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Pediatrics_Nelson. Imaging studies such as abdominal CT and serial physical examinations are the primary methods of obtaining information on which to base decisions regarding operative intervention. Abdominal wall bruising is an important physical examination finding and is associated with significant intra-abdominal injury in more than 10% of patients. Operative intervention may be required in patients whose vital signs are persistently unstable in the face of aggressive fluid resuscitation, even in the absence of extravascular volume loss or an enlarging abdomen. The presence of peritoneal irritation or abdominal wall discoloration, together with signs of intravascular volume loss, indicates the need for laparotomy. Most blunt solid organ injury is handled nonoperatively. Clinical observation is important, because most failures with nonoperative management occur in the first 12 hours. Injury to the Spleen


Pediatrics_Nelson

Pediatrics_Nelson. Most blunt solid organ injury is handled nonoperatively. Clinical observation is important, because most failures with nonoperative management occur in the first 12 hours. Injury to the Spleen The most frequently injured abdominal organ in children is the spleen. Suspicion of a splenic injury should be heightened if there are left upper quadrant abrasions or tenderness. A positive Kehr sign (pressure on the left upper quadrant eliciting left shoulder pain) is due to diaphragmatic irritation by the ruptured spleen and strongly suggests splenic injury. CT scans are used to identify and grade splenic injury. Nonoperative management is the treatment of choice formost serious splenic injuries, unless there is continued largeblood loss or hemodynamic instability. If a splenectomy isperformed, patients should receive penicillin prophylaxis andshould receive pneumococcal and Haemophilus influenzaevaccines to decrease the increased risk of overwhelming sepsis.


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Pediatrics_Nelson. Major trauma to the liver is a serious cause of morbidity. Severe hemorrhage is more common in patients with liver injury than with other abdominal injuries because of its dual blood supply. Without significant vascular injury, hepatic injury presents and behaves clinically like a splenic injury. Nonoperative management is recommended but requires close clinical observation for signs of ongoing blood loss or hemodynamic instability. As with splenic injury, there is a grading system based on the pattern of injury.


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Pediatrics_Nelson. The kidney is less frequently injured than the liver or spleen, and when injured is often associated with other injuries. A young child’s kidney is more vulnerable to trauma than an adult’s because of a more compliant rib cage and relatively immature abdominal muscle development. The diagnosis of renal injury is based on history and physical examination coupled with urinalysis showing blood and increased protein levels. An ultrasound or CT may also be useful. Low-grade renal injury is usually managed conservatively, with bed rest, catheter drainage, and monitoring for resolution of injury by ultrasound or CT. Surgery may be required for falling hemoglobin levels, refractory shock, or urinary obstruction caused by clots.


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Pediatrics_Nelson. Injuries of the pancreas are less common in children than inadults but are seen in bicycle handlebar injuries, motor vehicle crashes, and nonaccidental trauma. The diagnosis is difficult unless there is obvious injury to overlying structures,such as the stomach or duodenum. Diffuse abdominal tenderness, pain, and vomiting may be accompanied by elevations of amylase and lipase but may not occur until severaldays after the injury. Hemodynamic instability secondaryto retroperitoneal hemorrhage may be the presenting sign.Nasogastric suction and parenteral nutrition are indicatedin the management of these patients. Nonoperative management is appropriate for contusions, but surgical interventionmay be required in patients with distal transection. Drainage of pseudocysts, in patients who develop them, may berequired if they are unresponsive to bowel rest and parenteralnutrition.


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Pediatrics_Nelson. Injury to the intestine occurs less frequently than injury to solid intra-abdominal organs and varies with the amount of intestinal contents. A full bowel is likely to shear more easily than an empty bowel. Shearing occurs at points of fixation (the ligament of Treitz, the ileocecal valve, and the ascending and descending peritoneal reflections). Pneumoperitoneum should prompt surgical exploration. Serial physical examinations are useful when the clinical picture is uncertain. Duodenal hematoma can occur in the absence of perforation. Duodenal hematomas result from blunt injury to the abdomen, and affected patients often present with persistent pain and bilious emesis. Most hematomas respond to nonoperative management with gastric decompression and parenteral nutrition.


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Pediatrics_Nelson. Patients requiring hospitalization for multiple trauma are at risk for a variety of complications based on the type and severity of injury. Sepsis and multiple organ failure may occur in children with multiple trauma. Delays in enteral nutrition because of an ileus may further increase the risk of sepsis secondary to translocation of bacteria across the intestinal mucosa. Renal failure secondary to myoglobinuria may be seen in children who sustain crushing or electrical injuries and burns. Deep venous thrombosis is less common in the pediatric population, but prophylaxis for children who will be immobilized because of injury is often provided. Unintentional injury is the leading cause of death for children ages 1 to 18; however, many of these deaths occur in the field, immediately after the injury. Once admitted to the hospital, mortality rates are much lower. Morbidities are numerous and include hypoxic-ischemic brain injury, loss of limbs, and psychological dysfunction.


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Pediatrics_Nelson. SEE CHAPTER 41. Drowning, as defined by the World Congress on Drowning in 2002, is the process of experiencing respiratory impairment from submersion/immersion in liquid. Drowning can further be categorized as fatal or nonfatal, but other terms such as near-drowning, secondary drowning, or dry drowning should be abandoned. Initially, submersion or immersion results in aspiration of small amounts of fluid into the larynx, triggering breath holding or laryngospasm. In many cases, the laryngospasm resolves, and larger volumes of water or gastric contents are aspirated into the lungs, destroying surfactant and causing alveolitis and dysfunction of the alveolar-capillary gas exchange. The resulting hypoxemia leads to hypoxic brain injury that is exacerbated by ischemic injury after circulatory collapse.


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Pediatrics_Nelson. Drowning deaths overall have decreased over the past decade; however, drowning is still a significant cause of morbidity and mortality. In 2010, drowning was the leading cause of injury death for children 1 to 4 years of age and the second leading cause of injury death for children 1 to 18 years of age. Boys are four times more likely than girls to drown. The most common location of drowning varies by age, with drowning in natural bodies of water becoming more frequent in older age groups.


Pediatrics_Nelson

Pediatrics_Nelson. Hypoxemia is the result of laryngospasm and aspiration during drowning. Victims may also develop respiratory distress secondary to pulmonary endothelial injury, increased capillary permeability, and destruction of surfactant. Clinical manifestations include tachypnea, tachycardia, increased work of breathing, and decreased breath sounds with or without crackles. The hypoxic-ischemic injury that may occur can lead to depressed myocardial function resulting in tachycardia, impaired perfusion, and potentially cardiovascular collapse. After resuscitation, acute respiratory distress syndrome is common. Altered mental status may be present and requires frequent monitoring of neurologic status. Following submersion in cold water, hypothermia may result in relative bradycardia and hypotension and place the child at risk for cardiac dysrhythmias.


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Pediatrics_Nelson. After resuscitation, arterial blood gas measurement assists in assessing pulmonary gas exchange. A chemistry profile may reveal elevated liver enzymes if hypoxemia and ischemia were of long duration and provide baseline renal functions. Electrolytes are often obtained, although alterations of serum electrolytes are minimal, even in freshwater drowning.


Pediatrics_Nelson

Pediatrics_Nelson. Resuscitation of a drowning victim includes the basic ABCs (see Chapter 38). Victims of unwitnessed drowning require stabilization of the cervical spine because of the possibility of a fall or diving injury. Optimizing oxygenation and maintaining cerebral perfusion are two of the major foci of treatment. Rewarming the hypothermic patient requires careful attention to detail, including acid-base and cardiac status. Further treatment is based on the patient response to initial resuscitation. Some children begin breathing spontaneously and awaken before arrival at an emergency department. If the episode was significant, these children still require careful observation for pulmonary complications over the subsequent 6 to 12 hours. Children who have evidence of lung injury, cardiovascular compromise, or neurologic compromise should be monitored in an intensive care unit. Pulmonary dysfunction often results in hypoxemia. Oxygen supplementation should be implemented to maintain normal oxygen


Pediatrics_Nelson

Pediatrics_Nelson. or neurologic compromise should be monitored in an intensive care unit. Pulmonary dysfunction often results in hypoxemia. Oxygen supplementation should be implemented to maintain normal oxygen saturations. Mechanical ventilation may be needed in patients with significant pulmonary or neurologic dysfunction. Cardiovascular compromise is often the result of impaired contractility because of hypoxic-ischemic injury. The use of intracranial pressure monitoring devices and medical management with hypothermia and sedation is controversial and has not been shown to improve outcomes. Prophylactic antibiotics have not been shown to be beneficial and may increase the selection of resistant organisms.


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Pediatrics_Nelson. The outcome of drowning is determined by the successof immediate resuscitation efforts and the severity of thehypoxic-ischemic injury to the brain. Patients who have regained consciousness on arrival to the hospital will likelysurvive with intact neurologic function. Unfavorable prognostic markers include the need for CPR for more than 25 minutes, continued CPR at the hospital, Glasgow Coma Scaleof 5 or less, fixed and dilated pupils, seizures, and coma formore than 72 hours. Despite the decreased incidence of drowning since the 1990s, few prevention strategies have been shown to be effective. Exceptions include implementation of mandatory four-sided fencing around pools (decreasing the number of children <5 years of age who drown) and immediate provision of CPR to children who drown. The use of safety flotation devices in older children during water sport activities may be beneficial. Enhanced supervision is required to reduce the incidence of infants drowning in bathtubs.


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Pediatrics_Nelson. The pathophysiology of burn injury is caused by disruption of the three key functions of the skin: regulation of heat loss, preservation of body fluids, and barrier to infection. Burn injury releases inflammatory and vasoactive mediators resulting in increased capillary permeability, decreased plasma volume, and decreased cardiac output. The body then becomes hypermetabolic with increased resting energy expenditure and protein catabolism. This hypermetabolic state may continue for up to a year after injury. Burns usually are classified on the basis of four criteria: 1. Depth of injury 2. Percent of body surface area involved 3. Location of the burn 4. Association with other injuries


Pediatrics_Nelson

Pediatrics_Nelson. Burns usually are classified on the basis of four criteria: 1. Depth of injury 2. Percent of body surface area involved 3. Location of the burn 4. Association with other injuries More than 100,000 children sustain a burn injury each year. Burns are the third leading cause of injury-related death for children ages 1 to 9 and are a major cause of morbidity. Boys are more likely to sustain a burn injury, as are children age 6 and under. Scald burns are more common in younger children as compared to older children. Overall, thermal burns secondary to scald or flame are much more common than electrical or chemical burns. Most fire-related childhood deaths and injuries occur in homes.


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Pediatrics_Nelson. The depth of injury should be assessed by the clinicalappearance. Categories of first-degree, second-degree, andthird-degree are commonly used; however, classification bydepth (superficial, superficial partial-thickness, deep partial-thickness, and full-thickness) conveys more information aboutthe structures injured and the likely need for surgical treatmentand may be more clinically useful. Superficial (first-degree) burns are red, painful, anddry. Commonly seen with sun exposure or mild scald injuries, these burns involve injury to the epidermis only. Theyheal in 2 to 5 days without scarring and are not included inburn surface area calculations. Superficial partial-thickness (second-degree) burns involve the entire epidermis andsuperficial dermis. These burns have fluid-containing blisters. 2 of head 91 2 of one thigh 23 2 of one lower leg 21


Pediatrics_Nelson

Pediatrics_Nelson. 2 of head 91 2 of one thigh 23 2 of one lower leg 21 Figure 44-1 This chart of body areas, together with the table inserted in the figure showing the percentage of surface area of head and legs at various ages, can be used to estimate the surface area burned in a child. From Solomon JR: Pediatric burns, Crit Care Clin 1:159–174, 1985.


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Pediatrics_Nelson. After debridement the underlying dermis will appear erythematous and wet, will be painful, and will blanch underpressure. Healing is dependent on the uninjured dermis andusually occurs within about 2 weeks without the need forskin grafting and without scarring. Deep partial-thickness(also second-degree) burns involve the entire epidermis anddeeper portions of the dermis. These burns may also haveblistering, but the dermal base is less blanching, mottled pinkor white, and less painful than superficial partial-thicknessburns. They behave more like full-thickness burns and willoften require excision and grafting. Full-thickness (third-degree and fourth-degree) burns involve all skin layers. Theyappear dry, white, dark red, brown, or black in color. Theydo not blanch and are usually insensate. Full-thickness burnsrequire surgical management. Fourth-degree burns involveunderlying fascia, muscle, or bone and may require reconstruction in addition to grafting. Inhalation injuries should be


Pediatrics_Nelson

Pediatrics_Nelson. Full-thickness burnsrequire surgical management. Fourth-degree burns involveunderlying fascia, muscle, or bone and may require reconstruction in addition to grafting. Inhalation injuries should be suspected if there are facial burns, singed nasal hairs, orcarbonaceous sputum. Hoarseness on vocalization also isconsistent with a supraglottic injury. Inhalation injuries mayresult in bronchospasm, airway inflammation, and impairedpulmonary function.


Pediatrics_Nelson

Pediatrics_Nelson. There are multiple methods and charts available for calculating the percentage of skin surface involved in a burn.One method that may be used for children of various agesis presented in Figure 44-1. The extent of skin involvement of older adolescent and adult patients may be estimated as follows: each upper extremity, 9%; each lower extremity, 18%;anterior trunk, 18%; posterior trunk, 18%; head, 9%; andperineum, 1%. The location of the burn is important in assessing the risk of disability. The risk is greatest when the face, eyes, ears, feet, perineum, or hands are involved. Inhalation injuries not only cause respiratory compromise but also may result in difficulty in eating and drinking.


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Pediatrics_Nelson. Initial laboratory testing, including complete blood count, type and crossmatch for blood, coagulation studies, basic chemistry profile, arterial blood gas, and chest radiograph, can be helpful for patients with major burns. A carboxyhemoglobin assessment should be performed for any suspected inhalation exposure (a house or closed-space fire or a burn victim who requires cardiopulmonary resuscitation). Cyanide levels should be considered in children who sustain smoke inhalation and have altered mental status. Unusual patterns of burns may increase suspicion of child abuse and result in appropriate evaluation to assess for nonaccidental trauma to the skeleton or central nervous system.


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Pediatrics_Nelson. For severe burns, care is best managed by a multidisciplinary team in a qualified burn center. The American Burn Association criteria for patients who should be transferred to a burn center are: partial and full-thickness burns greater than 10% total body surface area (TBSA) in patients less than 10 years old or more than 50 years old, or greater than 20% TBSA in other age groups; partial and full-thickness burns involving the face, hands, feet, genitalia, perineum, or major joints; electrical burns; chemical burns; inhalation injury; burn injury in patients with preexisting medical conditions that could complicate management, prolong recovery, or increase mortality rate; any burn with concomitant trauma in which the burn injury poses the greatest risk; burn injury in children admitted to hospitals without qualified personnel or equipment for pediatric care; burn injury in patients requiring special social, emotional, or rehabilitative support, including child abuse cases.


Pediatrics_Nelson

Pediatrics_Nelson. Initial treatment should follow the ABCs of resuscitation. Airway management should include assessment for the presence of airway or inhalation injury, with early intubation if such an injury is suspected. Smoke inhalation may be associated with carbon monoxide toxicity; 100% humidified oxygen should be given if hypoxia or inhalation is suspected.


Pediatrics_Nelson

Pediatrics_Nelson. The systemic capillary leak that occurs after a serious burn makes initial fluid and electrolyte support of a burned child crucial. The first priority is to support the circulating blood volume, which requires the administration of intravenous fluids to provide maintenance fluid and electrolyte requirements and to replace ongoing burn-related losses. Formulas exist to help guide fluid management; however, no formula accurately predicts the fluid needs of every burn patient. Children with a significant burn should receive a rapid bolus of 20 mL/kg of lactated Ringer solution. Thereafter, the resuscitation formula for fluid therapy is determined by the percent of body surface burned. Total fluids are 2 to 4 mL/kg/percent burn/24 hours, with half the estimated burn requirement administered during the first 8 hours. (If resuscitation is delayed, half of the fluid replacement should be completed by the end of the eighth hour post-injury.) Fluids should be titrated to achieve adequate


Pediatrics_Nelson

Pediatrics_Nelson. during the first 8 hours. (If resuscitation is delayed, half of the fluid replacement should be completed by the end of the eighth hour post-injury.) Fluids should be titrated to achieve adequate perfusion, one marker of which is urine output greater than 1 mL/kg/hour. Controversy exists over whether and when to administer colloid during fluid resuscitation. Colloid therapy may be needed for patients with extensive burns.


Pediatrics_Nelson

Pediatrics_Nelson. Because burn injury produces a hypermetabolic response, children with significant burns require immediate nutritional support. Enteral feeds should be started early unless there is a specific contraindication. Children with critical burn injury may require parenteral nutrition if unable to tolerate full enteral feeds. Consider supplementation of vitamins and trace elements. Factors that may modify the hypermetabolic state such as beta blockers, androgenic steroids, and others are being investigated.


Pediatrics_Nelson

Pediatrics_Nelson. Wound care starts with cleaning and debriding the wound. Effective pain control is important to allow for complete debridement. Topical agents and dressings are then applied to control bacterial colonization, decrease evaporative losses, and aid in pain control. Commonly used topical agents include silver sulfadiazine (Silvadene) or, if the burn is shallow, polymyxin B/bacitracin/neomycin (Neosporin) ointment. Silver nitrate and mafenide acetate (Sulfamylon) are alternative antimicrobial agents. Sulfamylon has the benefit of penetrating eschar, but it is painful and can cause metabolic acidosis. Silver nitrate is used less commonly because of poor tissue penetration and potential for electrolyte abnormalities. These agents Monitor for infection, avoid prophylactic antibiotics Hypovolemia Fluid replacement Hypothermia Adjust ambient temperature: dry blankets in field Laryngeal edema Endotracheal intubation, tracheostomy Carbon monoxide 100% oxygen, hyperbaric oxygen poisoning


Pediatrics_Nelson

Pediatrics_Nelson. Laryngeal edema Endotracheal intubation, tracheostomy Carbon monoxide 100% oxygen, hyperbaric oxygen poisoning Cyanide poisoning 100% O2 plus amyl nitrate, sodium nitrate, and sodium thiosulfate Cardiac dysfunction Inotropic agents, diuretics Gastric ulcers H2-receptor antagonist, antacids Compartment syndrome Escharotomy incision Contractures Physical therapy Hypermetabolic state Enteral and parenteral nutritional support Renal failure Supportive care, dialysis Transient antidiuresis Expectant management Anemia Transfusions as indicated Psychological trauma Psychological rehabilitation Pulmonary infiltrates PEEP, ventilation, oxygen Pulmonary edema Avoid overhydration, give diuretics Pneumonia Antibiotics Bronchospasm β-Agonist aerosols PEEP, Positive end-expiratory pressure.


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Pediatrics_Nelson. PEEP, Positive end-expiratory pressure. inhibit but do not prevent bacterial growth. Various grafts, such as cadaver allografts, porcine xenografts, or skin substitutes, have been used initially to cover wounds. For full-thickness burns, skin autografting and skin substitutes are required for eventual closure. SEE TABLE 44-1. Most children who sustain burns recover without significant disability; however, burns remain the third leading cause of injury-related deaths in children ages 1 to 9. Estimation of morbidity is difficult to ascertain from databases. Physical scarring and emotional impact of disfiguring burns are longterm consequences of burn injuries.


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Pediatrics_Nelson. About 92% of burns occur in the home. Prevention is possible by using smoke and fire alarms, having identifiable escape routes and a fire extinguisher, and reducing hot water temperature to 49°C (120°F). Immersion full-thickness burns develop after 1 second at 70°C (158°F), after 5 seconds at 60°C (140°F), after 30 seconds at 54.5°C (130°F), and after 10 minutes at 49°C (120°F). The most common agents ingested by young children include cosmetics, personal care products, analgesics, and cleaning solutions. Fatal childhood poisonings are commonly caused by analgesics, antihistamines, sedative/hypnotics, and fumes/ gases/vapors.


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Pediatrics_Nelson. More than 2 million human exposures are called in to poison control centers in the United States each year. More than half of all exposures are in children (63% in 2010) with a male predominance in children under 13, but a female predominance in adolescence. Most ingestions in young children are unintentional, with intentional ingestions becoming more common in children 13 and older. Most ingestions occur at home (91%) and are single substance (90%).


Pediatrics_Nelson

Pediatrics_Nelson. Any child who presents with unexplained symptoms including altered mental status, seizure, cardiovascular compromise, or metabolic abnormality should be considered to have ingested a poison until proven otherwise. A history and physical examination by someone who understands the signs and symptoms of various ingestions often provide sufficient clues to distinguish between toxic ingestion and organic disease (Table 45-1). Determination of all substances that the child was exposed to, type of medication, amount of medication, and time of exposure is crucial in directing interventions. Available data often are incomplete or inaccurate, requiring a careful physical examination and laboratory approach. A complete physical examination, including vital signs, is necessary. Certain complexes of symptoms and signs are relatively specific to a given class of drugs (toxidrome) (Table 45-2).


Pediatrics_Nelson

Pediatrics_Nelson. A poisoned child can exhibit any one of six basic clinical patterns: coma, toxicity, metabolic acidosis, heart rhythm aberrations, gastrointestinal symptoms, and seizures. Coma is perhaps the most striking symptom of a poison ingestion, but it also may be seen as a result of several other causes including trauma, a cerebrovascular accident, asphyxia, or meningitis. A careful history and clinical examination are needed to distinguish among these alternatives. Hydrocarbon ingestion occasionally may result in systemic toxicity, but more often it leads to pulmonary toxicity. Hydrocarbons with low viscosity, low surface tension, and high volatility pose the greatest risk of producing aspiration pneumonia; however, when swallowed, they pose no risk unless emesis is induced. Emesis or lavage should not be initiated in a child who has ingested volatile hydrocarbons.


Pediatrics_Nelson

Pediatrics_Nelson. Caustic ingestions may cause dysphagia, epigastric pain, oral mucosal burns, and low-grade fever. Patients with esophageal lesions may have no oral burns or may have significant signs and symptoms. Treatment depends on the agent ingested and the presence or absence of esophageal injury. Alkali agents may be solid, granular, or liquid. Liquid agents are tasteless and produce full-thickness liquefaction necrosis of the esophagus or oropharynx. When the esophageal lesions heal, strictures form. Ingestion of these agents also creates a long-term risk of esophageal carcinoma. Treatment includes antibiotics if there are signs of infection and dilation of late-forming (2 to 3 weeks later) strictures.


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Pediatrics_Nelson. Ingested button batteries also may produce a caustic mucosal injury. Batteries that remain in the esophagus may cause esophageal burns and erosion and should be removed with an endoscope. Acid agents can injure the lungs (with hydrochloric acid fumes), oral mucosa, esophagus, and stomach. Because acids taste sour, children usually stop drinking the solution, limiting the injury. Acids produce a coagulation necrosis, which limits the chemical from penetrating into deeper layers of the mucosa and damages tissue less severely than alkali. The signs, symptoms, and therapeutic measures are similar to those for alkali ingestion. A poisoned child may also have a high anion gap metabolic acidosis (mnemonic MUDPILES) (Table 45-3), which Table 45-1 Historical and Physical Findings in Poisoning ODOR Bitter almonds Cyanide Acetone Isopropyl alcohol, methanol, paraldehyde, salicylate Garlic Arsenic, thallium, organophosphates, selenium


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Pediatrics_Nelson. Garlic Arsenic, thallium, organophosphates, selenium Miosis Narcotics (except propoxyphene, meperidine, and pentazocine), organophosphates, muscarinic mushrooms, clonidine, phenothiazines, chloral hydrate, barbiturates (late) Mydriasis Atropine, cocaine, amphetamines, antihistamines, cyclic antidepressants, PCP, LSD Nystagmus Phenytoin, barbiturates, ethanol, carbamazepine, PCP, ketamine, dextromethorphan Lacrimation Organophosphates, irritant gas or vapors Poor vision Methanol, botulism, carbon monoxide Needle tracks Heroin, PCP, amphetamine Dry, hot skin Anticholinergic agents, botulism Diaphoresis Organophosphates, muscarinic mushrooms, aspirin, cocaine Alopecia Thallium, arsenic, lead, mercury Erythema Boric acid, mercury, cyanide, anticholinergics ORAL SIGNS Salivation Organophosphates, salicylate, corrosives, strychnine, ketamine Dry mouth Amphetamine, anticholinergics, antihistamine Burns Corrosives, oxalate-containing plants Gum lines Lead, mercury, arsenic


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Pediatrics_Nelson. Dry mouth Amphetamine, anticholinergics, antihistamine Burns Corrosives, oxalate-containing plants Gum lines Lead, mercury, arsenic Dysphagia Corrosives, botulism INTESTINAL SIGNS Diarrhea Antimicrobials, arsenic, iron, boric acid, cholinergics Constipation Lead, narcotics, botulism Hematemesis Corrosives, iron, salicylates, NSAIDs CARDIAC SIGNS Tachycardia Atropine, aspirin, amphetamine, cocaine, cyclic antidepressants, theophylline Bradycardia Digitalis, narcotics, clonidine, organophosphates, β-blockers, calcium channel blockers Hypertension Amphetamine, LSD, cocaine, PCP Hypotension Phenothiazines, barbiturates, cyclic antidepressants, iron, β-blockers, calcium channel blockers, clonidine, narcotics Depressed respiration Alcohol, narcotics, barbiturates Increased respiration Amphetamines, aspirin, ethylene glycol, carbon monoxide, cyanide Pulmonary edema Hydrocarbons, organophosphates CENTRAL NERVOUS SYSTEM SIGNS


Pediatrics_Nelson

Pediatrics_Nelson. Increased respiration Amphetamines, aspirin, ethylene glycol, carbon monoxide, cyanide Pulmonary edema Hydrocarbons, organophosphates CENTRAL NERVOUS SYSTEM SIGNS Ataxia Alcohol, barbiturates, anticholinergics, narcotics Coma Sedatives, narcotics, barbiturates, salicylate, cyanide, carbon monoxide, cyclic antidepressants, alcohol Hyperpyrexia Anticholinergics, salicylates, amphetamine, cocaine Muscle fasciculation Organophosphates, theophylline Muscle rigidity Cyclic antidepressants, PCP, phenothiazines, haloperidol Peripheral neuropathy Lead, arsenic, mercury, organophosphates Altered behavior LSD, PCP, amphetamines, cocaine, alcohol, anticholinergics LSD, Lysergic acid diethylamide; MSG, monosodium glutamate; NSAID, nonsteroidal anti-inflammatory drug; PCP, phencyclidine.


Pediatrics_Nelson

Pediatrics_Nelson. LSD, Lysergic acid diethylamide; MSG, monosodium glutamate; NSAID, nonsteroidal anti-inflammatory drug; PCP, phencyclidine. Acetaminophen Nausea, vomiting, pallor, delayed jaundice– hepatic failure (72–96 hr) Amphetamine, Tachycardia, hypertension, hyperthermia, cocaine, and psychosis and paranoia, seizures, mydriasis, sympathomimetics diaphoresis, piloerection, aggressive Anticholinergics Mania, delirium, fever, red dry skin, dry mouth, tachycardia, mydriasis, urinary retention Carbon monoxide Headache, dizziness, coma, other systems affected Cyanide Coma, convulsions, hyperpnea, bitter almond odor Ethylene glycol Metabolic acidosis, hyperosmolarity, (antifreeze) hypocalcemia, oxalate crystalluria Iron Vomiting (bloody), diarrhea, hypotension, hepatic failure, leukocytosis, hyperglycemia, radiopaque pills on KUB, late intestinal stricture, Yersinia sepsis Narcotics Coma, respiratory depression, hypotension, pinpoint pupils, bradycardia


Pediatrics_Nelson

Pediatrics_Nelson. Narcotics Coma, respiratory depression, hypotension, pinpoint pupils, bradycardia Cholinergics Miosis, salivation, urination, diaphoresis, (organophosphates, lacrimation, bronchospasm (bronchorrhea), nicotine) muscle weakness and fasciculations, emesis, defecation, coma, confusion, pulmonary edema, bradycardia Salicylates Tachypnea, fever, lethargy, coma, vomiting, diaphoresis, alkalosis (early), acidosis (late) Cyclic Coma, convulsions, mydriasis, hyperreflexia, antidepressants arrhythmia (prolonged Q-T interval), cardiac arrest, shock KUB, Kidney-ureter-bladder radiograph. is assessed easily by measuring arterial blood gases, serum electrolyte levels, and urine pH. An osmolar gap, if present, strongly suggests the presence of an unmeasured component, such as methanol or ethylene glycol. These ingestions require thorough assessment and prompt intervention.


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Pediatrics_Nelson. Dysrhythmias may be prominent signs of a variety of toxic ingestions, although ventricular arrhythmias are rare. Prolonged Q-T intervals may suggest phenothiazine or antihistamine ingestion, and widened QRS complexes are seen with ingestions of cyclic antidepressants and quinidine. Because many drug and chemical overdoses may lead to sinus tachycardia, this is not a useful or discriminating sign; however, sinus bradycardia suggests digoxin, cyanide, a cholinergic agent, or β-blocker ingestion (Table 45-4). Gastrointestinal symptoms of poisoning include emesis, nausea, abdominal cramps, and diarrhea. These symptoms may be the result of direct toxic effects on the intestinal mucosa or of systemic toxicity after absorption. Methanol,* metformin Uremia* Diabetic ketoacidosis* Paraldehyde,* phenformin Isoniazid, iron Lactic acidosis (cyanide, carbon monoxide) Ethanol,* ethylene glycol* Salicylates, starvation, seizures Chloral hydrate, calcium carbonate


Pediatrics_Nelson

Pediatrics_Nelson. Chloral hydrate, calcium carbonate Heavy metals (lead, zinc, barium, arsenic, lithium, bismuth as in Play-Doh, potassium chloride KUB, Kidney-ureter-bladder radiograph. *Indicates hyperosmolar condition. Seizures are the sixth major mode of presentation for children with toxic ingestions, but poisoning is an uncommon cause of afebrile seizures. When seizures do occur with intoxication, they may be life-threatening and require aggressive therapeutic intervention. Laboratory studies helpful in initial management include specific toxin-drug assays; measurement of arterial blood gases and electrolytes, osmoles, and glucose; and calculation of the Drugs Associated with Major Modes of Presentation


Pediatrics_Nelson

Pediatrics_Nelson. Drugs Associated with Major Modes of Presentation Amphetamine Antiarrhythmics Anticholinergics Antihistamines Arsenic Carbon monoxide Chloral hydrate Cocaine Cyanide Cyclic antidepressants Digitalis Freon Phenothiazines Physostigmine Propranolol Quinine, quinidine Theophylline *Causes of methemoglobinemia: amyl nitrite, aniline dyes, benzocaine, bismuth subnitrate, dapsone, primaquine, quinones, spinach, sulfonamides. anion or osmolar gap. A full 12-lead electrocardiogram should be part of the initial evaluation in all patients suspected of ingesting toxic substances. Urine screens for drugs of abuse or to confirm suspected ingestion of medications in the home may be revealing. Quantitative toxicology assays are important for some agents (Table 45-5), not only for identifying the specific drug, but also for providing guidance for therapy, anticipating complications, and estimating the prognosis.


Pediatrics_Nelson

Pediatrics_Nelson. The four foci of treatment for poisonings are supportive care, decontamination, enhanced elimination, and specific antidotes. Supportive care is the mainstay of treatment in most cases. Prompt attention must be given to protecting and maintaining the airway, establishing effective breathing, and supporting the circulation. This management sequence takes precedence over other diagnostic or therapeutic procedures. If the level of consciousness is depressed, and a toxic substance is suspected, glucose (1 g/kg intravenously), 100% oxygen, and naloxone should be administered.


Pediatrics_Nelson

Pediatrics_Nelson. The intent of gastrointestinal decontamination is to prevent the absorption of a potentially toxic ingested substance and, in theory, to prevent the poisoning. There has been great controversy about which methods are the safest and most efficacious. Recommendations from the American Academy of Clinical Toxicology (AACT) and the European Association of Poison Centres and Clinical Toxicologists (EAPCCT) follow. Syrup of ipecac should not be administered routinely to poisoned patients because of potential complications and lack of evidence that it improves outcome. Likewise, gastric lavageshould not be used routinely, if ever, in the management of poisoned patients because of lack of efficacy and potential complications. Single-dose activated charcoal decreases drug absorption when used within 1 hour of ingestion; however, it has not been shown to improve outcome. Thus, it should


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Pediatrics_Nelson. Acetaminophen N-Acetylcysteine 140 mg/kg PO initial dose, then 70 mg/kg Most effective within 16 h of ingestion PO q4hr × 17 doses 150 mg/kg IV over 1 hr, followed by 50 mg/ kg IV over 4 hr, followed by 100 mg/kg IV over 16 hr Benzodiazepine Flumazenil 0.2 mg IV, may repeat to 1 mg max Possible seizures, arrhythmias, DO NOT USE FOR UNKNOWN INGESTIONS β-Blocking agents Glucagon 0.15 mg/kg IV, followed by infusion of 0.05–0.15 mg/kg/hr Carbon monoxide Oxygen 100%; hyperbaric O2 Half-life of carboxyhemoglobin is 5 hr in room air but 1.5 hr in 100% O2 Cyclic antidepressants Sodium bicarbonate 1–2 mEq/kg IV, followed by continuous Follow potassium levels and replace as infusion; titrated to produce pH of 7.5–7.55 needed be used selectively in the management of a poisoned patient. Charcoal is ineffective against caustic or corrosive agents, hydrocarbons, heavy metals (arsenic, lead, mercury, iron, lithium), glycols, and water-insoluble compounds.


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Pediatrics_Nelson. The administration of a cathartic (sorbitol or magnesium citrate) alone has no role in the management of the poisoned patient. The AACT has stated that based on available data, the use of a cathartic in combination with activated charcoal is not recommended. Whole-bowel irrigation using polyethylene glycol (GoLYTELY) as a nonabsorbable cathartic may be effective for toxic ingestion of sustained-release or enteric-coated drugs. Aminoglycosides—gentamicin, tobramycin, and amikacin Chloramphenicol Vancomycin The AACT does not recommend the routine use of whole-bowel irrigation. However, there is theoretical benefit in its use for potentially toxic ingestions of iron, lead, zinc, or packets of illicit drugs.


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Pediatrics_Nelson. Multiple-dose activated charcoal should be considered onlyif a patient has ingested a life-threatening amount of carbamazepine, dapsone, phenobarbital, quinine, or theophylline. Alkalinization of urine may be helpful for salicylate or methotrexate ingestion. Dialysis may be used for substances that havea low volume of distribution, low molecular weight, low proteinbinding, and high degree of water solubility, such as methanol,ethylene glycol, salicylates, theophylline, bromide, and lithium. SEE TABLE 45-6. When in doubt about therapy, contacting one of the U.S. Poison Control Centers (1-800-222-1222) can help to determine what additional treatment is necessary. Most poisonings result in minimal or no toxicity. Major toxicity is seen in fewer than 1% of ingestions, with fatality in fewer than 0.1%. Only 12% of children 12 and under with poisoning require treatment in a health care facility, compared with 48% of adolescents.


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Pediatrics_Nelson. Properly educating parents regarding safe storage of medications and household toxins is necessary for preventing ingestions. If a child has ingested poison, a poison control center should be called. Iron Deferoxamine Infusion of 5–15 mg/kg/hr IV (max 6 g/24 hr) Hypotension (worse with rapid infusion rates) Succimer (2,3-dimercaptosuccinic acid ([DMSA]) 35–50 mg/kg/day IV × 5 days; continuous infusion or divided q 12 hours 10 mg/kg/dose PO tid × 5 days, then 10 mg/kg/dose PO bid × 14 days May cause sterile abscesses. Prepared in peanut oil, do not use in patients with peanut allergy. Few toxic effects, requires lead-free home plus compliant family Opiates Naloxone 0.1 mg/kg IV, ET, SC, IM for children, up to 2 Naloxone causes no respiratory mg, repeat as needed depression From Kliegman RM, Stanton BF, St. Geme JW, et al., editors: Nelson Textbook of Pediatrics, ed 19, Philadelphia, 2011, Saunders, pp 256–257.


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Pediatrics_Nelson. From Kliegman RM, Stanton BF, St. Geme JW, et al., editors: Nelson Textbook of Pediatrics, ed 19, Philadelphia, 2011, Saunders, pp 256–257. ET, Endotracheal; IM, intramuscular; IV, intravenous; PO, oral; SC, subcutaneous. *See Table 45-4 for causes of methemoglobinemia.


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Pediatrics_Nelson. An acutely ill pediatric patient may have pain, discomfort, andanxiety resulting from injury, surgery, and invasive procedures(intubation, bone marrow aspiration, venous access placement)or during life-sustaining mechanical ventilation. Clear goalsshould be identified to allow provision of optimal analgesia orsedation without compromising the physiologic status of thepatient. Anxiolysis, cooperation, amnesia, immobility, and lackof awareness all are goals of sedation and can be accomplishedwith various drugs (Table 46-1). Many of these goals can beachieved with behavioral techniques (preprocedural teaching),but sedation is often a necessary adjunct for painful procedures.Pain may be expressed by verbal or visible discomfort, crying,agitation, tachycardia, hypertension, and tachypnea. A varietyof scales have been developed in an attempt to quantify painand allow more directed therapy. Few of these scales are wellvalidated, especially in populations of acutely ill children


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Pediatrics_Nelson. A varietyof scales have been developed in an attempt to quantify painand allow more directed therapy. Few of these scales are wellvalidated, especially in populations of acutely ill children withphysiologic derangements secondary to the underlying pathology. Pain caused by procedural interventions should always betreated with analgesics in addition to sedation (Table 46-2).


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Pediatrics_Nelson. A medical evaluation must be performed for any patient receiving procedural sedation to identify underlying medical conditions that may affect the choice of sedative agents. Specific attention must be paid to assessment of the airway (for ability to maintain a patent airway) and respiratory system (asthma, recent respiratory illness, loose teeth), cardiovascular status (especially adequacy of volume status), factors affecting drug metabolism (renal or liver disease), and risk of aspiration (adequate nothing-by-mouth status, gastroesophageal reflux). During the administration of procedural sedation, assessment of status must include monitoring of oxygen saturation, heart rate, and respiratory rate, as well as some assessment of effectiveness of ventilation. This assessment must be performed by someone who is not involved in the procedure; this person is also responsible for recording vital signs and drugs administered on a time-based graph. Monitoring must be continued until the child


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Pediatrics_Nelson. by someone who is not involved in the procedure; this person is also responsible for recording vital signs and drugs administered on a time-based graph. Monitoring must be continued until the child has returned to baseline. Patients who are receiving long-term sedation (e.g., to maintain endotracheal tube placement) may need only local anesthesia for painful procedures but may benefit from additional sedation or analgesia as well.


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Pediatrics_Nelson. Many ventilated pediatric patients require sedation and some analgesia while intubated. The most common choice is a combination of a longer acting benzodiazepine and an opioid. Avoidance of oversedation is important. Use of appropriate pain and sedation scores allows for titration of medications to achieve goals of the sedation plan. Long-term use of benzodiazepines and opioids leads to tolerance, a problematic occurrence that must be considered as medications are added and weaned. True addiction is a rare occurrence, especially when medications are provided at the minimum level needed to achieve adequate sedation and pain control. Table 46-1 Agents that Produce Sedation SEDATIVES EFFECT CONCERNS Midazolam Anxiolysis, sedation, muscle relaxation, amnesia Tolerance is possible; apnea, hypotension, depressed myocardial function; short action Lorazepam Anxiolysis, sedation, muscle relaxation, amnesia Same as midazolam; long action


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Pediatrics_Nelson. Lorazepam Anxiolysis, sedation, muscle relaxation, amnesia Same as midazolam; long action Ketamine Anesthesia, analgesia, amnesia Dissociative reactions, tachycardia, hypertension, increased bronchial secretions, emergent delirium, hallucinations; increases intracranial pressure Chloral hydrate Sedative Emesis, hypotension, arrhythmias, hepatic dysfunction Propofol Rapid-onset sedative for induction and Metabolic acidosis in children; may depress cardiac function maintenance of anesthesia Table 46-2 Agents that Produce Analgesia ANALGESIC EFFECT COMPLICATIONS Acetaminophen and NSAIDs Moderate analgesia, antipyresis Ceiling effect, requires PO administration NSAIDs—gastrointestinal bleed, ulceration Opioids No ceiling effect; respiratory depression, sedation, pruritus, nausea/vomiting, decreased gastric motility, urinary retention, tolerance with abuse potential Fentanyl, alfentanil, Analgesia, sedation No adverse effects on cardiovascular system; stiff chest syndrome sufentanil


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Pediatrics_Nelson. Fentanyl, alfentanil, Analgesia, sedation No adverse effects on cardiovascular system; stiff chest syndrome sufentanil NSAIDs, Nonsteroidal anti-inflammatory drugs; PO, oral. The subjective aspect of pain requires that self-reporting be used for assessment. Visual analog scales, developed for adult patients (allowing patients to rate pain on a scale of 1 to 10), have been used for older children. Pain scales for younger children often incorporate behavioral and physiologic parameters, despite the imprecision of physiologic responses. Local anesthetics, such as lidocaine, can be used for minor procedures. However, lidocaine requires subcutaneous or intradermal injection. The use of EMLA, a cream containing lidocaine and prilocaine, is less effective than intradermal lidocaine but is preferred by many patients.


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Pediatrics_Nelson. Patient-controlled analgesia is an effective method for providing balanced analgesia care in older children andadolescents. Children using patient-controlled analgesiahave better pain relief and experience less sedation thanpatients receiving intermittent, nurse-controlled, bolusanalgesics. Analgesics can be administered through thepatient-controlled analgesia pump with continuous basal infusions, bolus administration, or both. Morphine is the most frequent opioid used for patient-controlled analgesia. Monitoring of oxygen saturations and respiratory rate arecrucial with continuous opioid infusions because of the shiftin CO2 response curve and potential to decrease ventilatoryresponse to hypoxia.


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Pediatrics_Nelson. Monitoring of oxygen saturations and respiratory rate arecrucial with continuous opioid infusions because of the shiftin CO2 response curve and potential to decrease ventilatoryresponse to hypoxia. Epidural analgesia decreases the need for inhalation anesthetics during surgery and can provide significant analgesia without sedation in the postoperative period. Decreased costs and length of stay also may be benefits of epidural analgesic approaches. Medications used in epidurals include bupivacaine and morphine. Adverse effects include nausea and vomiting, motor blockade, and technical problems requiring catheter removal. Infection and permanent neurologic deficits are rare. Kleinman ME, Chameides L, Schexnayder SM, et al: Part 14: pediatric advanced life support: 2010 American Heart Association guidelines for car diopulmonary resuscitation and emergency cardiovascular care, Circulation 122(Suppl 3):S876–S908, 2010


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Pediatrics_Nelson. Kliegman RM, Stanton BF, St. Geme JW, et al, editors: Nelson Textbook of Pediatrics, ed 19, Philadelphia, 2011, Elsevier Paul A. Levy and Robert W. Marion Among infants born in the United States, 2% to 4% have congenital malformations, abnormalities of form or function identifiable at birth. At 1 year of age, the number approaches 7%, because some anomalies may not be identifiable until after the neonatal period. The prevalence of congenital malformations is much greater in inpatient pediatric populations; 30% to 50% of hospitalized children have congenital anomalies or genetic disorders. The clinical geneticist attempts to identify the etiology, mode of inheritance, and risk that a disorder might occur in the affected child’s siblings. In evaluating children with congenital malformations, the patient’s condition may be classified into one of five different categories: 1. Single-gene mutations, accounting for 6% of children with congenital anomalies 2.


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Pediatrics_Nelson. Single-gene mutations, accounting for 6% of children with congenital anomalies 2. Chromosomal disorders, accounting for approximately 7.5% 3. Multifactorially inherited conditions, accounting for 20% 4. Disorders that show an unusual pattern of inheritance, accounting for 2% to 3% 5. Conditions caused by exposure to teratogens, accounting for 6% DNA is composed of four nucleotide building blocks: adenine, guanine, cytosine, and thymine. Each nucleotide islinked to other nucleotides, forming a chain. The DNA molecule consists of two chains of nucleotides held togetherby hydrogen bonds. The purine nucleotides, adenine andguanine, cross-link by hydrogen bonds to the pyrimidines,thymine and cytosine. Because of this cross-linking, thenucleotide sequence of one strand sets the other strand’s sequence. Separating the two strands permits complementary nucleotides to bind to each DNA strand; this copies theDNA and replicates the sequence.


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Pediatrics_Nelson. DNA exists as multiple fragments that, together with a protein skeleton (chromatin), form chromosomes. Human cells have 23 pairs of chromosomes, with one copy of each chromosome inherited from each parent. Twenty-two pairs of chromosomes are autosomes; the remaining pair is called the sex chromosomes. Females have two X chromosomes; males have one X and one Y.


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Pediatrics_Nelson. Spread along the chromosomes, like beads on a string,DNA sequences form genes, the basic units of heredity. Atypical gene contains a promoter sequence, an untranslatedregion, and an open reading frame, all arrayed from the 5′ to the 3′ end of the DNA. In the open reading frame, everythree nucleotides represent a single codon, coding for a particular amino acid. In this way, the sequence of bases dictatesthe sequence of amino acids in the corresponding protein.Some codons, rather than coding for a specific amino acid,act as a “start” signal, whereas others serve as “stop” signals. Between the start and stop codons, genes consist oftwo major portions: exons, regions containing the code thatultimately corresponds to a sequence of amino acids, andintrons (intervening sequence), which do not become partof the amino acid sequence.


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Pediatrics_Nelson. Genes are transcribed into messenger RNA (mRNA), then translated into proteins. During transcription, RNA is processed to remove introns. The mRNA serves as a template to construct the protein. Human genetic material contains 3.1 billion bases. Lessthan 2% of the DNA codes for proteins, comprising thegenome’s approximately 21,000 genes. Through a mechanism called alternative splicing, these 21,000 genes maycreate more than 100,000 proteins. The remainder of theDNA, the portion not involved in protein formation, hadbeen termed junk DNA, but a project called ENCODE(Encyclopedia of DNA Elements) found that much of thispresumed junk DNA is functional and likely serves some regulatory function.


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Pediatrics_Nelson. Disease may be caused by changes or mutations in the DNA sequence, with the point mutation, a change in a single DNA base, being the most common type. A point mutation that changes a codon and the resulting amino acid thatgoes into the protein is referred to as a missense mutation. A nonsense mutation is a point mutation that changes thecodon to a “stop” codon so that transcription stops prematurely. A frameshift mutation often stems from the loss or addition of one or more DNA bases; this causes a shift in how the DNA is transcribed and generally leads to premature stop codons.


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Pediatrics_Nelson. To identify specific patterns of inheritance, geneticists construct and analyze pedigrees, which are pictorial representations of a family history. Males are represented by squares and females by circles. Matings are connected with a solid line between each partner’s symbols. Unmarried couples are often connected by a dashed line. Children from a couple are represented below their parents and are the next generation. Grandparents, uncles, and aunts are added in similar fashion. Children of aunts and uncles also may be included. Ages or birthdays may be written next to or underneath each symbol. The proband (the patient who is the initial contact) is indicated with an arrow. Affected individuals are indicated by shading, or some other technique, which should be explained in a key. Carriers for a disorder (e.g., sickle cell disease) usually are indicated by a dot in the center of their symbol (Fig. 47-1). Figure 47-1 Pedigree showing affected individuals and carriers.


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Pediatrics_Nelson. Figure 47-1 Pedigree showing affected individuals and carriers. To be useful, pedigrees should include representatives of at least three generations of family members. If a single copy of a gene bearing a mutation is sufficient to cause disease and that gene is not on one of the sex chromosomes, that condition is inherited in an AD fashion (Table 47-1). In AD disorders, an affected parent has a 50% chance of passing the mutated gene to each child (Fig. 47-2; Table 47-2). Possessing one working gene and one nonworking gene is termed heterozygous. If both copies are the same, they are referred to as homozygous.


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Pediatrics_Nelson. Some people who are obligate carriers of a mutation known to cause an AD disorder may not show clinical signsof the disorder, whereas other such individuals manifest symptoms. This phenomenon is referred to as penetrance.If all individuals who carry a mutation for an AD disordershow signs of that disorder, the gene is said to have complete penetrance. Many AD disorders show decreased penetrance. Often, AD disorders show variability in symptoms expressed in different individuals carrying the same mutated gene. Some individuals have only mild clinical symptoms, whereas others have more severe disease. This phenomenon is referred to as variable expressivity.


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Pediatrics_Nelson. AD disorders sometimes appear in a child of unaffectedparents because of a spontaneous mutation. Known in some cases to be associated with advanced paternal age(>35 years of age), spontaneous mutations may account formost individuals with some disorders. Approximately 80%of patients with achondroplasia have a spontaneous mutation in the fibroblast growth factor receptor type 3 (FGFR3)gene. The following are examples of autosomal dominantdisorders. Table 47-1 Autosomal Dominant Diseases DISEASE FREQUENCY COMMENTS Achondroplasia Thanatophoric dysplasia Crouzon syndrome with acanthosis nigricans Nonsyndromic craniosynostosis ∼1:12,000 Mutations are in the gene for fibroblast growth factor receptor-3 on chromosome 4p16.3. 40% of cases are new mutations (different mutations in the same gene cause achondroplasia, thanatophoric dysplasia, Crouzon syndrome with acanthosis, and nonsyndromic craniosynostosis)


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Pediatrics_Nelson. Neurofibromatosis 1 1:3500 About 50% of cases result from new mutations in the gene for neurofibromin, a tumor suppressor gene located at 17q11.2. Expression is quite variable Huntington disease (HD) Variable in populations, The disease is caused by a (CAG) repeat expansion in the “Huntington” 1:5000–1:20,000 protein gene on chromosome 4p16.3 Marfan syndrome (FBN-1) 1:10,000 The syndrome is caused by mutations in the fibrillin 1 (FBN 1) gene on chromosome 15q21.1; there is variable expression Caused by a defect in cartilage-derived bone, achondroplasia (ACH) is the most common skeletal dysplasia in humans. The bony abnormalities lead to short stature, macrocephaly, a flat midface with a prominent forehead, and rhizomelic shortening of the limbs. The disorder occurs in approximately 1 in 12,000 births.


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Pediatrics_Nelson. ACH is caused by mutations in the FGFR3 gene. Early in development, FGFR3 is expressed during endochondral bone formation. More than 95% of cases of ACH are caused by one of two mutations in the same base pair (site 1138). This site, extremely active for mutations, is known as a mutational hot spot. As they grow, children with ACH often develop associated medical and psychological problems. Hydrocephalus and central apnea may occur because of narrowing of the foramen magnum and compression of the brainstem and may present a life-threatening complication in infancy. Bowing of the legs may occur later in childhood because of unequal growth of the tibia and fibula. Dental malocclusion, obstructive apnea, and hearing loss due to middle ear dysfunction are common in later childhood. During later childhood and adolescence, the psychological effects of the short stature may manifest. In adulthood, further complications include compression of


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Pediatrics_Nelson. Affected individual Individual with decreased penetrance Figure 47-2 Pedigree showing decreased penetrance for an auto-somal dominant disorder. Proband (arrow) is affected. Maternal grandfather also is affected. The individual’s mother is presumed to be the carrier of the gene, even though she may show only slight symptoms of disease. Each child of an affected parent has a one in two chance of being affected Males and females are equally affected Male-to-male transmission occurs Traits generally involve mutations in genes that code for regulatory nerve roots and sciatica. People with ACH have normal life spans and normal intelligence.


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Pediatrics_Nelson. The diagnosis of ACH is made on the basis of clinical findings; characteristic x-ray abnormalities confirm the diagnosis. Molecular testing is available but is usually reserved for cases that are difficult to diagnose or those in which prenatal diagnosis is requested. Prenatal diagnosis is possible by molecular testing, using fetal cells obtained through amniocentesis or chorionic villus sampling. One of the most common AD disorders, NF1 is estimated to be present in 1 in 3500 individuals. NF1 is caused by a mutation in the gene NF1, which codes for the protein neurofibromin. Although the penetrance of NF1 is 100%, the expression is extremely variable. Many affected individuals have features so mild that they are never diagnosed. SEE CHAPTER 186.


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Pediatrics_Nelson. A condition that occurs in approximately 1 in 10,000 individuals, MFS shows pleiotropy, the condition in which abnormalities in multiple organ systems are caused by a mutation in asingle gene. Caused by a mutation in the FBN1 gene, clinical symptoms in MFS mostly involve three systems: cardiac, ophthalmologic, and skeletal. Skeletal findings include a tall, thinbody habitus (dolichostenomelia), spider-like fingers and toes(arachnodactyly), abnormalities of the sternum (pectus excavatum or carinatum), scoliosis, pes planus, and joint laxity.Eye findings include high myopia, which can lead to vitreoretinal degeneration; an abnormal suspensory ligament of thelens, which can lead to ectopia lentis (dislocation of the lens);and cataracts. Cardiac findings include progressive dilatationof the aortic root. Aortic insufficiency followed by aortic dissection is a common complication. Other clinical features of MFS include dural ectasia, abnormal pulmonary septation,and striae. Diagnostic


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Pediatrics_Nelson. the aortic root. Aortic insufficiency followed by aortic dissection is a common complication. Other clinical features of MFS include dural ectasia, abnormal pulmonary septation,and striae. Diagnostic criteria for MFS are summarized inTable 47-3.


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Pediatrics_Nelson. New mutations in FBN1 account for 25% of cases of MFS. The gene is large and complex; more than 600 mutations have been identified in affected individuals. Many of the symptoms of MFS are caused not by the defect in the fibrillin protein itself but rather by an excess in transforming growth factor-beta (TGF-β), a protein usually bound by fibrillin. Losartan, an angiotensin II receptor antagonist that also lowers levels of TGF-β, may prevent aneurysms in patients with MFS. Disorders that are inherited in an AR manner manifest only when both copies of a gene pair located on a non-sex chromosome have a mutation (Tables 47-4, 47-5). Affected children usually are born to unaffected parents, each of whom carries one copy of the mutation. If both members of a couple are carriers (or heterozygotes) for this mutation, each of their offspring has a 25% chance of being affected (Fig. 47-3). SEE CHAPTER 150. MFS† (Z ≥2, if >20 years) (Z ≥3, if <20 years) Facial features (3 of 5)§ 1


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Pediatrics_Nelson. SEE CHAPTER 150. MFS† (Z ≥2, if >20 years) (Z ≥3, if <20 years) Facial features (3 of 5)§ 1 Data from Loeys BL, et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet 47:476-485, 2010. FBN1, Fibrillin-1; MASS, myopia, mitral valve prolapse, borderline aortic root dilatation (Z <2), striae, skeletal findings; MVPS, mitral valve prolapse syndrome. *Aortic root dilatation (measured at the Sinuses of Valsalva); †Loeys-Dietz syndrome (LDS), Shprintzen-Goldberg syndrome (SGS), and the vascular form of Ehlers Danlos (vEDS) should be excluded. If clinical features are suggestive, then DNA testing for TGFBR1, TGFBR2 (LDS), COL3A1 (vEDS) or collagen biochemistry should be done to help rule out these disorders. ‡Maximum Total: 20 points; more than 7 points indicates systemic involvement. §Facial Features: Dolicocephaly, enophthalmos, downslanting palpebral fissures, malar hypoplasia, retrognathia. SEE CHAPTERS 55 AND 185.


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Pediatrics_Nelson. SEE CHAPTERS 55 AND 185. More than 1000 genes have been identified on the X chromosome, whereas only about 200 are believed to be present on theY chromosome. Females, whose cells have two copies of an X chromosome, possess two copies of each gene on the X chromosome, whereas males, who have one X chromosome and a Y chromosome, have only one copy of these genes. Early in femaleembryonic development, one X chromosome is randomly inactivated in each cell. There are many X-linked disorders (colorblindness, Duchenne muscular dystrophy, hemophilia A) in which heterozygous (carrier) females show some manifestationsof the disorder due to skewed X chromosome inactivation. Adrenal hyperplasia, congenital 1:5000 Phenotype variation corresponds roughly to allelic variation. A deficiency causes (CAH, 21-hydroxylase deficiency, virilization in females. CA21H, CYP21, cytochrome The gene is located at 6p21.3 within the HLA complex and within 0.005 centimorgans P450, subfamily XXI) (cM) of HLA B


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Pediatrics_Nelson. The gene is located at 6p21.3 within the HLA complex and within 0.005 centimorgans P450, subfamily XXI) (cM) of HLA B Cystic fibrosis (CF) 1:2500 whites The gene CF transmembrane conductance regulator (CFTR) is on chromosome 7q31.2 Friedreich ataxia (FA, frataxin) 1:25,000 Frataxin is a mitochondrial protein involved with iron metabolism and respiration. The gene is on chromosome 9q13-q21, and the common mutation is a GAA expanded triplet repeat located in the first intron of the gene. FA does not show anticipation Trait appears in siblings, not in their parents or their offspring On average, 25% of siblings of the proband are affected (at the time of conception, each sibling has a 25% chance of being affected) A normal sibling of an affected individual has a two thirds chance of being a carrier (heterozygote) Males and females are likely to be affected equally Rare traits are likely to be associated with parental consanguinity


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Pediatrics_Nelson. Males and females are likely to be affected equally Rare traits are likely to be associated with parental consanguinity Traits generally involve mutations in genes that code for enzymes (e.g., phenylalanine hydroxylase–deficient in PKU) and are associated with serious illness and shortened life span PKU, Phenylketonuria. Most disorders involving the X chromosome are recessive. With only one copy of the X chromosome, males are more likely to manifest these diseases than females. Each son born to a female carrier of an X-linked recessive trait has a 50% chance of inheriting the trait, but none of this woman’s daughters would be affected (each daughter has a 50% chance of being a carrier). An affected father transmits the mutation to all of his daughters, who are carriers, but not to his sons; having received their father’s Y chromosome, they would not be affected (thus there is no male-to-male transmission) (Tables 47-6, 47-7 and Fig. 47-4). SEE CHAPTER 182. SEE CHAPTER 151.


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Pediatrics_Nelson. SEE CHAPTER 182. SEE CHAPTER 151. Figure 47-3 Pedigree of family showing autosomal recessive inheritance. Only a few X-linked dominant disorders have been described. Both males and females are affected by this group of disorders, but females have less severe symptoms due to X-chromosome inactivation. This is the case for X-linked vitamin D–resistant rickets (hypophosphatemic rickets), a disorder in which the kidney’s ability to reabsorb phosphate is impaired. Phosphate levels and resulting rickets are not as severe in females as in males. However, many X-linked dominant disorders are lethal inmales. Affected mothers can have affected or normal daughters but only normal sons. Affected sons die in utero. This isthe case in incontinentia pigmenti, which has a characteristic swirling skin pattern of hyperpigmentation that develops aftera perinatal skin rash with blistering. Affected females also have variable involvement of the central nervous system, hair, nails,


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Pediatrics_Nelson. Fragile X syndrome (FRAXA; 1:4000 males The gene is located at Xq27.3 numerous other names) The condition is attributable to a CGG triplet expansion that is associated with localized methylation (inactivation) of distal genes. Females may have some expression. Instability of the site may lead to tissue mosaicism; lymphocyte genotype and phenotype may not correlate Incidence of the trait is higher in males than in females Trait is passed from carrier females, who may show mild expression of the gene, to half of their sons, who are more severely affected Each son of a carrier female has a one in two chance of being affected Trait is transmitted from affected males to all of their daughters; it is never transmitted father to son


Pediatrics_Nelson

Pediatrics_Nelson. Each son of a carrier female has a one in two chance of being affected Trait is transmitted from affected males to all of their daughters; it is never transmitted father to son Because the trait can be passed through multiple carrier females, it may skip generations teeth, and eyes. In Rett syndrome, caused by mutations in the MECP2 gene, females are normal at birth, but later in the firstyear of life develop microcephaly and developmental regressionand plateau. About 50% of patients develop seizures. Girls oftenare diagnosed with autism and, by 2 years of age, adopt a hand-washing posture that causes them to lose all purposeful hand movements. Often termed polygenic inheritance, multifactorially inheriteddisorders result from the interplay of genetic and environmental Figure 47-4 Pedigree showing X-linked recessive inheritance.


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Pediatrics_Nelson. Often termed polygenic inheritance, multifactorially inheriteddisorders result from the interplay of genetic and environmental Figure 47-4 Pedigree showing X-linked recessive inheritance. factors. In addition to 20% of congenital malformations, including cleft lip and palate and spina bifida, most common disordersof childhood and adult life, such as asthma, atherosclerosis, diabetes, and cancer, result from an interaction between genes andthe environment. These disorders do not follow simple mendelian modes of inheritance; rather, affected individuals tend to cluster in families. The disorders occur more often in firstand second-degree relatives than would be expected by chance, and they are more likely to be concordant (although not 100%) inmonozygotic twins than in dizygotic twins. Available @ StudentConsult.com


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Pediatrics_Nelson. Available @ StudentConsult.com Occurring in about 1 in 300 children, hypertrophic pyloric stenosis (HPS) is five times more likely to occur in males than in females. When a child with HPS is born, the recurrence risk in future progeny is 5% to 10% for males and 1.5% to 2% for females. In adulthood, the risk of an affected male having an affected child is markedly increased over the general population: 4% of sons and 1% of daughters of such men would be likely to be affected. Even more striking is the risk to children born to affected females: 17% to 20% of sons and 7% of daughters are affected.


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Pediatrics_Nelson. The thickness of the pyloric muscle may be distributed across a bell-shaped curve; the position on the bell-shaped curve is determined by many factors, including the expression of multiple, unknown genes. HPS may result when an individual’s genetic and environmental influences cause him or her to fall to an extreme position on this curve, past a certain point, which is called a threshold. In HPS, this threshold is farther to the left for males than it is for females. Before 1998, myelomeningocele affected 1 in 1000 liveborninfants in the United States. Anencephaly occurred with a similar frequency, although most infants were either stillborn or diedin the neonatal period. Since 1998, because of the supplementation of food staples with folic acid, both of these conditions havebecome far less frequent. Multiple genetic and nongenetic factorsdictate the speed with which the neural tube closes, as follows: 1.


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Pediatrics_Nelson. The frequency of neural tube defects (NTDs) varies greatly in different ethnic groups. NTDs are more common in the British Isles, where, in 1990, they occurred in 1 in 250 live births, and far less common in Asia, where the frequency was 1 in 4000. These ethnic differences suggest a genetic component. 2. Couples from the British Isles who move to the United States have a risk intermediate between the risks in the United Kingdom and the United States, suggesting an environmental component. 3. The occurrence of NTDs exhibits seasonality. In the United States, affected infants are more likely to be born during late fall and early winter, again suggesting an environmental component. 4. Periconceptual supplementation with folic acid has significantly lowered the risk of having an infant with an NTD. This nutritional influence suggests an environmental component. 5.


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Pediatrics_Nelson. 4. Periconceptual supplementation with folic acid has significantly lowered the risk of having an infant with an NTD. This nutritional influence suggests an environmental component. 5. Parents who have one child with an NTD are 20 to 40 times more likely to have a second affected child; this provides further evidence of a genetic component. Disorders with Unusual Patterns of Inheritance Human cells contain non-nuclear DNA; a single chromosome is present in each mitochondrion, and mutations within this DNA are associated with a group of diseases.


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Pediatrics_Nelson. Mitochondrial DNA (mtDNA), which is circular and 16.5 kb in length, replicates independently of nuclear DNA. Involved in energy production used to run the cell, mtDNA codes for a few respiratory chain proteins (most mitochondrial proteins are coded on nuclear DNA) and for a set of transfer RNAs unique to mitochondrial protein synthesis. Virtually all mitochondria are supplied by the oocyte, which means that mtDNA is maternally derived. A woman with a mutation in mtDNA passes this mutation to all of her children. More than one population of mitochondria may be present in the oocyte, a phenomenon called heteroplasmy. The mtDNA mutation may be present in a few or many mitochondria. When the fertilized egg divides, mitochondria are distributed randomly. The presence of symptoms in the offspring, and their severity, depends on the ratio of mutant to wild-type mtDNA present in a particular tissue. If an abundance of mutant mitochondria exists in tissue that has high energy requirements


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Pediatrics_Nelson. and their severity, depends on the ratio of mutant to wild-type mtDNA present in a particular tissue. If an abundance of mutant mitochondria exists in tissue that has high energy requirements (brain, muscle, and liver), clinical symptoms occur. If fewer mutant mitochondria are present, few clinical symptoms may be seen.


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Pediatrics_Nelson. MELAS (mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes) is an example of a mitochondrial disorder. Normal in early childhood, individuals affected with MELAS develop episodic vomiting, seizures, and recurrent cerebral insults that resemble strokes between 5 and 10 years of age. In 80% of cases, analysis of the mtDNA reveals a specific mutation (A3242G) in MTTL1, a gene that codes for a mitochondrial transfer RNA. In families in which MELAS occurs, a range of symptoms is seen in first-degree relatives, including progressive external ophthalmoplegia, hearing loss, cardiomyopathy, and diabetes mellitus. Although all offspring of a woman who carries a mutation would be affected, because of heteroplasmy, the severity of disease varies, depending on the percentage of mitochondria bearing the mutation that are present.


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Pediatrics_Nelson. Evaluation of a child with uniparental disomy (UPD) reveals a normal karyotype. However, chromosomal markers for one particular chromosome are identical to the markers found on the chromosomes of the patient’s mother or father (but not both). In UPD, the individual inherits two copies of one parent’s chromosome and no copy from the other parent. UPD probably occurs through a few mechanisms, but the most common results from a spontaneous rescue mechanism. At the time of conception, through nondisjunction, the fertilized egg is trisomic for a particular chromosome, with two copies of one parent’s chromosome and one copy of the other parent’s chromosome; conceptuses with trisomy often miscarry early in development. Fetuses with UPD survive because they spontaneously lose one of three copies of the affected chromosome. If the single chromosome from one parent is lost, the patient has UPD.


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Pediatrics_Nelson. An alternate explanation involves monosomy for a chromosome rather than trisomy. Had the conceptus, at the time of conception, inherited only a single copy of a chromosome, spontaneous duplication of the single chromosome would lead to UPD. Available @ StudentConsult.com


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Pediatrics_Nelson. Available @ StudentConsult.com Prader-Willi syndrome (PWS), which occurs in approximately 1 in 10,000 infants, is characterized by hypotonia of prenatal onset; postnatal growth delay; a characteristic appearance, including almond-shaped eyes and small hands and feet; developmental disability; hypogonadotropic hypogonadism; and obesity after infancy. Early in life, affected infants are so hypotonic that they cannot consume enough calories to maintain their weight. Nasogastric feeding is invariably necessary, and failure to thrive is common. During the first year of life, muscle tone improves and children develop a voracious appetite. Some 60% to 70% of individuals with PWS have a small deletion of chromosome 15 (15q11). In individuals without a deletion, 20% have UPD of chromosome 15.


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Pediatrics_Nelson. Angelman syndrome (AS) is a condition with moderate to severe mental retardation, absence of speech, ataxic movementsof the arms and legs, a characteristic craniofacial appearance,and a seizure disorder that is characterized by inappropriatelaughter. AS is also characterized by a deletion in the 15q11region in 70% of affected individuals; UPD for chromosome15 can be demonstrated in approximately 10% of AS patients. If the deletion occurs in paternal chromosome 15, the affected individual has PWS, whereas AS results from a deletion occurring only in the maternal chromosome 15. When UPD is responsible, maternal UPD results in PWS, whereas paternal UPD results in AS. To summarize, if a copy of paternal chromosome 15q11.2 is lacking, PWS occurs; if maternal chromosome 15q11.2 is lacking, AS results.


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Pediatrics_Nelson. This phenomenon is explained by genomic imprinting. Imprinting is an epigenetic phenomenon, a nonheritablechange in the DNA that causes an alteration in gene expressionbased on parental origin of the gene. PWS is caused by deficiency of the protein product of the gene SNRPN (small nuclearribonucleoprotein). Although present on both maternally andpaternally derived chromosome 15, SNRPN is expressed onlyin the paternally derived chromosome. Expression is blocked inthe maternal chromosome because the bases of the open readingframe are methylated; this physical change in the DNA preventsgene expression. PWS results whenever a paternal chromosome15 is missing, either through deletion or through UPD.


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Pediatrics_Nelson. AS results from a lack of expression of ubiquitin-protein ligase E3A (UBE3A), a second gene in the chromosome 15q11.2 region. UBE3A is normally expressed only in the maternally derived chromosome 15. Although present in paternal chromosome 15, UBE3A is methylated, and gene expression is blocked. Therefore, if either the critical region of maternal chromosome 15 is deleted, or paternal UPD occurs, the individual will manifest symptoms of AS. Expansion of a Trinucleotide Repeat Available @ StudentConsult.com More than 50% of human DNA appears as repeat sequences, two or three bases repeated over and over again. Disorders caused by expansion of trinucleotide repeats include Fragile X syndrome, Huntington disease, myotonic dystrophy, Friedreich ataxia, and the spinocerebellar ataxias. Although an increase in the number of the three repeated bases is at the heart of each disorder, the molecular mechanism differs.


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Pediatrics_Nelson. Fragile X syndrome (FRAX), which occurs with a frequency of approximately 1 in 2000 children, is the most common cause of inherited intellectual disability. Features include characteristic craniofacial findings (large head; prominent forehead, jaw, and ears); macro-orchidism with testicularvolume twice normal in adulthood; a mild connective tissue disorder, including joint laxity, patulous eustachian tubes, and mitral valve prolapse; and a characteristic neurobehavioral profile, including intellectual disability (ranging from mild to profound) and autism spectrum disorders.


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Pediatrics_Nelson. Positional cloning in the Xq27 region identified a tripletrepeat region composed of one cytosine and two guanineresidues (CGG). These repeats occur in the CpG island, apart of the promoter region of a gene that has been calledFMR1. Unaffected individuals who have no family historyof FRAX have 0 to 45 CGG repeats (most have 25 to 35). Inindividuals with FRAX, the number of repeats is greater than200; such people are said to have a full mutation. Between these two categories, a third group has 56 to 200 repeats;always phenotypically normal, these individuals are premutation carriers.


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Pediatrics_Nelson. FRAX results from a failure to express FMRP, the protein product of the FMR1 gene. “Fragile X Mental Retardation Protein” (FMRP) shuttles mRNA between the nucleus and cytoplasm in the central nervous system and other areas (e.g., the developing testis) during early embryonic development. Although FMRP is produced in unaffected individuals and premutation carriers, in those with the full mutation, FMRP transcription of the protein is blocked because the large number of CGG repeats in the CPG island become methylated (an epigenetic phenomenon). Thus, FRAX occurs as a consequence of a loss-of-function mutation—the failure of expression of FMRP because of methylation of the promoter sequence.


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Pediatrics_Nelson. In female premutation carriers, an expansion in the number of repeats from the premutation to the full mutation range may occur during gametogenesis. The cause of this expansion is not understood. Although these females do not have symptoms and signs of FRAX, premutation carriers may manifest premature ovarian failure and/or a neurologic condition known as fragile X tremor/ataxia syndrome later in life.


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Pediatrics_Nelson. Approximately 6.5% of all birth defects are attributed toteratogens—chemical, physical, or biologic agents that have the potential to damage embryonic tissue and result in congenital malformations. Agents known to be teratogenic include drugs (prescription and nonprescription); intrauterine infections (rubella); maternal diseases, such as diabetes mellitus; and environmental substances, such as alcohol and heavy metals. Knowledge of teratogenic agents and their effect on the developing fetus is important, because limiting exposure to these agents is an effective way to prevent birth defects (see Chapters 58, 59, and 60). Rubella was the first maternal infection known to cause a pattern of malformations in fetuses affected in utero. Cytomegalovirus, Toxoplasma gondii, herpes simplex, and varicella are additional potentially teratogenic in utero infections (see Chapter 66).


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Pediatrics_Nelson. Maternal diabetes mellitus and maternal phenylketonuria can result in congenital anomalies in the fetus. Strict control of these disorders before and during pregnancy protects the developing child (see Chapter 59). Fetal alcohol spectrum disorder, which occurs in 10 to 20 per 1000 children, may be the most common teratogenic syndrome. Features include prenatal and postnatal growth deficiency, developmental disabilities, microcephaly, skeletal and cardiac anomalies, and a characteristic facial appearance. To cause the full-blown fetal alcohol syndrome, pregnant women must drink alcohol throughout the pregnancy. Lesser consumption during all or part of the gestation will lead to milder symptoms. Warfarin, retinoic acid, and phenytoin are additional teratogenic agents (see Chapter 59).


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Pediatrics_Nelson. Warfarin, retinoic acid, and phenytoin are additional teratogenic agents (see Chapter 59). High-dose radiation exposure during pregnancy in Hiroshima and Nagasaki, Japan, was shown to increase the rate of spontaneous abortion and result in children born with microcephaly, mental retardation, and skeletal malformations. Estimates of exposure to cause these effects were approximately 25 rad. The dose from routine radiologic diagnostic examinations is in the millirad range. Individuals referred to a geneticist because of suspicion of a genetic disorder are called probands; individuals who come for genetic counseling are consultands. Referral for genetic evaluation may be made for a wide variety of reasons and at different stages of life (fetus, neonate, childhood, pregnancy). Families with relatives affected with genetic disorders may have questions about how a disorder is inherited. The inheritance pattern and the risk of having an affected child can be discussed with a geneticist.


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Pediatrics_Nelson. In some cultures, it is common for relatives to mate. This relatedness or consanguinity does not increase the likelihood of offspring having any particular single genetic disorder, but it may increase the chance that a child will be born with a rare autosomal recessive (AR) condition, as the mutated gene segregates through that family. Generally, the closer the relation between the partners, the greater the chance that the couple shares one or more mutated genes in common, increasing the risk that offspring will have an AR disorder. The risk of first cousins producing a child with an AR disorder is 1 in 64. In evaluating these couples, it is important to determine which ethnic group they belong to and to test for conditions commonly found in that group.


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Pediatrics_Nelson. It is common for couples to be screened for disorders that may occur more commonly in their particular ethnic group. People of Ashkenazi Jewish background may choose to be screened for heterozygosity for a panel of AR disorders, including Tay-Sachs disease, Niemann-Pick disease, Bloom syndrome, Canavan disease, Gaucher syndrome, cystic fibrosis, Fanconi anemia, and familial dysautonomia. People of African-American ancestry may choose to be screened for sickle cell anemia. People whose ancestors originated in the Mediterranean basin may be screened for thalassemia.


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Pediatrics_Nelson. Historically, prenatal screening involved maternal serum screening for α-fetoprotein (AFP), a protein secreted during fetal life by the liver, gastrointestinal tract, and yolk sac. Some of the AFP crosses the placenta and enters the maternal circulation. Although maternal serum screening was initially used to detect high levels of AFP associated with neural tube defects (NTDs) and the disruption of fetal integument such as omphalocele or gastroschisis, low levels of AFP were found to be associated with fetal aneuploidy. Approximately 50% of fetuses with autosomal trisomies (Down syndrome, trisomy 18, trisomy 13) will be detected by low maternal serum AFP levels. Three other proteins—unconjugated estriol (uE3),inhibin A, and human chorionic gonadotropin (HCG)—were added to the maternal serum screening to create the quad screen. The addition of these compounds increased the detection rate to about 80%.


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Pediatrics_Nelson. The quad screen is done in the second trimester. Duringthe first trimester, measurement of a fluid collection of the posterior neck of the developing fetus is termed nuchaltranslucency. An increase in the nuchal translucency is amarker for chromosomal anomalies as well as genetic and structural abnormalities in the fetus. This association provided a noninvasive first trimester marker. Once standardization of nuchal translucency measurements was done,the detection rate for aneuploidy approached 70%. Testing for abnormalities with two first trimester analytes, freeβ-HCG and PAPP-A (pregnancy associated plasma protein)has enhanced first trimester screening to a detection rate ofalmost 90%.


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Pediatrics_Nelson. Although the risk of nondisjunction resulting in aneuploidy rises as a woman gets older (and more so for womenolder than 35 years of age), all pregnant women should beindividually counseled as to their risk for aneuploidy andother fetal abnormalities. A combination of first and second trimester screening together with the women’s age producesan individualized risk factor. It is important to emphasizethat both of these first and second trimester screening testsare just screens to identify increased risk. If this risk is high,or if there is concern about fetal anomalies from family history, ultrasound, or serum screening, then a more definitivetest, either chorionic villus sampling (CVS) or amniocentesis, is offered as further testing. Fetal cells are usually testedfor chromosomal abnormalities by cytogenetic techniques,but the use of chromosomal microarray is becoming more common. Biochemical testing for a known family history ofan inherited metabolic disorder can also be done on the


Pediatrics_Nelson

Pediatrics_Nelson. by cytogenetic techniques,but the use of chromosomal microarray is becoming more common. Biochemical testing for a known family history ofan inherited metabolic disorder can also be done on the fetal cells, as well as molecular screening for familial mutations forknown disorders


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Pediatrics_Nelson. Historically, serum screening has required the use of invasive testing follow-up to confirm findings. Because invasive testing carries a small but real risk of pregnancy loss, many women were not willing to submit to an amniocentesis or CVS. What has been needed is a noninvasive definitive test, one in which fetal risk is negligible. Recently, the search for such a noninvasive test has been successful. Prenatal diagnosis using cell-free fetal DNA in maternal blood offers the ability to detect trisomies in fetuses using nothing more than a sample of the mother’s blood. Although still in the research stage, this technique is being piloted in high-risk pregnancies. It is common for pregnant women to have a screening sonogram at 18 weeks’ gestation. An anatomy scan is done to look for congenital anomalies. Brain, heart, kidneys, lungs, and spine are examined.


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Pediatrics_Nelson. It is common for pregnant women to have a screening sonogram at 18 weeks’ gestation. An anatomy scan is done to look for congenital anomalies. Brain, heart, kidneys, lungs, and spine are examined. The presence of either acute or chronic maternal illness during pregnancy may lead to complications in the developing fetus. Chronic conditions may expose the fetus to maternal medications that are potentially teratogenic. Acute illnesses such as varicella, Lyme disease, and cytomegalovirus expose the fetus to infectious agents that may cause birth defects. Other factors, such as maternal smoking, alcohol use, and maternal exposure to radiation or chemicals, also may necessitate genetic counseling. Two percent to four percent of newborns have a genetic abnormality or birth defect. This broad definition of a birth defect includes not only a visible malformation but also functional defects that might not be apparent at birth.


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Pediatrics_Nelson. Birth defects have a significant impact on childhood morbidity and mortality. Almost 11% of childhood deaths can be traced to a genetic cause. If contributing genetic factors related to childhood deaths are considered, this increases to almost 25%. Consultation with a geneticist for a newborn or infant may be prompted by many different findings, including the presence of a malformation, abnormal results on a routine newborn screening test, abnormalities in growth (e.g., failure to gain weight, increase in length, or abnormal head growth), developmental delay, blindness or deafness, and the knowledge of a family history of a genetic disorder or chromosomal abnormality or (as a result of prenatal testing) the presence of a genetic disorder or chromosomal abnormality in the infant.


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Pediatrics_Nelson. Adolescents and adults may be seen by a geneticist for evaluation of a genetic disorder that has late onset. Some neurodegenerative disorders, such as Huntington disease and adult-onset spinal muscular atrophy, present later in life. Some forms of hereditary blindness (retinal degenerative diseases) and deafness (Usher syndrome, neurofibromatosis type 2) may not show significant symptoms until adolescence or early adulthood. Genetic consultation also may be prompted for a known family history of a hereditary cancer syndrome(breast, thyroid, colon, and ovarian cancers). Individuals may wish to have testing done to determine if they carry a mutation for these syndromes and would be at risk for developing certain types of cancers. A known family history or personal history of a genetic disorder or chromosomal abnormality might prompt testing in anticipation of pregnancy planning.


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Pediatrics_Nelson. A pedigree usually is drawn to help visualize various inheritance patterns. Answers to questions about the family help determine if there is an autosomal dominant, AR, X-linked, or sporadic disorder. When a child is affected with the new onset of an AD disorder, it is necessary to closely examine the parents to check for the presence of manifestations. If the parents are unaffected, the child’s condition is most likely the result of a new mutation; the risk of recurrence is extremely low (although not 0, because of the possibility of gonadal mosaicism in one of the parents). When one parent is affected (even mildly so due to varying penetrance), the recurrence risk rises to 50%. With X-linked disorders, the focus is on the maternal family history to determine if there is a significant enough risk to warrant testing.


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Pediatrics_Nelson. Questions about the couple’s age are important to ascertain the risk related to maternal age for chromosome abnormalities and paternal age for new mutations leading to AD and X-linked disorders. A history of more than two spontaneous abortions increases the risk that one of the parents has a balanced translocation and the spontaneous abortions are due to chromosomal abnormalities in the fetus.


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Pediatrics_Nelson. During a genetic consultation, it is important to gather information about the pregnancy (see Chapters 58, 59, and 60). A maternal history of a chronic medical condition, such as a seizure disorder or diabetes, has known consequences in the fetus. Medication used in pregnancy can be teratogenic; the pregnant woman’s exposure to toxic chemicals (work related) or use of alcohol, cigarettes, or drugs of abuse can have serious effects on the developing fetus. Maternal infection during pregnancy with varicella, Toxoplasma, cytomegalovirus, and parvovirus B19, among others, has been found to cause malformations in the fetus. Follow-up is needed if an amniocentesis or CVS reveals abnormal results. A fetal ultrasound may detect a malformation that needs follow-up when the infant is born. Often hydronephrosis is detected prenatally. These infants need a repeat ultrasound soon after birth.


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Pediatrics_Nelson. An infant born prematurely is likely to have more complications than a term infant. An infant can be small, appropriate, or large for his or her gestational age; each of these has implications for the child (see Chapters 58, 59, and 60). In general, the finding that an infant is small for gestational age is suggestive of exposure to a teratogen or the presence of a chromosomal abnormality. Children with inborn errors of metabolism who have intermittent symptoms often have a history of multiple hospitalizations for dehydration or vomiting. Children with neuromuscular disorders may have a normal period followed by increasing weakness or ataxia. Children with lysosomal storage diseases, such as the mucopolysaccharidoses, often have recurrent ear infections and can develop sleep apnea.


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Pediatrics_Nelson. Many genetic disorders are associated with developmental disabilities. However, the onset of the disability may not always be present from the newborn period; many inborn errors of metabolism, including storage disorders, cause developmental manifestations after a period of normal development (see Chapters 7 and 8). Some adult-onset disorders have no symptoms until the teens or later. Assessing school problems is important. The type of learning problem, age at onset, and whether there is improvement with intervention or continued decline all are important for proper assessment. A careful and thorough physical examination is necessary for all patients with signs, symptoms, or suspicion of genetic disease. Sometimes subtle clues may lead to an unsuspected diagnosis. Features suggestive of a syndrome are discussed in more detail in Chapter 50.


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Pediatrics_Nelson. An individual’s chromosomal material, known as the karyotype,can be analyzed using cells capable of dividing. In pediatrics, lymphocytes obtained from peripheral blood are the usual source forsuch cells, but cells obtained from bone marrow aspiration, skinbiopsy (fibroblasts), or, prenatally, from amniotic fluid or chorionic villi also can be used. Cells are placed in culture medium andstimulated to grow, their division is arrested in either metaphaseor prophase, slides are made, the chromosomes are stained withGiemsa or other dyes, and the chromosomes are analyzed.


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Pediatrics_Nelson. In metaphase, chromosomes are short, squat, and easy to count. Metaphase analysis should be ordered in children whose features suggest a known aneuploidy syndrome, such as a trisomy or monosomy. Chromosomes analyzed in prophase are long, thin, and drawn out; analysis gives far more details than are seen in metaphase preparations. Prophase analysis is ordered in individuals with multiple congenital anomalies without an obvious disorder.


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Pediatrics_Nelson. Fluorescent in situ hybridization (FISH) allows the identification of the presence or absence of a specific region of DNA. A complementary DNA probe specific for the region in question is generated, and a fluorescent marker is attached. The probe is incubated with cells from the subject and viewed under a microscope. The bound probe fluoresces, allowing the number of copies of the DNA segment in question to be counted. This technique is useful in Prader-Willi syndrome and Angelman syndrome, in which a deletion in a segment of 15q11.2 occurs, and in velocardiofacial (DiGeorge) syndrome, which is associated with a deletion of 22q11.2.


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Pediatrics_Nelson. Microarray comparative genomic hybridization (array CGH)has supplanted prophase analysis in cases in which a subtlechromosomal deletion or duplication (copy number variant) issuspected. In array CGH, DNA from the individual being studied and a normal control is labeled with fluorescent markers and hybridized to thousands of FISH-like probes for sequencesspread around the genome. The probes are derived from knowngenes and noncoding regions. By analyzing the ratio of intensityof the fluorescent marker at each site, it is possible to determinewhether the individual in question has any difference in copynumber compared with the control DNA. Direct DNA analysis allows identification of mutations in a growing number of genetic disorders. Using polymerase chain reaction, the specific gene in question can be amplified and analyzed. The website www.genetests.org lists disorders in which direct DNA analysis is available and identifies laboratories performing such testing.