (20 µg of ethinyl estradiol or 1.25 mg of conjugated estrogen daily by 2 yr) are reached. Medroxy­ progesterone acetate (MPA 5-10 mg from day 11 to 21) should be added two years after initiation of treatment or once withdrawal bleeding has started.

Delayed Puberty in Boys

Delayed puberty is more common in boys than girls and is usually due to a constitutional delay. Lack of pubertal changesbytheageof 14 yrissuggestive of delayedpuberty.

Endocrine and Metabolic Disorders -

Etiology

Constitutional delay in growth and puberty is the commonest cause of delayedpuberty in boys (Table 17.28).These boys have growth retardation and delayed bone age. Family history of delayedpubertyispresent. Gonadotropin levels are prepubertal similar to hypogonadotropic hypo­ gonadism.

Hypogonadotropic hypogonadism may be reversible due to systemicillnesses orpermanentdue toneurologicalinsult (infection, surgery, radiation ortumor). Kallmann syndrome is an important cause of isolated gonadotropin deficiency and presents with impaired smell sensation. Delayed puberty is common in dysmorphic syndromeslikePrader-

Table 17.28: Etiology of delayed puberty in boys

Hypogonadotropic hypogonadism

Transient

Constitutional delay of puberty and growth

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

Nutritional disorders: Malnutrition, anorexia nervosa, bulimia nervosa

Endocrinedisorders: Hypothyroidism,hyperprolactinemia,type 1 diabetes mellitus

Permanent

Isolated hypogonadotropic hypogonadism

Genetic disorders: KALI, GnRH receptor, LH, FSH, DAXl mutations

Dysmorphic syndromes: CHARGE, Prader-Willi, Laurence Moon Bartlet Biedl, Robinow

Multiple pituitary hormone deficiency

Malformations: Holoprosencephaly, septo-optic dysplasia, midline defects

Genetic disorders : PROPl, LH gene deletions

Brain tumors: Craniopharyngioma, germinoma, glioma CNS insults: Surgery, infection, radiation, trauma Infiltrative disorders: Histiocytosis, sarcoidosis, hemo- chromatosis

Hypergonadotropic hypogonadism

Chromosomal abnormalities: Klinefelter syndrome, gonadal dysgenesis

Steroidogenic defects: StAR, 17a-hydroxylase, 17P-hydroxy­ steroid dehydrogenase deficiency, Smith Lemli Opitz syndrome

Testicular insults: Radiotherapy, chemotherapy, trauma, torsion, infections

Malformations: Vanishing testis syndrome, cryptorchidism

Inefficient testosterone action: Sa-reductase deficiency Resistance to testosterone action: Androgen insensitivity syndrome

DAXl dosage sensitive sex reversal; FSH follicle stimulatinghormone; GnRH gonadotropin releasing hormone; LH luteinizing hormone; KALI Kallman syndrome gene 1, stAR steroidogenic acute regulatory protein

Willi, Laurence Moon Bartlet Biedl,Noonan and Robinow syndromes.

Hypergonadotropic hypogonadism (testicular failure) may be related to chromosome abnormalities (Klinefelter syndrome), partial gonadal dysgenesis, steroidogenic defectsandacquired testicularinjury(infection, radiation, chemotherapy) (Fig. 17.19).

Evaluation

Clinical. Family history of delayed pubertyprovides a clue to constitutional delay in puberty. History of delayed growth spurt and onset of shaving in father and brothers is common. A history of continued growth in adult years is often present. Features of any systemic disease should be enquired. History of head injury, neurosurgery and intracranial space occupying lesions suggest a defect in the hypothalamic-pituitary axis. CNS examination including olfactory sensation should be performed. Features of dysmorphic syndromes are usually evident on examination.

Investigations. Initial step includes estimation of LH, FSH and testosterone levels. Elevated gonadotropin levels (hypergonadotropic hypogonadism) should be followed up by karyotype and evaluation for biosynthetic defects. Individuals with low LH and FSH levels may have constitutional delay in puberty or hypogonadotropic

Fig. 17.19: Klinefelter syndrome. Note the tall stature and gynecomastia

hypogonadism. They may be distinguished by hCG stimulation test or GnRH stimulation tests (Table 17.29). However, these tests are nondiscriminatory in most cases and followup after a course of testosterone is the best strategy. Patients with hypogonadotropic hypogonadism shouldundergoevaluationof hypothalamic-pituitary axis and neuroimaging.

Table 17.29: Differentiation of constitutional delay from permanent hypogonadotropic hypogonadism

DHEAS dehydroepiandrosterone synthase

Management

Testosterone treatment should be deferred till the age of 14 yr and bone age of 13.5 yr. Children with suspected constitutional delay in puberty should receive three monthly injectionsoftestosteroneenanthate (100 mg).This should be repeated if adequate response is not achieved. Serum testosterone levels should be estimated three months after the last dose of the drug. Low testosterone levels indicate hypogonadotropic hypogonadism and the need for continued treatment.

Turner Syndrome

Turner syndrome is the most important cause of hypergonadotropic hypogonadism in girls. The disorder affects 1 in 2,500 newborn phenotypic females. These girls present with short stature, classical phenotypic features and delayed puberty. Most common karyotype is 45, X. Mosaic forms like 45, X/46, XX and 45, X/46, XY have also been observed. Premature atresia of ovarian follicles and bilateral streak gonads are features of this condition.

Clinical Features

Short stature is the most frequent finding. Turner syndrome may be identifiable at birth by the presence of lymphedema, cystic hygroma and left-sided obstructive cardiac lesions.Features of Turner syndrome in childhood include cubitus valgus (wide carrying angle), shield chest withwidelyspacednipples, webbedneck and shortfourth metacarpal (Table 17.30). Cardiac associations like

Table 17.30: Features of Turner syndrome

coarctation of aorta, mitral valve prolapse and aortic stenosis are common. Renal malformationslikehorseshoe kidney, reduplication of renal pelvis and agenesis may also be present. Endocrine associations of the disease include hypothyroidism and diabetes mellitus.

Assessment

Ultrasound pelvis reveals hypoplastic uterus and poorly developed ovaries. FSH levels are elevated. Karyotype is indicated in all patients with Turner syndrome to exclude the presence of a Y chromosome, which is associated with gonadoblastoma in 25-30% cases. Echocardiography and ultrasound for kidneys should be done in all patients for screening cardiac and renal malformations. Thyroid profile and blood sugar should be done at baseline and yearly. Periodic hearing evaluation for deafness is recommended (Table 17.31).

Management

GH therapy (0.1-0.15 unit/kg/day) is indicated in Turner syndrome for improving stature. Estrogen treatment should be deferred till the ageof 12 yr to ensure adequate

Table 17.31: Evaluation for associations of Turner syndrome

Endocrine and Metabolic Disorders -

growth. Gonadectomy is recommended in patients with a Y chromosome in view of high risk of gonadoblastoma.

Suggested Reading

Bajpai A, Menon PS. Contemporary issues in precocious puberty. Indian J Endocrinol Metab, 2011;5172-9

Carel J-C, Eugster EA, Rogol A, et al. Consensus statement on the use of gonadotropin-releasing hormone analogs in children. Pediatrics 2009;123:e752-o2

Dattani MT, Hindmarsh PC. Normal and abnormal puberty. In: Clinical Pediatric Endocrinology, 5th edn, Eds: C Brook, P Clayton, R Brown. Oxford: Blackwell Publishing, 2005;183-10

Disorders of Sexual Differentiation

Disorders of sexual differentiation (DSD) previously termed as intersex disorders, are rare but constitute a medical, social and psychological emergency.

Physiology

Sexual differentiation is a complex process involving a close interaction of genetic, phenotypic and psychological factors. Usually genetic sex guides gonadal sex, which is responsible for the determination of phenotypic mani­ festations and gender identity (Fig. 17.20.) Any deviation from this pattern results in DSD.

Gonadal differentiation. Germ cells arise from the celomic epithelium of hindgut and migrate to the gonadal ridge at 4-6 weeks of gestation. These cells combine with

Fig. 17.20: The process of sexual development and its disorders. Dax1 dosage sensitive sex reversal; SF1 steroidogenic factor 1; SOX9 transcription factor related to SRY; SRY sex determining region on the Y chromosome; wr1 Wilms tumor 1 gene

somatic cells to give rise to the bipotential gonad. A transcriptional factor present on Y chromosome called the sex determiningregion of the Y chromosome (SRY) is one of the most important regulators of sexual differentiation. SRY actsin conjunction with other genes likeWilms tumor gene 1 (WTl), SOX9 (a transcription factor on X chromo­ some) and dosage-sensitive sex reversal (DAXl) gene to induce testicular development. In the absence of SRY, the bipotential gonad develops into ovary.

Genital differentiation. Following development of testis, antimi.illerian hormone secreted by Sertoli cells induces regression of mi.illerian ducts. Testosterone produced by Leydig cells is responsible for sustenance of Wolffian ducts. Dihydrotestosterone (DHT), produced by action of Sa-reductase on testosterone, is responsible for male external genital development (scrotal fusion and development of corpus spongiosum and penile corpus cavernosa). Feminization is the default process of sexual development. In the absence of antimi.illerian hormone and testosterone, mi.illerian ducts differentiate into fallopian tubes, uterus and the upper third of the vagina. Labioscrotal swellings and urethral folds do not fuse and give rise to labia majora and minora respectively. The genital tubercles form the clitoris while canalization of the vaginal plate creates the lower portion of the vagina. Prenatal exposure to androgens may lead to labioscrotal fusion, while exposure thereafter usually causes clitoro­ megaly alone and no labial fusion.

Classification

DSD may be caused by defects in gonadal differentiation (gonadal dysgenesis), androgen production (increased in females and reduced in males) or action (androgen insensitivity syndrome) (Table 17.32).

Table 17.32: Karyotype based classification of disorders of sexual differentiation (DSD)

SFl steroidogenic factor 1, SRY sex determining region on the Y chromosome, stAR steroidogenic acute regulatory protein

• Discordant to genotypic sex

Increased androgen production. Excess androgen production during the critical period of fetal development may result in masculinization of a female. These disorders are the commonest form of DSD. Congenital adrenal hyperplasia should be excluded in all children with DSD. 21- hydroxylase deficiency is characterized by deficiency of glucocorticoids and mineralocorticoids with elevated androgen levels. Delay in diagnosis could be fatal, underscoring the importance of early diagnosis. llP­ hydroxylase deficiency and 3P-hydroxysteroid dehydrogenase deficiency are the other forms of CAH that present with virilization. Transplacental androgen exposure due to maternal medications or hyperandrogenism may lead to virilization in newborn. These disorders are readily identifiable by history of virilization in mother. Rarely aromatase deficiency may be associated with virilization of mother during pregnancy and DSD in newborn.

Disorders of gonadal differentiation. These disorders are associated with abnormal gonadal development. The gonad is usually streak (no functional gonadal tissue). Combinations of partially functional testis or ovary or ovotestis may be observed. SRY gene deletion results in normalfemalephenotype with 46,XYkaryotype. Mutations in genes involved in the testicular differentiation (WTl, SOX9, steroidogenic factor 1 and DAXl) are other causes of 46, XY gonadal dysgenesis. These disorders are associated with renal (WTl mutation), skeletal (SOX9) and adrenalabnormalities (DAXl). 46, XY gonadal dysgenesis is associated with risk ofdevelopmentof gonadoblastoma. Asymmetric gonadal location may result in asymmetric genital appearance. 46, XX gonadal dysgenesis is usually caused by SRY translocation and presents as normal appearing male. Ovotesticular DSD, new term for true hermaphroditism, is characterized by the presence of both ovarian and testicular tissue in the same individual.

Inefficient androgen action. These disorders result from decreased production, activation or action of androgens.

Androgen insensitivity syndrome, previously referred to as testicular feminization syndrome, an X-linked disorder of androgen action, is the commonest cause and is charac­ terized by resistance to androgens. The disease forms a spectrum ranging from a normalfemale to boy with hypo­ spadias, to a male with infertility. Complete androgen insensitivitypresents in the neonatal period as a girl with inguinal masses and primary amenorrhea in older girls. Absent or sparse pubic and axillary hair is common. Mi.illerian structuresareabsent. High dihydrotestosterone levels are diagnostic. 5a-reductase deficiency is associated with reduced dihydrotestosterone production. Increased testosteroneduringpuberty acts on the androgen receptor leading to virilization. High testosterone and low dihydrotestosterone levels are diagnostic. Testosterone biosynthetic defects include deficiency of StAR, 3P-hydro­ xysteroid dehydrogenase, 17a-hydroxylase and 17P­ hydroxysteroid dehydrogenase enzymes. Diagnosis

requires estimation of testosterone precursors and basal and hCG stimulated testosterone and androstenedione levels.

Evaluation

DSD workup is indicated in the infants with genital ambiguity, girls withinguinal masses (probable androgen insensitivity syndrome), boys with cryptorchidism (probable 21-hydroxylase deficiency), penoscrotal hypospadias (probable undervirilization disorder) and adolescent girls with amenorrhea (probable androgen insensitivity syndrome). 21-hydroxylase deficiency should be excluded by estimating serum electrolytes and blood levels of 17-hydroxyprogesterone.

Clinical. Family history of genital ambiguity is suggestive of genetic disorders such as 21-hydroxylase deficiency or androgen insensitivity syndrome. CAH is likely if there is a history of fetal losses and sibling deaths and family history of consanguinity. On the other hand, history of similar disorder in healthy male relatives (brothers and maternal uncles) is suggestive of androgen insensitivity syndrome. Gonads in complete androgen insensitivity syndrome might have been mistaken for inguinal hernia and operated. Intake of progestational drugs during first trimester and features of virilization in mother should be enquired. Failure to thrive, polyuria and lethargy indicate 21-hydroxylase deficiency (Table 17.33). Virilization during puberty is suggestive of Sa-reductase deficiency, while feminization indicates androgen insensitivity syndrome. General examination should include assess­ ment for facial dysmorphism and hyperpigmentation. Maternal examination for features of hyperandrogenism like hirsutism, acne and change in voice should be done.

Genital examination. The most important step is identi­ fication of gonads. Bilaterally rounded structures below the inguinal canal are most likely testis. Unilateral gonads are suggestive of mixed gonadal dysgenesis. The labioscrotal region should be evaluated for the extent of fusion (Fig. 17.21). Mullerian structures can be confirmed by rectal examination. The length of phallus and number of openings in the urogenital region should be recorded.

Table 17.33: Clinical pointers to etiology of disorders of sexual differentiation (DSD)

Endocrine and Metabolic Disorders -

Fig. 17.21: Partial androgen insensitivity syndrome. Note the female appearance of the genitalia with an underdeveloped buried penis and poorly developed scrotum and testes

Asymmetrical labioscrotal region is suggestive of gonadal dysgenesis or ovotesticular DSD. The genitalia should be staged according to the classification proposed by Prader from grades I to V with grade I representing female with clitoromegaly and V male with cryptorchidism.

Investigations. Initial investigations should include karyo­ typing, estimation of electrolytes, serum 17-hydroproges­ terone and pelvic ultrasound. Fluorescent in situ hybridi­ zation can be used to deletethepresence of Y chromosome. Identification of Mullerian structures is an important part of evaluation of ambiguousgenitalia. Genitogramis help­ ful in determination of level of fusion, which is of surgical importance. Further investigations are guided by clinical and laboratory evaluation.

Mullerian structures with no palpable gonads indicate androgen excess state and need for estimation of 17a­ hydroxyprogesterone.Absence of Mullerian structures is suggestive of inefficient testosterone action and should be evaluated withestimation of testosterone and dihydro­ testerone. The presence of both Miillerian structures and palpable gonads indicate gonadal dysgenesis or ovotesticular DSD.Absent gonads and Milllerian structure may be caused by vanishing testis syndrome or dysfunctional intra-abdominal testis. Estimation of levels of anti-Mullerian hormone and hCG stimulation test are helpfulin differentiatingthetwo conditions. Childrenwith vanishing testis will have low levels of anti-Mullerian hormone and inappropriate response to hCG stimulation.

Management

Managementinvolvesparentalcounseling, decision about sex of rearing, timing of surgical correction and gonadec­ tomy.

Parental counseling. Birth of a child with DSD generates significant parental anxiety and stress. The most important

aspect ofcounselingis reassurance of parents that the child is healthy and the condition is amenable to surgical treatment. Gender specific connotation (his or her, testis, ovary) should be avoided and neutral terms like gonads and phallus be used. Future implicationsregarding sexual and fertility prospects should be discussed.

Decision about sex of rearing. Gender assignment should depend onthepotentialforfuturesexualandreproductive function, anatomical status, feasibility of reconstructive surgery and social acceptance and norms. Girls with virilizationdisordersusuallyhavepotentialforfertilityand should be reared as females. Individuals with complete androgen insensitivity syndrome should also be reared as females. Decision of sex of rearing is difficult in disorders ofinefficientandrogenaction.1hisshoulddependongenital appearance and surgical feasibility.

Surgery.Therehasbeenatrendofperformingearlysurgeries before gender identity is established. Most centers perform clitoroplasty at the age of 1 yr with vaginoplasty reserved duringpubertyforgirlswithvaginalstenosis.Gonadectomy shouldbedonein gonadal dysgenesis orovotesticular DSD, if a Y cell line is present.

Cryptorchidism (Undescended Testes)

Cryptorchidism is present in about 3% of full-term infants and 20% of premature infants. In most of these cases testes descend spontaneously by the age of one year with a decrease in the prevalence to 1%. Spontaneous testicular descent is unlikely after the age of one year and the prevalence in adult population is 0.8%.

Etiology

Most children with undescended testis do not have an identifiable underlying cause. Endocrinecausesaccount for only a small proportion of boys with undescended testis.

The possibility of salt wasting 21-hydroxylase deficiency presenting with sex reversal should be considered in

newborns with bilateral cryptorchidism. Undescended testis may be associated with hypopituitarism, dysmorphic syndromesand disordersofandrogenproduction andaction.

Evaluation

It is important to differentiate true undescended testis from retractile or ectopic testis due to therapeutic and prognostic implications (Fig. 17.22). Poorly developed scrotumand inability tobringdown thetestisto the scrotal sack suggests true undescended testis. Retractile testis is an otherwise fully descended testis that has an active cremasteric reflex, which retracts it into the groin.

Penoscrotal hypospadias and genital ambiguity is suggestive of disorders of androgen production or action. The hCG stimulation test should be done in boys with bilateral nonpalpable testis to differentiate abdominal testis from anorchia.

Management

Undescended testis is associated with significant complications like torsion, trauma, inguinal hernia, testicular dysfunction and development of malignancy.

These children should be treated early because of the increased risk for malignancy and infertility in later life.

The optimal time of therapy is before the age of one year. The commonly used medical treatment is human chorionic gonadotropin (hCG) 250 units below 1 yr, 500 units between 1and5yr and 1,000 units above5yr administered twice a week for 5-6 weeks. Good response occurs within a month. Retraction rate of testes after cessation of therapy

is high. If the response to hCG is poor, patient should be treated early with orchiopexy.

Micropenis

A penis whose length in stretched position is less than 2 SD below the mean for the age is termed micropenis.

Most often it is theresultof primary or secondarytesticular failure.

Etiology

Micropenisresultsfromdecreasedandrogenactionduring fetal life. It may be due to hypogonadotropic hypo­ gonadism as in Kallmann syndrome, Prader-Willi syn­ drome, septooptic dysplasia, or Klinefelter syndrome.It may also be a manifestation of partial androgen insensi­ tivity syndrome or testosterone biosynthetic defects.

Evaluation

Penilelength shouldbemeasuredin a fullystretchedstate by grasping the glans between thumb and forefinger. A firm ruler or caliper should be pressed against the pubic ramustodepressthesuprapubicfatpad.Themeasurement should be made along the dorsum to the tip of the glans penis excluding the length of foreskin. Penile size is often underestimatedinboyswithobesity (duetothesuprapubic fat) and hypospadias (due to chordee). Investigations should include estimation of gonadotropin and testo­ sterone levels. Low gonadotropin and testosterone levels indicates hypogonadotropic hypogonadism. Elevated gonadotropin levels (hypergonadotropic hypogonadism) should prompt evaluation for testicular dysgenesis, steroidogenicdefectsorandrogeninsensitivitysyndrome.

Management

All boys with micropenis are treated with a course of low dose testosterone (25 mg testosterone enanthate or cypionate monthly for three doses). The aim of this short courseof testosteronetreatmentis to increasepenilelength and not to induce puberty. Boys with micropenis should be reared as males as normal sexual function is usually attainable with early intervention.

Suggested Reading

HoukCP,Hughes IA,AhmedSF,LeePA.Summaryof consensus state­ ment on intersex disorders and their management. International Inter­ sex Consensus Conference. Pediatrics 2006;118:753-7

DIABETES MELLITUS

Diabetes mellitus is a metabolic disorder that is charac­ terized by hyperglycemia and glycosuria.Several distinct types of diabetes mellitus exist resulting from pancreatic dysfunction caused by genetic and environmental factors. The factors that contribute to hyperglycemia include decreased insulin secretion, decreased insulin action and increased glucose production.

Hyperglycemia resulting from diabetes mellitus causes damage to multiple organs resulting in multi organ damage. Diabetesmellitusistheleadingcause ofendstage renal disease, nontraumatic leg amputation and adult blindness.

Classification

Classification ofdiabetesmellitusis shown inTable 17.34. Most patients can be clearly classified as type 1 or 2

Endocrine and Metabolic Disorders -

Table 17.34: Classification of diabetes mellitus Type 1 diabetes mellitus

Absolute insulin deficiency resulting from P-cell destruction

Type 2 diabetes mellitus

Progressive insulin secretary defect in the background of insulin resistance

Gestational diabetes mellitus

Diabetes mellitus manifesting in pregnancy

Other specific types of diabetes mellitus

Genetic defects in P-cell function or insulin action, diseases of exocrine pancreas and drug or chemical induced diabetes

diabetes mellitus. However, occasionally an adolescent with type 2 diabetes may present with ketoacidosis, and patients with type 1 diabetes mellitus may present late and progress slowly.

Epidemiology

Diabeteshasbeenmorecommonlydiagnosedoverthepast two decades. The prevalence rates of impaired fasting glucose are also increasing. Type2 diabetes is increasing in prevalence more rapidly than type 1 due to increasing obesity and less active lifestyles of children. There is a significantgeographicvariationintheincidenceofdiabetes mellitus. Scandinavia has the highest incidence, with Finlandhavingtheincidence of35/100,000/yr.China and Japan have a much lower incidence of 1-3/100,000/yr. Indiandatasuggestanincidenceof10.5/100,000/yr.India wouldhave 79milliondiabeticsby2030, thehighestforany country in the world. Thevariability in incidence in type 1 diabetes is believed to be due to differences in frequency of high-risk HLA alleles in various ethnic groups.Type 1 diabetesisuncommonininfants. Theincidenceofdiabetes mellitus increases in children with advancing age all the way to adolescence, with peaks at 5 and 12 yr of age. Seasonal variationhasbeen notedwitha higher incidence in spring and fall.

Pathogenesis

Type 1 diabetes develops consequent to immune­ mediated destruction of pancreatic cells, resulting in severe impairment of insulin secretion in genetically susceptible children.

Genetic factors Genetic, environmental and auto­ immune factors are believed to result in the development of type 1 diabetes. Genetic susceptibility to diabetes involves multiple genes (polygenic inheritance). Poly­ morphisms in the HLA complex account for almost 50% of the genetic risk for typeI diabetes. Certain haplotypes confer significant risk ofacquiring diabetes, yet others are protective. Most children with diabetes in United States have either the DR3 and/or DR4 antigens. Association with DR3 has been reported in Indians.

ConcordanceoftypeI diabetes in identical twinsranges from 30-70%. 7% of children whose fathers have type 1

diabetes develop type 1 diabetes. Mothers with type 1 diabetes do not confer a similar risk. Siblings are not at higher risk of developing type 1 diabetes.

Environmental factors Many environmental agents are thought to trigger the development of type 1 diabetes mellitus, including viruses, bovine milk protein and nitrosourea compounds.

Autoimmune factors and autoimmunity Individuals susceptible to development of diabetes have normal cell mass at birth. Autoimmune destruction affects only the cells of the islets, even though the a and delta cells are functionally and embryologically similar. The pancreatic islets are infiltrated with lymphocytes 'insulinitis'. Once the islet cells are completely destroyed inflammation abates andtheisletcellsatrophy. Clinical diabetes occurs when the pancreas loses 80% or more of its insulin secretary ability.

Islet cell antibodies (ICA) can be measured in the serum of 70-80 % of Caucasian patients at the time of diagnosis. These include antibodies directed at pancreatic islet molecules such asinsulin, IA-2/ICA-512andGAD-65. The presence of these antibodies predates the clinical presentation ofdiabetesanddeclines after clinical disease has manifested. Autoantibody production in Indian children is less common and their titres are lower as compared to Caucasian children.

Cl inical Features

Children and adolescents usually present with symptoms of diabetes that have often been ongoing for a month or two prior to seeking physician contact, with an acute increase in symptoms over the last week. Symptoms of type 1 diabetes mellitus include polyuria, nocturia, polydypsia, recent weight loss, polyphagia and fatigue. Recent acute infection is often noted at presentation. Approximately 50% children present with acute compli­ cation of diabetes or diabetic ketoacidosis.

Diagnosis

The National Diabetes Data group and the World Health Organizationhave outlineddiagnosticcriteriafordiabetes mellitus (Table 17.35).

Random blood sugar of 200 mg/dl or more associated with theclassicsymptomsof diabetesmellitus(polydipsia, polyuria and weight loss) is diagnostic. Oral glucose tolerance is not routinely recommended. Fasting blood

Table 17.35: Criteria for diagnosis of diabetes mellitus

Symptoms of diabetes and a random blood glucose concen­ tration 11.1 mmol/1 (200 mg/di) or

Fasting blood sugar 7 mmol/1 (126 mg/di) or

Two hour plasma glucose 11.l mmol/1 (200 mg/di) during an oral glucose tolerance test

sugar is also reliable and convenient test. Elevated glycated hemoglobin (HbAlC) is diagnostic of diabetes mellitus. However, it is not completely reliable when dealing with mild elevations of blood sugars.

Screening

Epidemiologic studies indicate that diabetes is often presentforover a decade inpatients eventually diagnosed with type 2 diabetes mellitus. 50% or more patients with Type 2 diabetes have one or more of the complications of diabetes at the time of diagnosis. High risk adolescents should therefore be screened for diabetes.

Course of Illness

Most children respond to insulin therapy. Once insulin is initiated, blood sugars gradually decline. Often, after around a week of insulin therapy, the need for exogenous insulin declines, due to a transient recovery of insulin secretion. This phase is called the "honeymoon phase of diabetes". Some children can go completely insulin free during this time. The honeymoon phase lasts from a few days to a month. It can rarely extend as long as one year. Insulinneeds increase overtime till such time aswhen the pancreas can no longer secrete insulin. At this point the daily insulinrequirementplateaus at 0.8-1 unit /kg/day.

Treatment

The goals of therapy of type 1 and 2 diabetes mellitus are to:

•Eliminate symptoms related to hyperglycemia

•Reduce and delay the complications

•Achieve a normal lifestyle and normal emotional and social development

•Achieve normal physical growth and development

•Detect associated diseases early

A comprehensive approach is adopted to achieve these goals. Symptoms of diabetes abate with blood sugars <200 mg/dl; making the first goal relatively easier to achieve. However, achieving the other goals require focus on diabetes education, medical nutritional therapy and well­ planned appropriate insulintherapy that is customized to theneedsofeachpatient.Theavailabilityofinsulinanalogs and insulins with long duration of action with minimal/ absent peaks allows insulin therapy to match glucose excursions with meals and at the same time provide baseline insulin for endogenous glucose production without significant hypoglycemia. Advances in self blood glucose monitoring, development of insulin pumps for accurate insulin delivery, continuous glucose monitoring systemsanddevelopmentofateam approachtothemana­ gementofdiabetescarehasgreatlyimproveddiabetescare. These developments and strategies have allowed many children and adolescents to achieve glycemicgoalsofnear normal blood sugars; goals that were previously almost impossible to achieve, with conventional insulin therapy of two injections a day.

Thecurrenttherapeuticregimen;whichinvolvesfrequent blood sugar monitoring and multiple insulin injections or continuous subcutaneous injection infusion, along with dietary modifications, is called intensive insulin therapy. Intensiveinsulintherapyinvolvesfrequentcommunication between the physician and the diabetes educator to accomplish insulin adjustments in a timely manner, with the goal of achieving near normal blood sugar at all times. Intensivetherapyresultisbetterbloodsugars,andreduced late complications of diabetes by 39-60%

Insulin therapy Current insulin preparations are generated using recombinant DNA technology. Animal insulins should be avoided. Amino acid substitutions on human insulin will alter insulin pharacokinetics and this has been usedto synthesize'designer' insulin preparations with particular desired characteristics. The insulin analog Lispro [Lys(B28) Pro(B29) human insulin] allows better control of blood sugar as its onset of action is faster than regular insulin and duration of action is shorter. Insulin Aspart also has rapid onset of action butdurationof action is longer than Lispro insulin. These modifications in insulin enable improved glycemic control during fasting as well as postprandial state. Table 17.36 provides the pharmacokinetics and specific characteristics of currently available insulins.

Insulinprescription Insulinrequirementsgenerallyrange from 0.5-1 unit/kg/day. At diagnosis, insulin therapy is initiated with four doses of short-acting insulin. The dose is evaluated and an appropriate home regimen of insulin is planned. The goal of therapy is to provide background insulin to maintain glycemic control during the fasting state, andto punctuatethis with multiple boluses ofshort­ acting insulins to maintain euglycemia during post­ prandial states in a titratable manner.

Currently, the most accurate method of achieving glycemic control uses the insulin pump. It utilizes insulin

delivery devices to accurately deliver a small baseline continuous infusion of insulin, coupled with parameters for bolus therapy-related to food intake and activity levels. The bolus insulin is determined by the amount of carbohydrate intake and the blood sugar level

In most traditional regimens, intermediate or long­ acting insulin is utilized to provide background insulin to maintain glycemic control during the fasting state. Short-acting insulin is used to provide glycemic control in the postprandial state. Insulin regimens in varying combinations are utilized to achieve near normal blood sugars at all timeswithminimalhypoglycemia. There are two main classes of insulin regimen: (i) NPH with short­ acting insulin analogues and (ii) Long-acting insulin, typically insulin Glargine (Lantus) with short-acting insulin, as depicted in Fig. 17.23.

In the NPH regimen two to three injections are given daily. This includes a combination of NPH and short­ acting insulin before breakfast, short-acting preparation at dinner and NPH at dinner or bedtime. In this regimen usually two-thirds of the total daily insulin is prescribed in the morning prior to breakfast and one-third is given in the evening. Hence, before breakfast, two-thirds of the morning insulin is given as NPH and one-third as short­ acting insulin. Pre-dinner 1/2-2/3 of the evening insulin

+

Lunch Dinner

Meal

Fig. 17.23: Intermediate and short-acting insulin regimen

is given as NPH and 1/3-1/2 of the evening insulin is given as short-acting insulin prior to dinner. When draw­ ing up a mixed dose of insulin, short-acting insulin is drawn before intermediate acting (cloudy) insulin, as accidental introduction of longer-acting insulin in short­ actinginsulincanresultinincreasingthedurationofeffect of short-acting insulin. A meal is planned incorporating three meals and two or three snacks.

Insulin is adjusted by reviewing blood sugars. Blood sugarsaremonitoredatleastfourtimesaday(priortomeals and at bedtime). It is important to follow the diet outlined intheplanandtoadheretomealtimings.Variationin meal amountsandtimingscanresultinwidefluctuationsinblood sugars,withhighbloodsugarsfromeatingexcessivelyand lowbloodsugarswithinsufficientfoodintakeanddelayed meals.Variationsinphysicalactivity andexercisewillalso affect the insulin/blood sugar dynamics.

A more physiologic insulin regimen utilizes multiple daily injections of Lispro or Aspart with baseline insulin levels achieved using Glargine insulin. Insulin Glargine is given once daily either in the morning or evening. Short­ acting insulin is given with every meal and snack. The dose of the short-acting insulin is determined by the amount of carbohydrate intake and the level of blood sugar. The dose of the short-acting insulin is calculated based on a carbohydrate ratio (units of insulin per g of carbohydrate ingested). Most infants and young children are on one unit of insulin per 20-30 g of carbohydrates, while older children on one unit per 10-15 g of carbo­ hydrate. Adolescents can require as much as 1 unit of insulin per 5 g of carbohydrate.

Continuous subcutaneous insulin infusion via insulin pump is beingincreasinglyusedinthewesternworld.The principle involved is essentially a refinement of the regi­ men above (insulin Glargine). Advantages of the insulin pumpare (i) the abilityto varythebasalinsulinduring the day and night by using multiple basal rates allowing adjustment of insulin for nocturnal and daytime require­ ments; (ii) usefulness in preventing early morning hyperglycemia secondary to Dawn phenomenon due to morninghormonalsurges; (iii)allowingalterationofbasal rates during exercise and hence preventing postactivity hypoglycemia;(iv)allowingbolusestobegivenindifferent wave forms to account for variable absorption from different foods. High fatfoods takes longer to metabolize and result in delayed hyperglycemia which can be addressedusingcomplexboluseswithdualwaveinfusion with a greater proportion of insulin given two hours after foodintake. Extendedbolusesareusedforfoodconsumed over two-three hours or longer in small portions.

Nutrition Therapy

Nutrition therapy in diabetes is important in preventing and treating existing diabetes. The goal of therapy is to match intakewithappropriateinsulin. Insulin therapy and

self blood glucose monitoring are integrated with appropriate nutrition and caloric intake. Flexibility in caloric intake, especially to allow exercise is desired. Nutritional plan which allows deviation in food intake incorporating individuals likes and dislikes is imple­ mented. Simple sugars are discouraged. Foodswith a low glycemic index and fiber is encouraged. The intake of saturated fats should be limited and the intake of trans fats should be minimized. Five sweeteners (acesulfame, aspartame, neotame, saccharin, sucralose) are approved for use in children. Excessive use should be avoided.

Exercise

Physical activity is important for children with diabetes. It increases glucose utilization and insulin sensitivity, improving metabolic control. It also builds self esteem. Longtermoutcomeof childrenwithdiabetesis better with regular exercise. Recommended activities include walk­ ing, jogging, swimming and organized sports.

Sick Day Care

Childrenwithdiabetesrequirecarefulmonitoringat home when they are ill or ketotic. If timely intervention is not provided they can develop diabetic ketoacidosis (OKA) a serious and life-threatening complication of diabetes. Children who are noted to have high blood sugars >240 mg/dl and or are ill should be tested for ketosis. Beta­ hydroxybutyrate and acetoacetic acid can be measured in blood or urine. Based on the level of ketosis additional insulin is provided every 2 hr. This ranges from 5-20% of the total daily dose as short-acting insulin. Blood sugar is monitored and parents are advised to administer addi­ tional oral fluids. Parents are advised to bring the child to the emergency if the child has altered sensorium, rapid breathing, fruity odor, signs of dehydration, persistent vomiting or persistent ketosis.

Type 2 Diabetes

Theincidenceoftype2diabetesinchildrenandadolescents is rising and parallels the increase in childhood obesity, at leastintheWestandinthemoreaffluentsections of Indian society.Changeindietaryhabitsandlifestylechangesseem to have contributed to this increase. Increase in TV watching,increaseintimespentplayingvideogamesrather than outdoor play have resulted in children acquiring a sedentary lifestyle. Distinguishing between type 1 and 2 diabetes in children can be difficult (Table 17.37). Often children with type 2 diabetes may have weight loss and ketoacidosis as the presenting feature. Sometimes autoantibodies are also present in children with type 2 diabetes. However, mostof thesechildrenare overweight, havefamilyhistoryoftype2diabetesandshowacanthosis nigricans. Children who present with ketosis are treated with insulin initially and transitioned to oral hypo­ glycemics once their endogenous glucose secretion