Pediatrics_Nelson

Pediatrics_Nelson. The etiology of acquired hypothyroidism is presented in Table 175-2. The clinical manifestations may be subtle. Hypothyroidism should be suspected in any child who has a decline in growth velocity, especially if not associated with weight loss (see Table 175-3). The most common cause of acquired hypothyroidism in older children in the United States is lymphocytic autoimmune thyroiditis (Hashimoto thyroiditis). In many areas of the world, iodine deficiency is the etiology of endemic goiter (endemic cretinism). The failure of the thyroid gland may be heralded by an increase of TSH before T4 levels decrease. In contrast to untreated congenital hypothyroidism, acquired hypothyroidism is not a cause of permanent developmental delay.


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Pediatrics_Nelson. Hashimoto thyroiditis. Also known as autoimmune or lymphocytic thyroiditis, Hashimoto thyroiditis is a common cause of goiter and acquired thyroid disease in older children and adolescents. A family history of thyroid disease is present in 25% to 35% of patients. The etiology is an autoimmune process targeted against the thyroid gland with lymphocytic infiltration and lymphoid follicle and germinal center formation preceding fibrosis and atrophy.


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Pediatrics_Nelson. Clinical manifestations include a firm, nontender euthyroid, hypothyroid, or, rarely, hyperthyroid (hashitoxicosis) diffuse goiter with a pebble-like surface. See Table 175-3 for signs and symptoms, which can be diverse. Onset typically occurs after 6 years of age with a peak incidence in adolescence with a female predominance. Associated autoimmune diseases include diabetes mellitus type 1 (DM1), adrenal insufficiency, and hypoparathyroidism. Autoimmune polyglandular syndrome type I consists of hypoparathyroidism, Addison disease, mucocutaneous candidiasis and, often, hypothyroidism. Autoimmune polyglandular syndrome type II consists of Addison disease, DM1, and frequently autoimmune Dull facies: thick lips, large tongue, depressed nasal bridge, Sinus bradycardia/heart block Cold extremities Cold intolerance Pallor ECG changes: low-voltage QRS complex


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Pediatrics_Nelson. Dull facies: thick lips, large tongue, depressed nasal bridge, Sinus bradycardia/heart block Cold extremities Cold intolerance Pallor ECG changes: low-voltage QRS complex Muscle weakness Hypotonia: constipation, potbelly Umbilical hernia Myxedema coma (carbon dioxide narcosis, hypothermia) Pseudohypertrophy of muscles Myalgia Physical and mental lethargy Developmental delay Delayed relaxation of reflexes Paresthesias (nerve entrapment: carpal tunnel syndrome) Cerebellar ataxia Delayed bone age Epiphyseal dysgenesis, increased upper-to-lower segment ratio Myxedema Serous effusions (pleural, pericardial, ascites) Hoarse voice (cry) Weight gain Menstrual irregularity Arthralgia Elevated CK Macrocytosis (anemia) Hypercholesterolemia Hyperprolactinemia Precocious puberty in severe cases CK, Creatine kinase; ECG, electrocardiographic. hypothyroidism. Trisomy 21 and Turner syndrome are predisposed to the development of autoimmune thyroiditis.


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Pediatrics_Nelson. CK, Creatine kinase; ECG, electrocardiographic. hypothyroidism. Trisomy 21 and Turner syndrome are predisposed to the development of autoimmune thyroiditis. The diagnosis may be confirmed by serum antithyroid peroxidase (previously antimicrosomal) and antithyroglobulin antibodies. Neither biopsy nor thyroid scan is indicated in Hashimoto thyroiditis, although the thyroid scan with reduced uptake may differentiate hashitoxicosis from Graves disease. Treatment with thyroid hormone sufficient to normalize TSH and free T4 is indicated for hypothyroidism in Hashimoto thyroiditis. Patients without manifestation of hypothyroidism require thyroid function testing (serum TSH and free T4)every 6 to 12 months to detect the later development of hypothyroidism. Goiter with a normal TSH usually is not an indication for treatment. Available @ StudentConsult.com


Pediatrics_Nelson

Pediatrics_Nelson. Most children with hyperthyroidism have Graves disease, the autonomous functioning of the thyroid caused by autoantibodies [thyroid stimulating immunoglobulins (TSIs)] stimulating the thyroid. The resulting excessive synthesis, release, and peripheral metabolism of thyroid hormones produce the clinical features. Hashimoto thyroiditis and thyrotoxicosis are on a continuum of autoimmune diseases; there is overlap in their immunologic findings. Antithyroid peroxidase and antithyroglobulin antibodies may be present in thyrotoxicosis, although the values are usually lower than in Hashimoto thyroiditis. Exceptionally high titers of antibodies may indicate the thyrotoxic phase of Hashimoto thyroiditis with the subsequent evolution toward permanent hypothyroidism. In Graves disease, serum free T4 or T3 or both levels are elevated, whereas TSH is suppressed. Rare causes of hyperthyroidism include McCune-Albright syndrome, thyroid nodule (often an adenoma), TSH hypersecretion, subacute


Pediatrics_Nelson

Pediatrics_Nelson. free T4 or T3 or both levels are elevated, whereas TSH is suppressed. Rare causes of hyperthyroidism include McCune-Albright syndrome, thyroid nodule (often an adenoma), TSH hypersecretion, subacute thyroiditis, and iodine or thyroid hormone ingestion.


Pediatrics_Nelson

Pediatrics_Nelson. Clinical manifestations. Graves disease presents as hyperthyroidism (Table 175-4) and is about five times more common in girls than in boys, with a peak incidence in adolescence. Personality changes, mood instability, and poor school performance are common initial problems. Tremor, anxiety, inability to concentrate, and weight loss may be insidious and confused with a psychological disorder until thyroid function tests reveal the elevated serum free T4 level. In rare cases, serum free T4 may be near-normal whereas serum T3 is selectively elevated (T3 toxicosis). A firm homogeneous goiter is usually present. Many patients complain of neck fullness. Thyroid gland enlargement is best visualized with the neck only slightly extended and with the examiner lateral to the patient. Palpation of the thyroid gland is best performed with the examiner’s hands around the neck from the back. The patient swallows so that the examiner can feel and examine the size, consistency, nodularity and motion


Pediatrics_Nelson

Pediatrics_Nelson. thyroid gland is best performed with the examiner’s hands around the neck from the back. The patient swallows so that the examiner can feel and examine the size, consistency, nodularity and motion of the gland. The examiner should watch the patient swallow to note any discernible enlargement or asymmetry of the thyroid lobes. Auscultation may reveal a bruit over the gland that needs to be differentiated from a carotid bruit.


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Pediatrics_Nelson. Treatment. Three treatment choices are available: pharmacologic, radioactive iodine, and surgical. Drugs. Medical therapy to block thyroid hormone synthesis consists of methimazole (0.4 to 0.6 mg/kg/day once or Shiny, smooth skin Cardiac failure—dyspnea Miscellaneous Proptosis, stare, exophthalmos, lid lag, ophthalmopathy Inability to concentrate Acute thyroid storm (hyperpyrexia, tachycardia, coma, high-output heart failure, shock) *Unusual except in subacute thyroiditis with hyperthyroid phase.


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Pediatrics_Nelson. twice daily) or propylthiouracil (5 to 7 mg/kg/day dividedevery 8 hours). Both medications are equally effective, however, propylthiouracil is no longer a first-line therapy secondary to concerns of severe liver injury and acute liver failure.A beta blocker, such as propranolol or atenolol, is startedif symptoms are severe to control cardiac manifestations and is tapered as the methimazole takes effect. Antithyroidmedication is usually continued for 1 to 2 years because theremission rate is approximately 25% per year. In patientscomplying with the treatment regimen, the 2-year courseof treatment can be repeated. Medication should suppressthyroid function to normal, without the need to add thyroidhormone replacement to normalize serum free T4. Complications of methimazole are muscle pain, rash, granulocytopenia, and jaundice. The granulocytopenia is an idiosyncraticcomplication of rapid onset, which is observed only in theearly months after institution of antithyroid medication and


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Pediatrics_Nelson. rash, granulocytopenia, and jaundice. The granulocytopenia is an idiosyncraticcomplication of rapid onset, which is observed only in theearly months after institution of antithyroid medication and requires monitoring the complete blood count. If asuppressed white blood cell count is observed, antithyroidtherapy must be discontinued. This potentially lethal rarecomplication affects 3 in 10,000 users a year. After resolution,the other of the two antithyroid medications can be startedbecause there is usually less than a 50% chance of a similarreaction from the other medication. Iodine administration, which may suppress thyroid function but becomes ineffectivein a few weeks, is sometimes used as a preparation for surgery but never for long-term therapy.


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Pediatrics_Nelson. Radioiodine. Radioiodine (131I) is slower in exerting therapeutic effects, may require repeated dosing, and is likely to cause permanent hypothyroidism. Hypothyroidism is the desired outcome because it is easier and safer to treat than continued hyperthyroidism. Although studies reveal no longterm consequences, concern remains about possible sequelae in children. This method of treatment is entering the mainstream for children and adolescents. Radioiodine given to a pregnant teenager renders the fetus hypothyroid and is contraindicated.


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Pediatrics_Nelson. Surgery. Surgical treatment consists of partial or completethyroidectomy. Risks associated with thyroidectomy includethe use of anesthesia and the possibility that the thyroidremoval will be excessive causing hypothyroidism or that itwill be inadequate resulting in persistent hyperthyroidism.In addition, keloid formation, recurrent laryngeal nervepalsy, and hypoparathyroidism (transient postoperative orpermanent) may occur. Thyroid storm caused by the releaseof large amounts of preformed hormone is a serious but rarecomplication. Even with optimal immediate postoperativeresults, patients may become hypothyroid within 10 years.


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Pediatrics_Nelson. Thyroid storm (see Table 175-4) is a rare medical emergency consisting of tachycardia, disorientation, elevated blood pressure, and hyperthermia. Treatment includes reducing the hyperthermia with a cooling blanket and administering a beta blocker to control the tachycardia, hypertension, and autonomic hyperfunction symptoms. Iodine may be given to block thyroid hormone release after an antithyroid medication is started. Hydrocortisone may be indicated for relative adrenal insufficiency, and therapy for heart failure includes diuretics and digoxin.


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Pediatrics_Nelson. This disorder results from transplacental passage of maternal TSIs and may be masked for several days until the short-lived effects of transplacental maternal antithyroid medication wear off (assuming the mother was receiving such medication), at which time the effects of TSIs are observed. Irritability, tachycardia (often with signs of cardiac failure simulating cardiomyopathy), polycythemia, craniosynostosis, bone age advancement, poor feeding, and failure to thrive are the clinical hallmarks. This condition may be anticipated if the mother is known to be thyrotoxic in pregnancy. Cure of hyperthyroidism before pregnancy (surgery or radioiodine treatment) limits or curtails T4 production but not the underlying immune disturbance producing TSIs; thus the infant still may be affected, at least transiently.


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Pediatrics_Nelson. Treatment for a severely affected neonate includes methimazole and, as needed, a beta blocker to help decrease symptoms. Because the half-life of the immunoglobulin is several weeks, spontaneous resolution of neonatal thyrotoxicosis resulting from transplacental passage of TSIs usually occurs by 2 to 3 months of age. Observation without treatment is indicated in patients who are minimally affected. About 2% of children develop solitary thyroid nodules, most of which are benign. Evaluation of a nodule includes thyroid function tests, neck ultrasound, and, if needed, fine-needle aspiration (FNA). Ultrasound guidance may be needed for aspiration of small nodules or those not palpable. Nodules found to be benign on FNA may be monitored through clinical exam and ultrasound.


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Pediatrics_Nelson. Carcinoma of the thyroid is rare in children (1% of all pediatric cancers in the 5to 9-year-old age group and up to 7% of cancers in the 15to 19-year-old age group). Papillary and follicular carcinomas represent 90% of childhood thyroid cancers. A history of therapeutic head or neck irradiation or radiation exposure from nuclear accidents predisposes a child to thyroid cancer. Carcinoma usually presents as a firm to hard, painless nonfunctional solitary nodule and may spread to adjacent lymph nodes. Rapid growth, hoarseness (recurrent laryngeal nerve involvement), and lung metastasis may be present. If the nodule is solid on ultrasound, is cold on radioiodine scanning, and feels hard, the likelihood of a carcinoma is high. Excisional biopsy usually is performed, but FNA biopsy also may be diagnostic.


Pediatrics_Nelson

Pediatrics_Nelson. Treatment includes total thyroidectomy, selective regional node dissection, and radioablation with 131I for residual or recurrent disease. The prognosis is usually good if the disease is diagnosed early. Medullary carcinoma of the thyroid may be asymptomatic except for a mass. Diagnosis is based on the presenceof elevated calcitonin levels, either in the basal state or after pentagastrin stimulation (difficult to obtain) and histologicexamination. This tumor most often occurs with multipleendocrine neoplasia 2a or 2b (MEN), possibly in a familial pattern. In some families, the presence of mutations ofthe RET proto-oncogene is predictive of the development of medullary carcinoma of the thyroid. The location of the mutation can help determine when removal of the thyroid iswarranted. Genetic screening of other members of the family is indicated after a proband is recognized. Prophylacticthyroidectomy is indicated for the family members with thesame allele.


Pediatrics_Nelson

Pediatrics_Nelson. Calcium and phosphate are regulated mainly by diet andthree hormones: parathyroid hormone (PTH), vitamin D,and calcitonin. PTH is secreted in response to a decrease inserum ionized calcium level. PTH attaches to its membrane receptor then acts via adenylate cyclase to mobilize calcium from bone into the serum and to enhance fractional reabsorption of calcium by the kidney while inducing phosphateexcretion; all increase the serum calcium concentration and decrease serum phosphate. Lack of PTH effect is heraldedby low serum calcium in the presence of elevated phosphatefor age. PTH stimulates vitamin D secretion by increasing renal 1α-hydroxylase activity and acts indirectly to elevateserum calcium concentration by stimulating the productionof 1,25-dihydroxyvitamin D from 25-hydroxyvitamin D.Calcitonin increases the deposition of calcium into bone; innormal states the effect is subtle, but calcitonin may be usedtemporarily to suppress extremely elevated serum calcium values.


Pediatrics_Nelson

Pediatrics_Nelson. 1,25-dihydroxyvitamin D enhances calcium absorption from the gastrointestinal tract, increasing serum calcium levels and bone mineralization. Vitamin D is derived from exposure of the skin to ultraviolet rays (usually via the sun) or from oral ingestion. It is modified first to 25-hydroxyvitamin D in the liver and then 1α-hydroxylated to the metabolically active form (1,25-dihydroxyvitamin D) in the kidney. The serum concentration of 25-hydroxyvitamin D is a better reflection of vitamin D sufficiency than the measurement of 1,25-hydroxyvitamin D (see Chapter 31). Available @ StudentConsult.com


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Pediatrics_Nelson. The clinical manifestations of hypocalcemia result fromincreased neuromuscular irritability and include musclecramps, carpopedal spasm (tetany), weakness, paresthesia, laryngospasm, and seizure-like activity. Tetany can bedetected by the Chvostek sign (facial spasms produced bylightly tapping over the facial nerve just in front of the ear) orby the Trousseau sign (carpal spasms exhibited when arterialblood flow to the hand is occluded for 3 to 5 minutes with a blood pressure cuff inflated to 15 mm Hg above systolic blood pressure). Total serum calcium concentration is usually measured, although a determination of serum ionizedcalcium, the biologically active form, is preferable. Albuminis the major reservoir of protein-bound calcium. Disordersthat alter plasma pH or serum albumin concentration mustbe considered when circulating calcium concentrations arebeing evaluated. The fraction of ionized calcium is inverselyrelated to plasma pH; alkalosis can precipitate hypocalcemiaby lowering


Pediatrics_Nelson

Pediatrics_Nelson. mustbe considered when circulating calcium concentrations arebeing evaluated. The fraction of ionized calcium is inverselyrelated to plasma pH; alkalosis can precipitate hypocalcemiaby lowering ionized calcium without changing total serumcalcium. Alkalosis may result from hyperpnea caused by anxiety or from hyperventilation related to physical exertion.Hypoproteinemia may lead to a false suggestion of hypocalcemia because the serum total calcium level is low even though the ionized Ca2+ remains normal. It is best to measure serum ionized calcium if hypocalcemia or hypercalcemia issuspected.


Pediatrics_Nelson

Pediatrics_Nelson. Primary hypoparathyroidism causes hypocalcemia but does not cause rickets. The etiology of primary hypoparathyroidism includes the following: 1. Congenital malformation (e.g., DiGeorge syndrome or other complex syndromes) resulting from developmental abnormalities of the third and fourth branchial arches (see Chapters 143 and 144) 2. Surgical procedures, such as thyroidectomy or parathyroidectomy, in which parathyroid tissue is removed either deliberately or as a complication of surgery for another goal 3. Autoimmunity, which may destroy the parathyroid gland Pseudohypoparathyroidism (all with hypocalcemia andhyperphosphatemia) may occur in one of four forms as follows: 1. Type Ia: an abnormality of the Gsa protein linking the PTH receptor to adenylate cyclase; biologically active PTH is secreted in great quantities but does not stimulate its receptor 2. Type Ib: normal phenotype, normal Gsa with abnormalities in the production of adenylate cyclase 3.


Pediatrics_Nelson

Pediatrics_Nelson. Type Ib: normal phenotype, normal Gsa with abnormalities in the production of adenylate cyclase 3. Type Ic: abnormal phenotype, normal production of adenylate cyclase, but a distal defect eliminates the effects of PTH 4. Type II: normal phenotype, normal production of adenylatecyclase, with a postreceptor defect, close to type Ib Pseudohypoparathyroidism is an autosomal dominant condition that may present at birth or later. Pseudohypoparathyroidism is associated with Albright hereditary osteodystrophywhose clinical manifestations include short stature, stockybody habitus, round facies, short fourth and fifth metacarpals,calcification of the basal ganglia, subcutaneous calcification,and developmental delay. Albright hereditary osteodystrophymay be inherited separately so that a patient may have a normal appearance with hypocalcemia or may have the Albrighthereditary osteodystrophy phenotype with normal serum calcium, phosphate, PTH, and response to PTH.


Pediatrics_Nelson

Pediatrics_Nelson. Transient neonatal hypocalcemia. During the first 3 days after birth, serum calcium concentrations normally decline in response to withdrawal of the maternal calcium supply via the placenta. Sluggish PTH response in a neonate may result in a transient hypocalcemia. Hypocalcemia caused by attenuated PTH release is found in infants of mothers with hyperparathyroidism and hypercalcemia; the latter suppresses fetal PTH release, causing transient hypoparathyroidism in the neonatal period. 25(OH)D, 25-Hydroxyvitamin D; Nl, normal; sl, slight; ↑, high; ↓, low. Normal serum magnesium concentrations are required for normal parathyroid gland function and action. Hypomagnesemia may cause a secondary hypoparathyroidism, which responds poorly to therapies other than magnesium replacement.


Pediatrics_Nelson

Pediatrics_Nelson. The etiology of hypocalcemia usually can be discerned by combining features of the clinical presentation with determinations of serum ionized calcium, phosphate, alkaline phosphatase, PTH (preferably at a time when the calcium is low), magnesium, and albumin. If the PTH concentration is not appropriately elevated in relation to the low serum calcium, hypoparathyroidism (transient, primary, or caused by hypomagnesemia) is present. Vitamin D stores can be estimated by measuring serum 25-hydroxyvitamin D. Renal function is assessed by a serum creatinine measurement or determination of creatinine clearance (Table 176-1).


Pediatrics_Nelson

Pediatrics_Nelson. Treatment of severe tetany or seizures resulting from hypocalcemia consists of intravenous calcium gluconate (1 to 2 mL/kg of a 10% solution) given slowly over 10 minutes while cardiac status is monitored by electrocardiogram for bradycardia, which can be fatal. Long-term treatment of hypoparathyroidism involves administering vitamin D, preferably as 1,25-dihydroxyvitamin D and calcium. Therapy is adjusted to keep the serum calcium in the lower half of the normal range to avoid episodes of hypercalcemia that might produce nephrocalcinosis and to avoid pancreatitis. Available @ StudentConsult.com


Pediatrics_Nelson

Pediatrics_Nelson. Available @ StudentConsult.com Rickets is defined as decreased or defective bone mineralization in growing children; osteomalacia is the same condition in adults. The proportion of osteoid (the organic portion of bone) is excessive. As a result, the bone becomes soft and the metaphyses of the long bones widen. In older infants, poor linear growth, bowing of the legs on weight bearing (which can be painful), thickening at the wrists and knees, and prominence of the costochondral junctions (rachitic rosary) of the rib cage occur. At this stage, x-ray findings are diagnostic.


Pediatrics_Nelson

Pediatrics_Nelson. In nutritional vitamin D deficiency, calcium is not absorbed adequately from the intestine (see Chapter 31). Poorvitamin D intake or avoidance of sunlight in infants exclusively breastfed may contribute to the development of rickets.Fat malabsorption resulting from hepatobiliary disease (biliary atresia, neonatal hepatitis) or other causes (cystic fibrosis) also may produce vitamin D deficiency because vitaminD is a fat-soluble vitamin. Defects in vitamin D metabolism by the kidney (renal failure, autosomal recessive deficiency of1α-hydroxylation, vitamin D–dependent rickets) or liver (defect in 25-hydroxylation) also can cause rickets. In familial hypophosphatemic rickets, the major defect in mineral metabolism is failure of the kidney to adequately reabsorb filtered phosphate so that serum phosphate decreases and urinary phosphate is high. The diagnosis of this X-linked disease usually is made within the first few years of life and is typically more severe in males.


Pediatrics_Nelson

Pediatrics_Nelson. The etiology of rickets usually can be determined by an assessment of the mineral and vitamin D status (25-hydroxyvitamin D <8 ng/mL suggests nutritional vitamin D deficiency) (see Table 176-1). Further testing of mineral balance or measurement of other vitamin D metabolites may be required.


Pediatrics_Nelson

Pediatrics_Nelson. Several chemical forms of vitamin D can be used for treatment of the different rachitic conditions, but their potencies vary widely. Required dosages depend on the condition being treated (see Chapter 31). Rickets may also be treated with 1,25-hydroxyvitamin D and supplemental calcium. In hypophosphatemic rickets, phosphate supplementation (not calcium) must accompany vitamin D therapy, which is given to suppress secondary hyperparathyroidism. Adequate therapy restores normal skeletal growth and produces resolution of the radiographic signs of rickets. Nutritional rickets is treated with vitamin D given as one large dose, in weekly larger doses, or multiple smaller replacement doses. Surgery may be required to straighten legs in untreated patients with long-standing disease.


Pediatrics_Nelson

Pediatrics_Nelson. The successive sequence of chromosomal sex, gonadal sex, and phenotypic sex leads to gender identity of the individual. Genes usually determine the morphology of internal organs and of gonads (gonadal sex); this directs the appearance of the external genitalia that form the secondary sex characteristics (phenotypic sex); self-perception of the individual (gender identity) and the perception of the individual by others (gender role) follow last. In most children, these features blend and conform, but, in some patients, one or more features may not follow this sequence, leading to the disorder of sexual development (DSD) (see Chapter 23).


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Pediatrics_Nelson. The internal and external genitalia are formed between 6and 13 weeks of gestation. Fetal gonad and external genitalia are bipotential and have the capacity to support development of a normal male or female phenotype (Fig. 177-1). In the presence of a gene called SRY for sex-determining regionon the Y chromosome, the primitive fetal gonad differentiatesinto a testis (Fig. 177-2). The Leydig cells of the testis secretetestosterone, which has direct effects (stimulating development of the wolffian ducts) but also is locally converted todihydrotestosterone (DHT) by the 5α-reductase enzyme.DHT causes enlargement, rugation, and fusion of the labioscrotal folds into a scrotum; fusion of the ventral surface of the penis to enclose a penile urethra; and enlargement of the 16.8 mm 49.0 mm 45.0 mm Figure 177-1 Differentiation of male and


Pediatrics_Nelson

Pediatrics_Nelson. Figure 177-1 Differentiation of male and Labia minora female external genitalia as proceeding from a Scrotum common embryonic anlage. Testosterone acts at 9 to 13 weeks of gestation to virilize the bipotential anlage. In the absence of testosterone action, the female phenotype develops. (From Grumbach MM, Conte FA: Disorders of sexual differentiation. In Wilson JD, Foster DW, editors: Textbook of Endocrinology, ed 8, Philadelphia, 1990, WB Saunders, p 873; adapted from Anus Spaulding MH, Contrib Embryol Instit 13:69−88, 1921.) phallus with ultimate development of male external genitalia.Testicular production and secretion of müllerian-inhibitorysubstance by Sertoli cells cause the regression and disappearance of the müllerian ducts and their derivatives, such as the fallopian tubes and uterus. In the presence of testosterone, the wolffian ducts develop into the vas deferens, seminiferoustubules, and prostate.


Pediatrics_Nelson

Pediatrics_Nelson. The female phenotype develops unless specific male influences alter development. In the absence of SRY, an ovary spontaneously develops from the bipotential, primitive gonad. Inthe absence of fetal testicular secretion of müllerian-inhibitorysubstance, a normal uterus, fallopian tubes, and posterior third of the vagina develop out of the müllerian ducts, and the wolffian ducts degenerate. In the total absence of androgens, the external genitalia appear female. The terms intersex, hermaphroditism, and pseudohermaphroditism are not useful. DSDs are categorized under three main subgroups according to karyotype (XX, XY, and sex chromosome for mosaic karyotypes).


Pediatrics_Nelson

Pediatrics_Nelson. Figure 177-2 A diagrammatic scheme of male sex determination and differentiation. SRY is the master gene controlling male sex differentiation, but there are many other genes and their products that control male and female sexual differentiation. DHT, Dihydrotestosterone; SRY, the gene for the testis-determining factor. (From Wilson JD, Foster DW, editors: Williams Textbook of Endocrinology, ed 8, Philadelphia, 1992, WB Saunders, p 918.) 46,XX Disorders of Sexual Development Available @ StudentConsult.com Hypertension Amenorrhea Precocious Puberty in the Male Precocious Puberty in the Female Ambiguous Genitalia Alkalemia


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Pediatrics_Nelson. Masculinization of the external genitalia of genotypic females (except for isolated enlargement of the clitoris, which can occur from later androgen exposure) is always caused by the presence of excessive androgens during the critical period of development (8 to 13 weeks of gestation) (Table 177-1). The degree of virilization can range from mild clitoral enlargement to the appearance of a male phallus with a penile urethra and fused scrotum with raphe. Congenital virilizing adrenal hyperplasia is the most common cause of female ambiguous genitalia; it is most commonly the result of an enzyme deficiency that impairs synthesis of glucocorticoids but does not affect androgen production. The impaired cortisol secretion leads to adrenocorticotropic hormone (ACTH) hypersecretion, which stimulates hyperplasia of the adrenal cortex and excessive adrenal production of androgens (see Chapter 178). 46,XY Disorders of Sexual Development Available @ StudentConsult.com


Pediatrics_Nelson

Pediatrics_Nelson. 46,XY Disorders of Sexual Development Available @ StudentConsult.com Underdevelopment of the male external genitalia occurs because of a relative deficiency of testosterone production or action (Table 177-2). The penis is small, with various degrees of hypospadias (penile or perineal) and associated chordee or ventral binding of the phallus; unilateral, but more often bilateral, cryptorchidism may be present. The testes should be sought carefully in the inguinal canal or labioscrotal folds by palpation or ultrasound. Rarely a palpable gonad in the inguinal canal or labioscrotal fold represents a herniated ovary or an ovotestis. The latter patients have ovarian and testicular tissue and usually ambiguous external genitalia. Production of testosterone by a gonad implies that testicular tissue is present and that at least some cells carry the SRY gene.


Pediatrics_Nelson

Pediatrics_Nelson. Testosterone production can be reduced by specific deficiencies of the enzymes needed for androgen biosynthesis or by dysplasia of the gonads. In the latter, if müllerian-inhibiting substance production also is reduced, a rudimentary uterus and fallopian tubes are present.


Pediatrics_Nelson

Pediatrics_Nelson. The complete form of androgen resistance or androgen insensitivity syndrome is the most dramatic example of resistance to hormone action by defects in the androgen receptor. Affected patients have a 46,XY karyotype, normally formed testes (usually located in the inguinal canal or labia majora), and female external genitalia with a short vagina and no internal müllerian structures. At the time of puberty, testosterone concentrations increase to normal or above normal male range. Because a portion of the testosterone is normally converted to estradiol in peripheral tissues and the estrogen cannot be opposed by the androgen, breast development ensues at the normal age of puberty without growth of pubic, facial, or axillary hair or the occurrence of menstruation.


Pediatrics_Nelson

Pediatrics_Nelson. 5α-Reductase deficiency presents at birth with predominantly female phenotype or with ambiguous genitalia, including perineoscrotal hypospadias. The defect is in 5α reduction of testosterone to its metabolite DHT. At puberty spontaneous secondary male sexual development occurs. Gender identity and gender role are significant psychological issues with these patients if diagnosed at puberty. Isolated P-450c17 deficiency with Adrenal function normal 17,20-desmolase deficiency possible mutations in DAX1, SOX9, GATA4, WT1 Complete androgen insensitivity Female external genitalia, absence of müllerian structures Partial androgen insensitivity As previous with ambiguous external genitalia 5α-Reductase deficiency Autosomal recessive, virilization at puberty StAR, Steroid acute regulatory protein. Sex Chromosome and Ovotesticular Disorders of Sexual Development Available @ StudentConsult.com


Pediatrics_Nelson

Pediatrics_Nelson. StAR, Steroid acute regulatory protein. Sex Chromosome and Ovotesticular Disorders of Sexual Development Available @ StudentConsult.com Turner syndrome and Klinefelter syndrome and their mosaic variants are classified as sex chromosome DSD. Mixed gonadal dysgenesis (45,X; 46,XY) often may present with genital ambiguity, asymmetric external genitalia, and inguinal hernias. There may be virilization on one side and none on the other. Similar findings may be seen with ovotesticular DSD, another classification of DSD. Available @ StudentConsult.com


Pediatrics_Nelson

Pediatrics_Nelson. Available @ StudentConsult.com Ambiguous genitalia in a newborn must be attended to with as little delay as possible and with informed sensitivity to the psychosocial context as required. The laboratory evaluations required might take days or weeks to complete, delaying a sex assignment and naming of the infant, such that choice often precedes diagnosis. Beyond infancy and childhood, and to offset any gender uncertainty in the patient and confusion in the parents, health care providers must help families come to an appropriate closure and gender choice.


Pediatrics_Nelson

Pediatrics_Nelson. On physical examination, it is essential to note where the urethral opening lies and whether there is fusion of the anterior portion of the labioscrotal folds. Endogenous excessive production of androgen (as in congenital adrenal hyperplasia [CAH]) in a female fetus between 9 and 13 weeks of gestation leads to ambiguous genitalia. If the vaginal opening is normal, and there is no fusion, but the clitoris is enlarged without ventral fusion of the ventral urethra, the patient had later exposure to androgens. A patient with a fully formed scrotum, even if small, and a normally formed but small penis, termed a microphallus, must have had normal exposure to and action of androgen during 9 to 13 weeks of gestation.


Pediatrics_Nelson

Pediatrics_Nelson. The major goal is a rapid identification of any life-threatening disorders (salt loss and shock caused by the salt-losing form of CAH). Although the classic approach to sex assignment has been based on the feasibility of genital reconstruction and potential fertility rather than on karyotypeor gonadal histology, the effects of prenatal androgen mustbe considered. Yet it may be inappropriate to raise a femaleinfant who is severely virilized from virilizing CAH as amale; nonetheless in most reported cases, sex assignment andadult gender role remain female, and fertility can be retainedbecause the internal organs are female. A 46,XY male withambiguous genitalia and an extremely small phallus that doesnot increase in size with androgen therapy (partial androgen resistance) traditionally has been raised as a female becausesurgical construction of a fully functional phallus is difficult. Some of these patients frequently revert spontaneouslyto a male gender identity. Present management of


Pediatrics_Nelson

Pediatrics_Nelson. been raised as a female becausesurgical construction of a fully functional phallus is difficult. Some of these patients frequently revert spontaneouslyto a male gender identity. Present management of ambiguous genitalia involves extensive open discussion with parentsinvolving the biology of the infant and the likely prognosis.Treatment should be individualized and managed by a team,including an experienced pediatric endocrinologist, urologistor gynecologist, psychologist, geneticist, and the primary carephysician.


Pediatrics_Nelson

Pediatrics_Nelson. The first step toward diagnosis is to determine whether thedisorder represents virilization of a genetic female (androgen excess) or underdevelopment of a genetic male (androgen deficiency) (see Fig. 177-2). Inguinal gonads that areevident on palpation usually are testes and indicate thatincomplete development of a male phenotype has occurred;this pattern is not consistent, and ovaries and ovotestes mayfeel similar. Similarly absence of female internal genitalia(detected by ultrasound) implies that müllerian-inhibitingsubstance was present and secreted by fetal testes. Karyotype determination is only one of many factors in decidingthe sexual identity for purposes of rearing; the SRY gene may be found on chromosomes other than the Y chromosome, and, conversely, a Y chromosome may lack an SRY gene (it may have been translocated to an X chromosome,leading to the development of a 46,XX maleXX sex reversal, testicular DSD).


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Pediatrics_Nelson. Statistically most virilized females have CAH; 90% of these females have 21-hydroxylase deficiency. The diagnosis is established by measuring the plasma concentration of 17-hydroxyprogesterone and androstenedione (see Chapter 178), which typically is hundreds of times above the normal range. Other enzymatic defects also may be diagnosed by quantifying circulating levels of the adrenal steroid precursor proximal to the defective enzyme block.


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Pediatrics_Nelson. Establishing an accurate diagnosis is more difficult in underdeveloped males. When certain types of adrenal hyperplasia coexist with defects in androgen production of the testes, excessive ACTH secretion elevates substantially levels of specific adrenal steroid precursors, allowing a diagnosis. If the defect is restricted to testosterone biosynthesis, the measurement of testosterone and its precursors in the basal state and after stimulation by hCG may be required. Patients with normal levels of testosterone either have persistent androgen resistance or have had an interruption of normal morphogenesis of the genitalia. Abnormalities of the sex chromosomes may be associated with dysgenetic gonads, which may be associated with persistence of müllerian structures.


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Pediatrics_Nelson. Treatment consists of replacing deficient hormones (cortisolin adrenal hyperplasia or testosterone in a child with androgen biosynthetic defects who will be raised as male), surgical restoration to make the individual look more appropriatefor the gender of rearing, and psychological support of thewhole family. Gonads and internal organs discordant forthe gender of rearing are often removed. Dysgenetic gonadswith Y-genetic material always should be removed because gonadoblastomas or dysgerminomas may develop in theorgan. Reconstructive surgery is usually performed by 2 yearsof age so that genital structure reflects gender of rearing. Thisrecommendation for reconstructive surgery is controversial;some advocate that surgery not be performed in infancy orearly childhood so that the child or young adolescent can be involved in the decision. A decision for gender of rearing isrecommended from birth; however the knowledge that theperson with a DSD may change gender later on is shared


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Pediatrics_Nelson. or young adolescent can be involved in the decision. A decision for gender of rearing isrecommended from birth; however the knowledge that theperson with a DSD may change gender later on is shared withparents from the outset.


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Pediatrics_Nelson. The adrenal gland consists of an outer cortex, which is responsible for the synthesis of steroids, and an inner medulla derived from neuroectodermal tissue, which synthesizes catecholamines. The adrenal cortex consists of three zones: an outer glomerulosa (end product is the mineralocorticoid aldosterone, which regulates sodium and potassium balance), a middle fasciculata (end product is cortisol), and an inner reticularis (synthesizes sex steroids). The general scheme of these synthetic steps is shown in Figure 178-1.


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Pediatrics_Nelson. Hypothalamic corticotropin-releasing hormone (CRH)stimulates the release of pituitary adrenocorticotropic hormone (ACTH, corticotropin), derived by selective processingfrom pro-opiomelanocortin. ACTH governs the synthesisand release of cortisol and adrenal androgens. Primary adrenal insufficiency or cortisol deficiency from any defect in theadrenal gland results in an oversecretion of ACTH; cortisoldeficiency also may occur from ACTH (secondary) or CRH (tertiary) deficiency, causing low serum ACTH concentrations and low cortisol. Endogenous (or exogenous) glucocorticoids feed back to inhibit ACTH and CRH secretion. The renin-angiotensin system and potassium regulate aldosterone secretion; ACTH has little effect on aldosterone production except in excess, when it may increase aldosteronesecretion.


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Pediatrics_Nelson. Steroids that circulate in the free form (not bound to cortisol-binding protein [transcortin]) may cross the placentafrom mother to fetus, but ACTH does not. The placenta plays an important role in steroid biosynthesis in utero, acting as a metabolic mediator between mother and child.Because the fetal CRH-ACTH-adrenal axis is operationalin utero, deficiencies in cortisol synthesis lead to excessiveACTH secretion. If a virilizing adrenal enzyme defect ispresent, such as 21-hydroxylase deficiency, the fetal adrenalgland secretes excess androgens, virilizing the fetus. Normalvariation of serum cortisol and ACTH levels leads to values that are high early in the morning and lower at night. Thisnormal diurnal variation may take months to years to fullydevelop.


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Pediatrics_Nelson. Figure 178-1 Diagram of the steroid biosynthetic pathways and the biosynthetic defects that result in congenital hyperplasia. The defect in patients with lipoid adrenal hyperplasia is not (except for one reported case) in the CYP11A1 (cholesterol side-chain cleavage) enzyme, but in StAR, the steroidogenic acute regulatory protein. This protein is involved in the transport of cholesterol from the outer mitochondrial membrane to the inner membrane, where the CYP11A1 enzyme is located. CYP11B1 (11β-hydroxylase) catalyzes 11β-hydroxylation of deoxycorticosterone and 11β-deoxycortisol primarily. CYP17 (17α-hydroxylase/17,20-lyase) catalyzes 17α-hydroxylation and splitting of the 17,20 bond, but for the latter it has preferential D5-17,20-lyase activity. CYP19 (aromatase) catalyzes the conversion of corticosterone to aldosterone. 3β-HSD I and 3β-HSD II, 3β-hydroxysteroid dehydrogenase/Δ4,5-isomerase types I and II; CYP21 (P450c21), 21-hydroxylase; 17β-HSD 3, 17β-hydroxysteroid dehydrogenase


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Pediatrics_Nelson. of corticosterone to aldosterone. 3β-HSD I and 3β-HSD II, 3β-hydroxysteroid dehydrogenase/Δ4,5-isomerase types I and II; CYP21 (P450c21), 21-hydroxylase; 17β-HSD 3, 17β-hydroxysteroid dehydrogenase type 3. In the human, deletion of a homozygous null mutation of CYP11A (P450ccc) is probably lethal in utero, but a heterogeneous mutation caused congenital lipoid adrenal hyperplasia. (From Melmed S, Polonsky K, Kronenberg H, et al, editors: Williams Textbook of Endocrinology, ed 10, Philadelphia, 2003, Saunders, p 917.)


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Pediatrics_Nelson. ADRENAL INSUFFICIENCY The dominant clinical features of congenital adrenal min eralocorticoid deficiency are hyponatremia and hyperkaDecision-Making Algorithms lemia, usually developing by 5 to 7 days after birth but not


Pediatrics_Nelson

Pediatrics_Nelson. Available @ StudentConsult.com immediately after birth. Vomiting, dehydration, and acidosis soon follow, as does hypotensive shock from glucocorticoid deficiency. Death may occur if the disorder remains undiag- nosed and untreated. In females the ambiguity of the external genitalia is an obvious clue that salt-losing congenital adrenal hyperplasia (CAH) or simple virilizing CAH must be ruled The clinical manifestations of inadequate adrenal function out. Because these forms cannot be distinguished clinically, all result from inadequate secretion or action of glucocorti-presentations of ambiguous genitalia should involve evaluacoids, mineralocorticoids, or both (Table 178-1). In the case tion for mineralocorticoid deficiency. In males the most com-of enzyme defects that affect the gonad and the adrenal gland, mon form of CAH, 21-hydroxylase deficiency, does not cause overproduction or underproduction of potent androgens can abnormal genitalia. There may be hyperpigmentation of the


Pediatrics_Nelson

Pediatrics_Nelson. and the adrenal gland, mon form of CAH, 21-hydroxylase deficiency, does not cause overproduction or underproduction of potent androgens can abnormal genitalia. There may be hyperpigmentation of the occur, depending on the site of enzyme blockade (see Fig. 178-scrotal skin, but this is a subtle sign. In all infants, the diagnosis 1). Progressive prenatal virilization of the external genitalia may of adrenal insufficiency may be overlooked or confused with occur in females; incomplete virilization may occur in males. pyloric stenosis. In pyloric stenosis, in contrast to salt-losing Ambiguity of the external genitalia is a common manifestation CAH, vomiting of stomach contents results in hypochloremia, of disordered fetal adrenal enzyme function. Precise diagnosis serum potassium is normal or low, and alkalosis is present. is essential for the prescription of appropriate therapy, long-This distinction may be lifesaving in preventing unnecessary term outlook, and genetic counseling. In


Pediatrics_Nelson

Pediatrics_Nelson. or low, and alkalosis is present. is essential for the prescription of appropriate therapy, long-This distinction may be lifesaving in preventing unnecessary term outlook, and genetic counseling. In patients with enzyme investigations or inappropriate therapy. defects, an elevation in the precursor steroid is present proxi-Not all forms of adrenal hyperplasia present at birth; the mal to the enzyme block and is metabolized through remain-spectrum of disorder ranges from severe (classic) to mild ing normal alternate enzyme pathways, whereas a deficiency of (late-onset) or nonclassic. Milder forms may manifest in steroids is present subsequent to the block. childhood, adolescence, or even young adulthood (not as


Pediatrics_Nelson

Pediatrics_Nelson. Cortisol deficiency Hypoglycemia Inability to withstand stress Vasomotor collapse Hyperpigmentation (in primary adrenal insufficiency with excess of adrenocorticotropic hormone) Apneic spells Muscle weakness, fatigue Aldosterone deficiency Hyponatremia Hyperkalemia Vomiting Urinary sodium wasting Salt craving Acidosis Failure to thrive Volume depletion Hypotension Dehydration Shock Diarrhea Muscle weakness glucocorticoid or mineralocorticoid deficiencies, but as androgen excess). In patients with congenital adrenal hypoplasia or adrenal hemorrhage, the secretion of all adrenal steroids is low. In contrast CAH leads to a diagnostic steroid pattern in blood and urine (see Fig. 178-1). Deficiency of 21-hydroxylase is the most common form (95%) and serves as a paradigm for these disorders. Available @ StudentConsult.com Hypertension Precocious Puberty in the Male Precocious Puberty in the Female Ambiguous Genitalia Hirsutism


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Pediatrics_Nelson. Available @ StudentConsult.com Hypertension Precocious Puberty in the Male Precocious Puberty in the Female Ambiguous Genitalia Hirsutism The incidence of classic 21-hydroxylase deficiency is about 1 in 15,000 among various white populations. Nonclassic CAH may occur with an incidence of 1 in 50 in certain populations. The gene for 21-hydroxylase lies on the short arm of chromosome 6; the genotype may be determined in a proband, permitting prenatal diagnosis in a subsequent pregnancy.


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Pediatrics_Nelson. Deficient 21-hydroxylase activity (P-450c21 deficiency) impairs the conversion of 17-hydroxyprogesterone (17-OHP) to 11-deoxycortisol and in the salt-losing form, of progesterone to deoxycorticosterone, a mineralocorticoid proximal in the pathway to the production of aldosterone. The decreased production of cortisol causes hypersecretion of ACTH, which stimulates the synthesis of steroids immediately proximal to the block and shunting of these to overproduction of androgens. The primary clinical manifestation is the virilization of the external genitalia of the affected female fetus; the development of the uterus, ovaries, and fallopian tubes remains unaffected by the androgens. The degree of virilization varies, ranging from mild clitoromegaly to complete fusion of labioscrotal folds, with severe clitoromegaly simulating a phallus (see Chapter 177). A male infant with this defect appears normal at birth, although penile enlargement may be apparent thereafter. The deficiency in


Pediatrics_Nelson

Pediatrics_Nelson. with severe clitoromegaly simulating a phallus (see Chapter 177). A male infant with this defect appears normal at birth, although penile enlargement may be apparent thereafter. The deficiency in aldosterone, found in about 75% of patients, causes salt wasting with shock and dehydration until the diagnosis is established and appropriate treatment is given.


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Pediatrics_Nelson. The treatment of 21-hydroxylase deficiency requires hydro-cortisone and fludrocortisone in the case of the salt-losing form. Therapy must be adjusted throughout childhood at regular intervals. Overtreatment will cause growth stunting and weight gain (cushingoid features), whereas undertreatment will cause excessive height gain, skeletal advance, and early appearance puberty, ultimately jeopardizing adult height potential. Late-onset CAH is typically noted years after birth. Affected subjects have milder manifestations without ambiguous genitalia, but they may have acne, hirsutism, and in girls irregular menstrual cycles or amenorrhea. Late-onset CAH in girls may be confused with polycystic ovarian syndrome.


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Pediatrics_Nelson. Biochemical diagnostic studies show elevated levels of serum 17-OHP, the substrate for the defective 21-hydroxylase enzyme activity. In newborns with CAH, the values are elevated a hundredfold to a thousandfold. In late-onset CAH, an ACTH stimulation test is necessary to show an abnormally high response of 17-OHP. Serum cortisol and aldosterone levels (in salt losers) are low, renin levels are high, whereas the testosterone level is elevated because it is derived from 17-OHP.


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Pediatrics_Nelson. The goals of treatment are to achieve normal linear growth and bone age advancement. Long-term therapy consists of providing glucocorticoids at a dose of approximately 10 to 15 mg/m2/24 hours in three divided doses of oral hydrocortisone or its equivalent. Mineralocorticoid therapy for salt losers consists of fludrocortisone at a dose of 0.1 to 0.2 mg/24 hours, often with sodium chloride supplementation in infancy and early childhood. Surgical correction of ambiguous external genitalia may be considered. The adequacy of glucocorticoid replacement therapy is monitored by determining serum concentrations of adrenal precursors, including androstenedione and 17-OHP for 21-hydroxylase deficiency. In addition, the assessment of linear growth and skeletal age, by bone age determination, is required as a reflection of appropriate therapy. To avoid adrenal insufficiency, threefold higher doses of glucocorticoids are given during stressful states such as febrile illnesses and surgery.


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Pediatrics_Nelson. is required as a reflection of appropriate therapy. To avoid adrenal insufficiency, threefold higher doses of glucocorticoids are given during stressful states such as febrile illnesses and surgery. Intramuscular hydrocortisone is used in severe emergencies or with illnesses involving emesis. Mineralocorticoid therapy is monitored with serum sodium, potassium, and plasma renin activity levels. Prenatal treatment with dexamethasone to suppress fetal ACTH-induced


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Pediatrics_Nelson. Hemorrhage Moderate to severe No No D D D D D D D D P-450c21 deficiency Absent to severe Yes No D D I I D D I I Unresponsiveness to † 17-KS, 17-Ketosteroid; 17-OHCS, 17-hydroxycorticosteroid; ACTH, adrenocorticotropic hormone; D, decrease; HSD, hydroxysteroid dehydrogenase; I, increase; Nl, normal; StAR, steroid acute regulatory protein. *Usually manifested after 5 days of age. †High normal Na+ and low normal to low K+. androgen production can reduce or eliminate the ambiguity of the external genitalia in affected female fetuses, if begun at approximately 7 weeks of gestation; this remains controversial.


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Pediatrics_Nelson. androgen production can reduce or eliminate the ambiguity of the external genitalia in affected female fetuses, if begun at approximately 7 weeks of gestation; this remains controversial. Other enzyme defects are rare in contrast to 21-hydroxylase deficiency. In 11-hydroxylase deficiency, the next most common cause of CAH, virilization occurs with salt retention and hypokalemia, as a result of the buildup of deoxycorticosterone (see Fig. 178-1), a potent mineralocorticoid. Hypertension develops as a result of excessive mineralocorticoid production. Table 178-2 summarizes the clinical and biochemical features of adrenal insufficiency in infancy. Available @ StudentConsult.com Addison disease is a rare acquired disorder of childhood, usually associated with autoimmune destruction of the adrenal cortex. It is a form of primary adrenal insufficiency with absence of glucocorticoid and mineralocorticoid.


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Pediatrics_Nelson. Clinical manifestations are hyperpigmentation, salt craving, postural hypotension, fasting hypoglycemia, anorexia, weakness, and episodes of shock during severe illness. Baseline and ACTH-stimulated cortisol values are subnormal, confirming the diagnosis; hyponatremia, hyperkalemia, and elevated plasma renin activity indicate mineralocorticoid deficiency. Addison disease may occur within the context of autoimmune polyglandular syndromes (APS I and APS II). Other rare causes of adrenal insufficiency include adrenal leukodystrophy and conditions that affect the hypothalamus-pituitary whether acquired, such as in craniopharyngioma, or iatrogenic, such as in irradiation for treatment of malignancy.


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Pediatrics_Nelson. Replacement treatment with 10 to 15 mg/m2/24 hours of hydrocortisone is indicated, with supplementation during stress at three times the maintenance dosage or the use of intramuscular hydrocortisone. The dose is titrated to allow a normal growth rate. Mineralocorticoid replacement with fludrocortisone is monitored by plasma renin activity and serum sodium and potassium determinations. Available @ StudentConsult.com


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Pediatrics_Nelson. Available @ StudentConsult.com Classic clinical manifestations of Cushing syndrome in children include progressive central or generalized obesity, marked failure of longitudinal growth, hirsutism, weakness, a nuchal fat pad, acne, striae, hypertension, and often hyper-pigmentation when ACTH is elevated. The most frequent cause is exogenous administration in the context of numerous conditions requiring long-term pharmacologic doses of glucocorticoids. Endogenous causes include adrenal adenoma, carcinoma, nodular adrenal hyperplasia, an ACTH-secreting pituitary microadenoma resulting in bilateral adrenal hyperplasia (Cushing disease), or an extremely rare ACTH-secreting tumor. Diagnostic tests include 24-hour urinary cortisol excretion, low-dose dexamethasone suppression test, high-dose dexamethasone suppression test (helps distinguish Cushing syndrome from Cushing disease), and late evening salivary cortisol sampling.


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Pediatrics_Nelson. Treatment of Cushing syndrome is directed to the etiology and may include excision of autonomous adrenal, pituitary, or ectopic ACTH-secreting tumors. Rarely adrenalectomy is needed to control the symptoms. Parenteral glucocorticoid therapy is necessary during and immediately after surgical treatment to avoid acute adrenal insufficiency. Backeljauw PF, Chernausek SD: The insulin-like growth factors and growth disorders of childhood, Endocrinol Metab Clin North Am 41(2):265–282, Kliegman RM, Stanton B, St Geme III J, et al: Nelson Textbook of Pediatrics, ed 19, Philadelphia, 2011, Elsevier Nimkarn S, Lin-Su K, New MI: Steroid 21 hydroxylase deficiency congenital adrenal hyperplasia, Pediatr Clin North Am 58(5):1281–1300, 2011 Palmert MR, Dunkel L: Clinical practice: delayed puberty, N Engl J Med 2 366(5):443–453, 2012 Péter F, Muzsnai A: Congenital disorders of the thyroid: hypo/hyper, Pediatr Clin North Am 58(5):1099–1115, 2011


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Pediatrics_Nelson. Péter F, Muzsnai A: Congenital disorders of the thyroid: hypo/hyper, Pediatr Clin North Am 58(5):1099–1115, 2011 Romero CJ, Nesi-França S, Radovick S: The molecular basis of hypopituitar ism, Trends Endocrinol Metab 20(10):506–516, 2009 Schatz DA, Haller MJ, Atkinson MA: Type 1 diabetes. Preface, Endocrinol Metab Clin North Am 39(3), 2010 481−667 Williams RM, Ward CE, Hughes IA: Premature adrenarche, Arch Dis Child 97(3):250–254, 2012 Jocelyn Huang Schiller and Renée A. Shellhaas 24


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Pediatrics_Nelson. Metab Clin North Am 39(3), 2010 481−667 Williams RM, Ward CE, Hughes IA: Premature adrenarche, Arch Dis Child 97(3):250–254, 2012 Jocelyn Huang Schiller and Renée A. Shellhaas 24 A neurologic evaluation, including history, physical examination, and judicious use of ancillary studies, allows the localization and diagnosis of nervous system pathology. The process andinterpretation of the neurologic examination varies with age; thenewborn is unique with many transient and primitive reflex patterns, whereas the examination of adolescents and adults is similar. Careful evaluation of social, cognitive, language, fine motorand gross motor skills, and their age appropriateness is key.


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Pediatrics_Nelson. Gathering neurologic history follows the traditional medical model with two additions: the pace of the process and the localization of the problem. The symptom evolution provides clues to the underlying process as symptoms may evolve in a progressive, static, or episodic fashion. Progressive symptoms may evolve suddenly (seizures, stroke); acutely over minutes or hours (epidural hemorrhage); subacutely over days or weeks (brain tumor); or slowly over years (hereditary neuropathies). Static neurologic abnormalities are observed early in life and do not change in character over time (cerebral palsy). Static lesions are often caused by congenital brain abnormalities or prenatal/perinatal brain injury. Intermittent attacks of recurrent, stereotyped episodes suggest epilepsy or migraine syndromes, among others. Episodic disorders are characterized by periods of symptoms, followed by partial or complete recovery (demyelinating, autoimmune, vascular diseases).


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Pediatrics_Nelson. Observation of the child’s appearance, movement, and behavior begins at the start of the encounter. For example, the child may display an unusual posture, abnormal gait, or lack of awareness of the environment. Because the brain and skin have the same embryonic origin (ectoderm), abnormalities of hair, skin, teeth, and nails areassociated with congenital brain disorders (neurocutaneousdisorders) such as neurofibromatosis (NF type 1) in which café au lait macules (flat, light brown macules) are characteristic. Adenoma sebaceum, fibrovascular lesions that look like acne on the nose and malar regions, nail fibromas, ash-leaf spots(hypopigmented macules), and Shagreen patches (flesh-coloredsoft plaques with prominent follicular openings) are commonlyseen in older children and adults with tuberous sclerosis.


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Pediatrics_Nelson. The head circumference is measured in its largest occipitofrontal circumference and plotted against standard growth curves (Chapter 5). Microcephaly and macrocephaly represent an occipitofrontal circumference 2 standard deviations (SDs) below or above the mean, respectively. Measurements plotted over time may show an accelerating pattern (hydrocephalus) or decelerating pattern (brain injury, degenerative neurologic disorder). The anterior fontanelle is slightly depressed and pulsatile when a calm infant is placed upright. A tense or bulging fontanelle may indicate increased intracranial pressure (ICP) but may also be seen in a crying or febrile infant. Premature closure of one or more sutures (craniosynostosis) results in an unusual shape of the head. Abnormal shape, location, and condition of the face, eyes, nares, philtrum, lips, or ears are found in many genetic syndromes.


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Pediatrics_Nelson. A careful ocular examination is essential and should include a search for epicanthal folds, coloboma, conjunctival telangiectasias, and cataracts. Direct ophthalmoscopy assesses the optic disks and macula for abnormalities such as papilledema or a cherry-red spot. A complete examination of the retina involves dilating the pupil and use of indirect ophthalmoscopy, typically requiring ophthalmologic consultation. Examination of the hands and feet may reveal abnormal creases or digits (Chapters 50, 201). The neck and spine should be examined for obvious (myelomeningocele) or subtle (cutaneous dimples, sinus tracts, hair tufts, subcutaneous lipomas) midline defects. Nervous system abnormalities may result in kyphosis or scoliosis (Chapter 202).


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Pediatrics_Nelson. Because of the developmental immaturity of infants, the neonatal neurologic examination primarily assesses the function of the basal ganglia, brainstem, and more caudal structures. The plasticity of the developing nervous system means that examination results should be used cautiously in predicting developmental outcomes. A healthy newborn infant should have periods of quiet, sustained wakefulness interspersed with active and quiet sleep. Grasp Placing finger in infant’s palm results in flexing of infant’s fingers Birth 6 mo Rooting Tactile stimulus about infant’s mouth results in the mouth pursuing the Birth 4–6 mo stimulus Trunk incurvation Stroking the skin along the edge of vertebrae produces curvature of the Birth 4 mo (Gallant) spine with concavity on the side of the stroke Placing When dorsum of foot is brought into contact with the edge of a surface, Birth 4–6 mo infant places foot on the surface


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Pediatrics_Nelson. Placing When dorsum of foot is brought into contact with the edge of a surface, Birth 4–6 mo infant places foot on the surface Asymmetrical tonic With infant supine, turning of the head results in ipsilateral extension of the Birth 3 mo neck arm and leg with flexion of opposite extremities in a “fencing” posture Parachute Infant is suspended face down by the chest. When infant is moved toward 8–10 mo Never a table, the arms extend as if to protect self Babinski Stroking lateral aspect of sole from heel up results in dorsiflexion of the Birth 12–18 mo great toe and fanning of the remaining toes Irritability, lethargy, or more severely depressed consciousness are nonspecific signs of abnormal brain function.


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Pediatrics_Nelson. Irritability, lethargy, or more severely depressed consciousness are nonspecific signs of abnormal brain function. Examination of the primitive reflexes provides assessment of the functional integrity of the brainstem and basal ganglia (Table 179-1). Many of these stereotyped motor responses are present at birth. They are symmetrical and disappear at 4 to 6 months of age, indicating the normal maturation of descending inhibitory cerebral influences. The grasp and rootingreflexes are inhibited by maturation of frontal lobes but may reappear later in life with acquired frontal lobe lesions. Asymmetry or persistence of the primitive reflexes may indicate focal brain or peripheral nerve lesions.


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Pediatrics_Nelson. Posture is the position that a calm infant naturally assumes when placed supine. An infant at 28 weeks of gestation shows an extended posture. By 32 weeks, there is a slight trend toward increase in tone and flexion of the lower extremities. At 34 weeks, the lower extremities are flexed; the upper extremities are extended. The term infant flexes lower and upper extremities. Recoil, the readiness with which an arm or leg springs back to its original position after passive stretching and release, is essentially absent in very premature infants but is brisk at term. Because of the asymmetric tonic neck reflex, it is essential to maintain the infant’s head in a neutral position (not turned to the side) during assessment of posture and tone. Spontaneous movements of premature infants are slow and writhing; those of term infants are more rapid.


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Pediatrics_Nelson. Spontaneous movements of premature infants are slow and writhing; those of term infants are more rapid. The purpose of the neurologic examination is to localize or identify the region within the neuraxis from which the symptoms arise. The mental status examination assesses the cerebral cortex. The cranial nerve examination evaluates the integrity of the brainstem. The motor examination evaluates upper and lower motor neuron function. The sensory examination assesses the peripheral sensory receptorsand their central reflections. Deep tendon reflexes assess upper and lower motor connections. Gait assessment evaluates the motor system in a dynamic state for better functional assessment.


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Pediatrics_Nelson. Alertness is assessed in infants by observing spontaneousactivities, feeding behavior, and visual ability to fix and follow objects. Response to tactile, visual, and auditory stimuliis noted. If consciousness is altered, the response to painful stimuli is noted. Observation of toddlers at play allowsa nonthreatening assessment of developmentally appropriate skills. In addition to language function, older childrencan be tested for reading, writing, numerical skills, fundof knowledge, abstract reasoning, judgment, humor, and memory.


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Pediatrics_Nelson. The simplest way to assess intellectual abilities is through language skills. Language function is receptive (understanding speech or gestures) and expressive (speech and use of gestures). Abnormalities of language resulting from cerebral hemisphere disorders are referred to as aphasias. Anterior, expressive, or Broca aphasia is characterized by sparse, non-fluent language. Posterior, receptive, or Wernicke aphasia is characterized by an inability to understand language, with speech that is fluent but nonsensical. Global aphasia refers to impaired expressive and receptive language. The cranial nerve evaluation assesses brainstem integrity but depends on the stage of brain maturation and the ability to cooperate. A colorful toy may capture a young child’s attention and permit observation of coordination, movement, and cranial nerve function.


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Pediatrics_Nelson. Smell can be assessed in verbal, cooperative children older than2 years of age. Aromatic substances (perfumes, vanilla) shouldbe used instead of volatile substances (ammonia), which irritate the nasal mucosa and stimulate the trigeminal nerve.


Pediatrics_Nelson

Pediatrics_Nelson. Full-term newborns in a quiet awake state follow human faces,lights in a dark room, or large, opticokinetic strips. Visual acuity has been estimated to be 20/200 in newborns and 20/20 in6-month-old infants. Standard visual charts displaying picturesinstead of letters can be used to assess visual acuity in toddlers.Peripheral vision is tested by surreptitiously bringing objectsinto the visual field from behind. A reduced pupillary reactionto light suggests anterior visual pathway lesions, including theretina, optic nerves, and chiasm. Unilateral optic nerve lesionsare identified by the swinging flashlight test. With an optic nerveabnormality, both pupils constrict when light is directed into thenormal eye. When light is swung over to the abnormal eye, bothpupils dilate inappropriately; this is called an afferent pupillary defect or Marcus Gunn pupil. Interruption of the sympatheticinnervation to the pupil produces Horner’s syndrome (ptosis,miosis, and unilateral facial anhidrosis). In


Pediatrics_Nelson

Pediatrics_Nelson. is called an afferent pupillary defect or Marcus Gunn pupil. Interruption of the sympatheticinnervation to the pupil produces Horner’s syndrome (ptosis,miosis, and unilateral facial anhidrosis). In this instance, anisocoria (unequal pupils) is more pronounced in a dark room,because the affected pupil is unable to dilate appropriately.Lesions of the posterior visual pathway, including the lateralgeniculate, optic radiations, and occipital cortex, have normalpupillary light reactions but are expressed by loss of visual fields.


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Pediatrics_Nelson. Cranial Nerves III, IV, and VI These three cranial nerves control eye movement and are most easily examined with the use of a colorful toy to capture the child’s attention. For infants too young to fix and follow, rotating the infant’s head assesses oculocephalic vestibular reflexes (doll’s eye maneuver). If the brainstem is intact, rotating a newborn or comatose patient’s head to the right causes the eyes to move to the left, and vice versa. In awake, older patients, voluntary eye movements mask the reflex.


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Pediatrics_Nelson. Abnormalities of these cranial nerves may cause diplopia (double vision). With unilateral third cranial nerve (oculomotor nerve) palsy, the involved eye deviates down and out (infraducted, abducted), with associated ptosis and a dilated, mydriatic pupil. Injury to cranial nerve IV (trochlear nerve) causes weakness of downward eye movement with consequent vertical diplopia. Cranial nerve VI (abducens nerve) palsy results in the inability to move the eye outward. Because cranial nerve VI has a long intracranial route within the sub-arachnoid space, failure of abduction of one or both eyes is a frequent, but nonspecific, sign of increased ICP.


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Pediatrics_Nelson. The muscles of mastication can be observed as an infant sucks and swallows. The corneal reflex can test cranial nerves V ophthalmic division and VII at any age. Facial sensation of light touch and pain can be determined with cotton gauze and pinprick. Facial sensation can be functionally assessed in an infant by gently brushing the cheek, which will produce the rooting reflex (turns head and neck with mouthing movement, as if seeking to nurse).


Pediatrics_Nelson

Pediatrics_Nelson. Facial muscles are assessed by observing the face during rest, crying, and blinking. At older, cooperative ages, children can be asked to smile, blow out their cheeks, blink forcibly, and furrow their foreheads. Weakness of all unilateral muscles of the face, including the forehead, eye, and mouth, indicates a lesion of the ipsilateral peripheral facial nerve (Bell palsy).Because the upper third of the face receives bilateral cortical innervation, if the weakness affects only the lower face and mouth, a contralateral lesion of upper motor neuron in the brain (tumor, stroke, abscess) must be considered.


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Pediatrics_Nelson. Lesions of cranial nerve VIII cause deafness, tinnitus, and vertigo. Normally, alert neonates blink in response to a bell or other abrupt, loud sound. Four-month-old infants turn their head and eyes to localize a sound. Hearing can be tested in a verbal child by whispering a word in one ear while covering the opposite ear. If there are any concerns about hearing, formal audiologic assessment is indicated. Lesions of the vestibular component of cranial nerve VIII produce symptoms of vertigo, nausea, vomiting, diaphoresis, and nystagmus. Nystagmus is an involuntary beating eye movement with a rapid phase in one direction and a slow phase in the opposite direction. By convention, the direction of the nystagmus is defined by the fast phase and may be horizontal, vertical, or rotatory.


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Pediatrics_Nelson. The gag reflex is brisk at all ages except the very immature neonate. An absent gag reflex suggests a lower motor neuron lesion of the brainstem, cranial nerves IX or X, neuromuscular junction, or pharyngeal muscles. Weak, breathy, or nasal speech; weak sucking; drooling and inability to handle secretions; gagging and nasal regurgitation of food are additional symptoms of cranial nerve X dysfunction. Observing the infant’s posture and spontaneous activity assesses the functions of the trapezius and sternocleidomastoid muscles. Head tilt and drooping of the shoulder suggest lesions involving cranial nerve XI. In later childhood, strength in these muscles can be tested directly and individually. Atrophy and fasciculation of the tongue, usually indicating a lesion of the anterior horn cells (spinal muscular atrophy [SMA]), can be observed at any age and are assessed most reliably when the infant is asleep. The tongue deviates toward the weak side in unilateral lesions.


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Pediatrics_Nelson. In infants, power is assessed by observation of spontaneous movements and movements against gravity. Arm and leg movements should be symmetrical, seen best when the infant is held supine with one hand supporting the buttocks and one supporting the shoulders. The limbs should easily lift up. Power is graded as follows: 5 Normal 4 Weak but able to provide resistance 3 Able to move against gravity but not against resistance 2 Unable to move against gravity


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Pediatrics_Nelson. Strength in toddlers is assessed by observing functional abilities, such as walking, stooping to pick up an object, and standing up from the floor. An older child should be able to easily reach high above his or her head, wheelbarrow walk, run, hop, go up and down stairs, and arise from the ground. Gower sign (child arises from lying on the floor by using his arms to climb up his legs and body) is a sign of significant proximal weakness. Subtle asymmetry can be detected when the child extends arms out in front with the palms upward and eyes closed. The hand on the weaker side cups and begins to pronate slowly (pronator drift). Cooperative children can undergo individual muscle strength testing. Muscle fasciculations indicate denervation from disease of the anterior horn cell or peripheral nerve.


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Pediatrics_Nelson. Tone represents the dynamic resistance of muscles to passivestretch. Lower motor and cerebellar lesions produce decreasedtone (hypotonia). Upper motor lesions produce increased tone (spasticity). In extrapyramidal disease, an increase in resistanceis present throughout passive movement of a joint (rigidity). Muscle bulk represents the volume of muscle tissue. In many lower motor neuron conditions (neuropathies, SMA), muscle bulk is diminished or atrophic. Excessive muscle bulk is seen in rare conditions, such as myotonia congenita; boys with Duchenne muscular dystrophy have pseudohypertrophy of their calves.


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Pediatrics_Nelson. Ataxia is the lack of coordination of movement, which is typically due to a dysfunction of the cerebellar pathways. Observation and functional analysis help assess coordination in infants and toddlers. Watching the child sit or walk assesses truncal stability. Exchanging toys or objects with the child permits assessment of intention tremor and dysmetria (errors in judging distance), signs of cerebellar dysfunction. Cooperative children can do repetitive finger or foot tapping to test rapid alternating movements. Cerebellar and corticospinal tract dysfunction produce slowing and irregularity during tests of rapid alternating movements.


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Pediatrics_Nelson. Watching a child creep, crawl, cruise, or walk is the best global assessment for the motor and coordination systems (Chapter 197). Subtle deficits and asymmetries in power, tone, or balance may be observed. The toddler gait is normally wide-based and unsteady. The base of the gait narrows with age. By 6 years, a child is able to walk on toes, walk on heels, and tandem walk (heel to toe). Cerebellar dysfunction results in a broad-based, unsteady gait accompanied by difficulty in executing turns. Corticospinal tract dysfunction produces a stiff, scissoring gait and toe walking. Arm swing is decreased, and the affected arm is flexed across the body. Extrapyramidal dysfunction produces a slow, stiff, shuffling gait with dystonic postures. A waddling gait occurs with hip weakness due to lower motor neuron or neuromuscular disorders. A steppage gait results from weakness of ankle dorsiflexors (common peroneal palsy).


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Pediatrics_Nelson. Deep tendon reflexes can be elicited at any age and are reported on a 5-point scale: 2 Normal 3 Exaggerated reflex, with spread to contiguous areas quadriceps response) 4 Clonus (self-limited or sustained)These reflexes are decreased in lower motor neuron diseases and increased in upper motor neuron disease. Babinski response, or extensor plantar reflex, is an upward movement of the great toeand flaring of the toes on stimulation of the lateral foot and is asign of corticospinal tract dysfunction. This reflex is unreliablein neonates except when asymmetrical because the “normal”response at this age varies. By 12 to 18 months of age, the plantarresponse should consistently be flexor (toes flexing down).


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Pediatrics_Nelson. The sensory examination of newborns and infants is limited to observing the behavioral response to light touch or gentle sterile pinprick. Stimulation of the limb should produce a facial grimace. A spinal reflex alone may produce withdrawal movement of the limb. In a cooperative child, the senses of pain, touch, temperature, vibration, and joint position can be tested individually. The cortical areas of sensation must be intact to identify an object placed in the hand (stereognosis) or a number written in the hand (graphesthesia) or to distinguish between two sharp objects applied simultaneously and closely on the skin (two-point discrimination).


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Pediatrics_Nelson. Analysis of cerebrospinal fluid (CSF) is essential when central nervous system (CNS) infection is suspected and provides important clues to other diagnoses (Table 179-2). Differentiating hemorrhagic CSF caused by a traumatic lumbar puncture (LP) from a true subarachnoid hemorrhage may be difficult. In most cases of traumatic LP, the fluid clears significantly as the sequence of tubes is collected. If there is clinical evidence of increased ICP (papilledema, depression of consciousness, focal neurologic deficits), caution must be exercised before performing an LP to limit risk of cerebral herniation. A computed tomography (CT) scan should be performed and confirmed to be normal before the LP if increased ICP is suspected. If increased ICP is present, it must be treated before an LP is performed. Brain or parameningeal abscess Parasitic infection Leak of dermoid contents


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Pediatrics_Nelson. Brain or parameningeal abscess Parasitic infection Leak of dermoid contents Increased CSF protein Infection Guillain-Barré syndrome Inflammatory disease (ADEM, multiple sclerosis) Leukodystrophy Venous thrombosis Hypertension Spinal block (Froin syndrome) Carcinomatous meningitis Bloody CSF Subarachnoid hemorrhage Subdural hemorrhage Intraparenchymal hemorrhage Hemorrhagic meningoencephalitis (group B streptococci, HSV) CNS trauma Vascular malformation Coagulopathy Traumatic lumbar puncture ADEM, Acute disseminated encephalomyelitis; CNS, central nervous system; HSV, herpes simplex virus. *In normal children, cells present should be lymphocytes.


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Pediatrics_Nelson. The electroencephalogram (EEG) records electrical activity generated by the cerebral cortex. EEG rhythms mature throughout childhood. There are three key features present: background patterns, behavioral state modulation, and presence or absence of epileptiform patterns. The background varies with age, but there should be general symmetry and synchrony between the background of the two hemispheres without any localized area of higher amplitude or slower frequencies (focal slowing). Fixed slow wave foci (1 to 3 Hz) delta rhythms suggest an underlying structural abnormality (brain tumor, abscess, stroke). Bilateral disturbances of brain activity (increased ICP, metabolic encephalopathy) must be suspected when there is diffuse slow wave activity (delta frequency). Spikes, polyspikes, and spike-and-wave abnormalities, either in a localized region (focal) or distributed bihemispherically (generalized), indicate an underlying seizure tendency.


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Pediatrics_Nelson. Electromyography and nerve conduction velocities (NCVs) assess for abnormalities of the neuromuscular apparatus, including anterior horn cells, peripheral nerves, neuromuscular junctions, and muscles. Normal muscle is electrically silent at rest. Spontaneous discharge of motor fibers (fibrillations)or groups of muscle fibers (fasciculation) indicates denervation, revealing dysfunction of anterior horn cells or peripheral nerves. Abnormal muscle responses to repetitive nerve stimulation are seen with neuromuscular junction disorders, such as myasthenia gravis and botulism. The amplitude and duration of the muscle compound action potentials are decreased in primary diseases of muscle. NCVs assess the action potential transmission along peripheral nerves. NCVs are slowed in demyelinating neuropathies (Guillain-Barré syndrome). The amplitude of the signal is diminished in axonal neuropathies.


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Pediatrics_Nelson. Imaging the brain and spinal cord is accomplished using CT or magnetic resonance imaging (MRI). CT is quick and accessible for emergency purposes. MRI provides fine detail and, with different sequences, permits detection of posterior fossa lesions, subtle cerebral abnormalities, vascular anomalies, low-grade tumors, and ischemic changes. For a child with a head injury or sudden headache, cranial CT is the study of choice because it can rapidly reveal intracranial hemorrhage or other large lesions. For a child with new-onset complex partial seizures, MRI is the study of choice, because an area of focal cortical dysplasia or other subtle lesions might not be apparent on CT. MRI also provides excellent views of the spinal cord. Cranial ultrasonography is a noninvasive bedside procedure used to visualize the brain and ventricles of infants and young children with open fontanelles.


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Pediatrics_Nelson. Headache is a common symptom among children and adolescents. Headaches can be a primary problem (migraines, tension-type headaches) or secondary to another condition. Secondary headaches are most often associated with minor illnesses such as viral upper respiratory infections or sinusitis, but may be the first symptom of serious conditions (meningitis, brain tumors), so a systematic approach is necessary. Available @ StudentConsult.com The temporal pattern of the headache must be clarified. Each pattern (acute, recurrent-episodic, chronic-progressive, chronic-nonprogressive) has its own differential diagnosis (Table 180-1).


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Pediatrics_Nelson. The temporal pattern of the headache must be clarified. Each pattern (acute, recurrent-episodic, chronic-progressive, chronic-nonprogressive) has its own differential diagnosis (Table 180-1). Tension-type headaches are the most common recurrent pattern of primary headaches in children and adolescents. They are generally mild and lack associated symptoms, so are not typically disruptive to patients’ lifestyle or activities. The pain is global and squeezing or pressing in character, but can last for hours or days. There is no associated nausea, vomiting, phonophobia, or photophobia. Headaches can be related to environmental stresses or symptomatic of underlying psychiatric illnesses, such as anxiety or depression.


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Pediatrics_Nelson. Migraine headaches are another common type of recurrent headaches and frequently begin in childhood. Headaches are stereotyped attacks of frontal, bitemporal, or unilateral, moderate to severe, pounding or throbbing pain that are aggravated by activity and last 1 to 72 hours. Associated symptoms include nausea, vomiting, pallor, photophobia, phonophobia, and an intense desire to seek a quiet dark room for rest. Toddlers may be unable to verbalize the source of their discomfort and exhibit episodes of irritability, sleepiness, pallor, and vomiting. Migraines can be associated with auras that may be typical (visual, sensory, dysphagic) or atypical. Aura can precede or coincide with the headache and typically persists for 15 to 30 minutes. Visual auras consist of spots, flashes, or lines of light that flicker in one or both visual fields. Atypical auras may also consist of brief episodes of unilateral or perioral


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Pediatrics_Nelson. Acute: Single episode of pain without a history of such episodes. The “first and worst” headache, which raises concerns for aneurysmal subarachnoid hemorrhage in adults, is commonly due to febrile illness related to upper respiratory tract infection in children. Regardless, more ominous causes of acute headache (hemorrhage, meningitis, tumor) must be considered. Acute recurrent: Pattern of attacks of pain separated by symptom-free intervals. Primary headache syndromes, such as migraine or tension-type headache, usually cause this pattern. Infrequently recurrent headaches can sometimes also be attributed to certain epilepsy syndromes (benign occipital epilepsy), substance abuse, or recurrent trauma.


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Pediatrics_Nelson. Chronic progressive: Most ominous of the temporal patterns— implies a gradually increasing frequency and severity of headache. The pathologic correlate is increasing ICP. Causes of this pattern include pseudotumor cerebri, brain tumor, hydrocephalus, chronic meningitis, brain abscess, and subdural collections. Chronic nonprogressive or chronic daily: Pattern of frequent or constant headache. Chronic daily headache generally is defined as >4-month history of >15 headaches/month, with headaches lasting >4 hours. Affected patients have normal neurologic examinations; psychological factors and anxiety about possible underlying organic causes are common.


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Pediatrics_Nelson. numbness, unilateral weakness, or vertigo that persist for hours, then resolve completely. Complex, atypical symptoms (e.g., hemiparesis, monocular blindness, ophthalmoplegia, or confusion), accompanied by a headache, warrant careful diagnostic investigation, including a combination of neuroimaging, electroencephalogram, and appropriate metabolic studies.


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Pediatrics_Nelson. Common causes of secondary headaches include head trauma, intercurrent viral illness, and sinusitis. Medication overuse headaches may complicate primary and secondary headaches. Serious causes of secondary headache include increasedintracranial pressure (ICP) caused by a mass (tumor, vascularmalformation) or intrinsic increase in pressure (pseudotumorcerebri). Increased ICP should be suspected if the headacheand associated vomiting are worse when lying down or on firstawakening; awaken the child from sleep; remit on arising; or areexacerbated by coughing, Valsalva maneuver, or bending over.Papilledema (Figure 180-1) or focal neurological deficits such ascranial nerve VI palsy may be seen on examination.


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Pediatrics_Nelson. For most children, a thorough history and physical examination provide an accurate diagnosis and obviate the need for further testing. Neuroimaging is usually not necessary. Imaging is warranted, however, when the neurologic examination is abnormal, there are unusual neurologic features during the headache, or the child has signs or symptoms of increased ICP. Focal neurological deficits, alteration of consciousness, or a chronic progressive headache pattern may warrant imaging. In these cases, brain magnetic resonance imaging, with and without gadolinium contrast, is the study of choice, providing the highest sensitivity for detecting posterior fossa lesions and other, more subtle abnormalities. When the headache has a sudden, severe onset, emergent computed tomography (CT) can quickly evaluate for intracranial bleeding. If the CT is negative, a lumbar puncture should be performed, with measurement of opening pressure and evaluation for red and white blood cells, protein, glucose, or


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Pediatrics_Nelson. for intracranial bleeding. If the CT is negative, a lumbar puncture should be performed, with measurement of opening pressure and evaluation for red and white blood cells, protein, glucose, or xanthochromia.


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Pediatrics_Nelson. Figure 180-1 Papilledema with dilation of the vessels, obliteration of the optic cup, loss of disc margin, and hemorrhages around disc. (From Kliegman RE, Behrman, RM, Jenson HB, editors: Nelson Text-book of Pediatrics, ed 18, Philadelphia, 2007, Saunders, p 2107.)


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Pediatrics_Nelson. Treating migraines requires an individually tailored regimen to address the frequency, severity, and disability produced by the headache. Intermittent symptomatic, or abortive, analgesics are the mainstay for treatment of infrequent, intense episodes of migraine. Symptomatic therapy requires early administration of an analgesic, rest, and sleep in a quiet, dark room. Acetaminophen or a nonsteroidal anti-inflammatory drug such as ibuprofen or naproxen sodium is often effective. Hydration and antiemetics are also useful adjunctive therapies. If these first-line medications are insufficient, triptan agents may be considered. Triptans, available in injectable, nasal spray, oral disintegrating, and tablet form, are serotonin receptor agonists that may alleviate migraine symptoms promptly. Triptans are contraindicated for patients with focal neurological deficits associated with their migraines or signs consistent with basilar migraine (syncope) because of the risk of stroke.


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Pediatrics_Nelson. Many children suffer with severe and frequent migraines that disrupt their daily lives. Children with more than one disabling headache per week may require daily preventive agents to reduce both attack frequency and severity. Preventative medications include tricyclic antidepressants (amitriptyline, nortriptyline), anticonvulsants (topiramate, valproic acid),antihistamines (cyproheptadine), beta-blockers (propranolol), and calcium channel blockers (flunarizine, verapamil). Before initiating daily medications, lifestyle modifications must be put into place to regulate sleep, daily routines, and exercise and identify any precipitating or aggravating influences, eliminating as many as possible (caffeine, certain foods, stress, missed meals, dehydration). Other adjunctive treatment options include psychological support, counseling, stress management, and biofeedback.


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Pediatrics_Nelson. A seizure is a transient occurrence of signs or symptoms resulting from abnormal excessive or synchronous neuronal activity in the brain. Available @ StudentConsult.com Migraine and variants Paroxysmal torticollis of infancy Paroxysmal vertigo (benign) Syncope Vasovagal syncope Breath-holding spells Cardiac syncope (arrhythmias, long QT syndrome) Apnea Metabolic disorders Hypoglycemia Inborn errors of metabolism Sleep disorders Narcolepsy, cataplexy Night terrors The differential diagnosis of paroxysmal disorders includes seizures and nonepileptic events (Table 181-1). Nonseizure paroxysmal events are often normal or benign phenomena, although some are clinically significant and consequential. A thorough medical history from the patient and primary witnesses is the most reliable tool for establishing the correct diagnosis.


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Pediatrics_Nelson. Acute symptomatic seizures are secondary to an acute problem affecting brain excitability, such as electrolyte imbalance or infection (Table 181-2). Epilepsy is defined as recurrent, unprovoked seizures. Epileptic seizures are generally classified as focal (or partial), arising from one region of the cortex, or generalized seizures, which arise from both hemispheres, simultaneously (Table 181-3). Approximately 4% to 10% of children experience at least one seizure. The incidence of childhood epilepsy is 1% to 2%. Simple focal (or partial) seizures arise from a specific anatomic focus and may or may not spread to surrounding brain regions. Clinical symptoms include motor (tonic, clonic, myoclonic), sensory, psychic, or autonomic abnormalities, but consciousness is preserved. The location and direction of spread of the seizure focus determine the clinical symptoms.


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Pediatrics_Nelson. Complex partial seizures can have similar sensorimotor signsbut also have associated alteration of consciousness. Althoughthe child may not be completely unresponsive, subtle slowing or alteration of mental status (dyscognitive features) may occur.Along with altered responsiveness, patients may have staring Malformation of cortical development Intrauterine infection Hypoxic-ischemic encephalopathy* Trauma Hemorrhage* METABOLIC CONDITIONS Hypoglycemia* GENERALIZED SEIZURES Absence (staring, unresponsiveness) *Common. Simple partial (consciousness not impaired) Motor signs (can be tonic, clonic, myoclonic) Special sensory (visual, auditory, olfactory, gustatory, vertiginous, somatosensory) Autonomic Complex partial/focal dyscognitive (consciousness impaired) Psychic (déjà vu, fear) Impaired consciousness at onset Development of impaired consciousness Focal seizures with secondarily generalized convulsions Jacksonian seizures


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Pediatrics_Nelson. Focal seizures with secondarily generalized convulsions Jacksonian seizures Tonic (sustained contraction) Clonic (rhythmic contractions) Tonic-clonic (tonic phase followed by clonic phase) Atonic (loss of tone) Myoclonic (rapid, shock-like contraction) Spasms (flexion or extension of trunk and extremities for <2 Underlying cause is identified Example: Focal epilepsy associated with a remote stroke Idiopathic Presumed to have a genetic etiology Example: Benign childhood epilepsy with centrotemporal spikes, childhood absence epilepsy, juvenile myoclonic epilepsy Cryptogenic Epilepsy of uncertain etiology


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Pediatrics_Nelson. Epilepsy of uncertain etiology Example: Infantile spasms with no identifiable cause and automatisms during complex partial seizures. Automatisms are automatic semipurposeful movements of the mouth (lip smacking, chewing) or extremities (rubbing of fingers, shuffling of feet). Focal seizures that manifest only with psychic or autonomic symptoms, such as a feeling of déjà vu during a temporal lobe seizure, can be difficult to recognize. When focal seizures spread to involve the whole brain and produce a generalized seizure, they are said to have secondarily generalized. Such spread is classically described as progression from face to arm to leg (Jacksonian march). It is often difficult to distinguish primary generalized tonic and clonic seizures from secondarily generalized focal seizures on purely clinical grounds. This distinction is important, however, because evaluation and treatment for focal or generalized epilepsy syndromes are quite different.


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Pediatrics_Nelson. Tonic, clonic, and biphasic tonic-clonic seizures may occur alone or in association with other seizure types. Typically the seizure begins abruptly but occasionally is preceded by a series of myoclonic jerks. During a tonic-clonic seizure, consciousness and control of posture are lost, followed by tonic stiffening and upward deviation of the eyes. Pooling of secretions, Provoking Hyperventilation Variable, but often none maneuver Photic stimulation Postictal phase None (return Confusion, sleepiness immediately to baseline) Number of Many per day Infrequent (rarely more seizures EEG features Interictal: normal Interictal: focal slowing or Ictal: 3-Hz sharp waves generalized spike-Ictal: Focal discharges wave (with or without secondary Neurological Normal Normal, or focal deficits examination


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Pediatrics_Nelson. Neurological Normal Normal, or focal deficits examination Neuroimaging Normal* Normal, or focal abnormalities (mesial temporal sclerosis, focal cortical dysplasia, neoplasm, encephalomalacia) *In the proper clinical context, and with an appropriate EEG, a diagnosis of absence epilepsy should be made without neuroimaging. †Oxcarbazepine and carbamazepine are relatively contraindicated for children with typical absence epilepsy, as their seizures can be exacerbated by these medications. pupillary dilation, diaphoresis, and hypertension are common. Clonic jerks follow the tonic phase. In the post-ictal phase, the child might be hypotonic. Irritability and headache are common as the child awakens.


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Pediatrics_Nelson. Seizures in which the primary clinical feature is staring can beeither absence (generalized) or complex partial seizures. Theclinical hallmark of absence seizures is a brief (less than 15 seconds) loss of environmental awareness accompanied by eye fluttering or simple automatisms, such as fumbling with the fingersand lip smacking. Absence seizures usually begin between 4and 6 years of age. Neurologic examination and brain imagingare normal. The characteristic electroencephalographic (EEG)patterns consist of generalized 3-Hz spike-and-wave activity. A clinical seizure can be provoked by hyperventilation or strobe light stimulation. Differentiating absence from complexpartial seizures can be difficult, but is essential for appropriateevaluation and treatment (Table 181-4). Atypical Absence, Myoclonic, and Atonic Seizures


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Pediatrics_Nelson. Atypical absence seizures manifest as episodes of impaired consciousness with automatisms, autonomic phenomena, and motor manifestations, such as eye opening, eye deviation, and body stiffening. They are associated with slower EEG discharges (2 Hz) and other seizure types. Myoclonus is a sudden jerk of all or part of the body; not all myoclonus is epileptic in nature. Nonepileptic myoclonus may be benign, as in sleep myoclonus, or indicate serious disease. Myoclonic epilepsy usually is associated with multiple seizure types. The underlying disorder producing myoclonic epilepsy may be static (juvenile myoclonic epilepsy) or progressive and associated with neurologic deterioration (neuronal ceroid lipofuscinosis). Myoclonic absence refers to the body jerks that commonly accompany absence seizures and atypical absence seizures. Although atonic seizures are typically brief (lasting 1 to 2 seconds), they are quite disabling because of a sudden loss of postural tone, resulting in falls and