MASTER THE BOARDS PEDIATRICS | SECOND EDITION | Btn Male eNom A Ae) ae UL This put matter ¢ account ofacom ©2013, All right Printed w98 ISBN-1 Kaplan I premiur & Schus PvtTABLE OF CONTENTS WTRODUCTION ...... 200 ccceeseceeeeveeeeseeeeseeesceeeecseseeen ee BE Chapter 1: ‘The Neonate 1 Cuapter 2: Genetic and Metabolic Disease ........2.+. cee 37 Chapree 3: Fluid, Electrolyte, and Nutritional Management Charter 4: Well-Child Care: Infancy Through Middle Childhood... .0.0sccsescseeeeeeseeee see 85 Cuaprer 5: Developmental, Behavioral, and Mental Health Disorders . Fae 107 Cuaprer 62. Psychosocial Issues/Problems and Ethical Issues in Pediatrics «02.2. .sscecseeeveeeeseeed35, Cuaprer 7: Respiratory Disorders ......2cc0ceceeseseesseeeeee 157 Cuaprer 8: Allergy and Asthma ... 181 Cuaprer 9: Immunodeficiencies .......0..6s6ceeesseeeeeee cee 201 Cuaprer 10: Collagen Vascular Disorders........20.0ccecceeece0-2UI Chapter 11: Disorders of the Eyes, Ears, Nose, and Throat.........225 Cuaprer 12: Cardiovascular Disease ........0.06.0cceeceseeeee 243 Cuaprer 13: Gastrointestinal Disorders. 285 Cuaprer 14: Genitourinary Disorders 313 Chapter 15: Infectious Diseases ..... . 34 Cuaprer 16: Endocrine Disorders.......0...0.6+ coe 381 Cuaprer 17: Orthopedic Disorders and Sports Medicine...........415 Cuaprer 18: Dermatological Disorders ........06.0ceeeceeeeee ABS Cuaprer 19: Adolescent Medicine.........600sceeeeeeceeeese 453 Cuarer 20: Emergency Medicine 473 Cuaprer 21: Hematology/Oncology .......0.0.cce0eeeeceeeeese 493 Cuapter 22: Neurological Disorders 525 INDEX... ee 561 Rererences ...... 373GENETIC AND METABOLIC DISEASE PART ONE: GENETICS AND DYSMORPHOLOGY Prenatal Diagnosis Major reasons for prenatal testing are: + Maternal age >35 years + Previous child with chromosomal anomaly + Affected parent with a microdeletion syndrome, parent with a balanced translocation + Need to determine fetal sex for possible severe X-linked traits Ultrasound + Performed safely throughout pregnancy for fetal anatomical abnormalities and for fetal size and growth iagnoses may be made as carly as the 16th week of gestation (e.g., anencephaly, myelo- meningocele, certain gastrointestinal defects, and congenital heart disease) + Ultrasound Doppler for blood-tlow velocity and vascular resistance (fetal hypoxia) Amniocentesis + Transabdominal needle aspiration of amniotic fluid between 15 and 18 weeks’ gestation + Risk of fetal loss, Can determine fetal lung maturity, karyotype, chromosomal abnor- malities, single gene defects, and enzyme analysis Alpha-fetoprotein + Can be analyzed in amniotic fluid or in maternal serum + Decreased in trisomies and aneuploidy + Increased in fetal death, intestinal atresias, neural tube defects, multiple gestation Chorionic villus sampling (CVS) Allows for earlier detection (10-12 weeks’ gestational age) of karyotype, DNA analysis, enzyme assay; risk of fetal loss 37Master THE Boaros: PeDiaTRics 38 Examples of Etiologies of Genetic Disorders Chromosomal maldistribution—Most result from error in cell division leading to genetic imbalance (e.g, monosomy, trisomy; increased mortality); error in first or second meiotic division is nondisjunction > abnormal chromosome number in sex cells; error later in embryonic development > mosaicism; older maternal age is a factor Chromosomal breakage—Break in at least one chromosome with subsequent rearrangement = translocation; a balanced translocation leads to no phenotypic expression; during meiosis 1, increased risk of imbalance in the germ cell (if the germ cell has the translocation chromosome and the normal one from the same parent > trisomy); therefore, in trisomies resulting from translocation, the parents must be karyotyped to look for @ balanced translocation carrier state; if ths is the case, the recurrence risk increases (4-5% vs. 1% for full trisomy, depending on maternal age). Breakage can also result in a deletion; 4 mictodeletion is so small that high-resolution methods are required for detection; most are new mutations, so recurrence risk is negligible unless parents have the deletion and ‘express the phenotype; in that case, the recurrence risk is 50%. Genetic imprinting—some genes assess different phenotypes depending on whether they are on the male or the female chromosome. In Prader-Willi syndrome, the inherited abnormality is from the paternal 15 chromosome, and in Angelman syndrome, the abnormal gene is inherited from the maternal 15 chromosome. Unstable gene mutations—the human genome contains short repeat trinucleotide sequences (purpose may be unknown); increased copies of these sequences leads to instability and an abnormality in the offspring. The best example of this is fragile X syndrome Uniparental disomy—Both alleles are from the same parent; initial trisomy and then climination of the extra chromosome; remaining may be from the same parent, which leads to genetic imbalance (some cases of mosaicism, imprinting effects and autosomal recessive effects. Patterns of Inheritance Autosomal dominant + Presence of the trait in a single allele produces the phenotypic expression. + Most likely pattern: one parent is heterozygous for the dominant trait and the other does not carry the trait (Aa x aa); 50% of the offspring will inherit the trait and express the phenotype (if both parents are heterozygous carriers [Aa x Aa], then 75% will express the phenotype. + Variability in penetrance leads to different expression (depending on the extent and degree of mutation) + Significant number of new mutations (especially with older paternal age).2: Generic AND MeTABoLIC Disease [-— Autosomal recessive + ‘The phenotypic expression requires the presence of both abnormal alleles. + Most likely pattern: both parents are heterozygous carriers (aA x aA); 25% of off- spring of each pregnancy will be homozygous recessive and therefore will express the phenotype; of the children who do not express the phenotype, two-thirds are car- riers; but there is low risk of random marriage to another carrier so the recurrence risk is low X-linked dominant + ‘The gene is carried on the x-chromosome and requires only one copy for expression, which results in phenotypic expression in females (XX) and severe or lethal effects in males (XY), + Inheritance: 50% of offspring of heterozygous XX carriers and normal males will be affected + 50% of girls and 50% of boys will show the phenotype (this is not a common inheri- tance pattern). X-linked reces: + One copy produces minor or no phenotypic expression, + Except in rare instances, only males are affected. Ifthe mother is a carrier, 50% of daughters are carriers and 50% of sons are affected. ‘Transmission, then, is through mildly affected or unaffected females. Mitochondrial inheritance + Mitochondria carry a circular genome (37 genes encoding 13 proteins of the subunits of the respiratory chain complex). + Inheritance is exclusively maternal, so no males are affected. All of the daughters will show the abnormality. Effects of mutations are worse over time. There are different pro- portions of normal vs, abnormal mitochondria in various tissues, and a threshold must, be exceeded for expression of the abnormality to occur. Muttifactorial inheritance + Threshold of phenotypic expression based on interactions between different genes and environmental factors. + Malformations seen at differing frequencies in different ethnic groups. + Normal parents with one affected child, risk for first-degree relatives is approximately the risk of the square root of the risk in the population (mostly 3-5%); with two affected children, the risk increases to 10-15%, + Significantly decreased risk in second-degree relatives, + Recurrence risk greater with greater numbers of affected family members and increas- ing severity of the abnormality. + Recurrence risk increases for relatives of the least affected sex (if there are obvious sex: differences in expression) 39.Master THE Boaros: PeDiaTRics 40 Patterns of Abnormal Morphogene: Malformation—Error in morphogenesis resulting in abnormal formation of tissues (dysplasia = abnormal arrangement of cells into tissues) Deformation—Normally formed tissues that become abnormal in form as a result of extrinsic with or without intrinsic forces; most common extrinsic force is uterine constraint (primigravida, abnormal fetal lie, large-for-gestational-age [LGA] fetus, multiple gestation, oligohydramnios, uterine fibromas, bicornate uterus, small uterus) + Combinations of extrinsic and intrinsic factors may lead to a number of positional limb deformations (see Chapter 17) + Breech presentation (late gestational, prolonged): head elongated with prominent ‘occiput; asymmetric shoulder compression with asymmetry of mandible; torticollis, hip dislocation; club foot + Plagiocephaly-torticollis sequence: most cases from uterine constraint; head com- pressed to one side in late gestation > asymmetric molding of head (often rhomboi may progress if uncorrected) and face (plagiocephaly) > shortening of the sternoclei domastoid with possible ischemia and fibrosis: mild cases resolve spontaneously or with neck-stretching exercises; more severe cases may require an orthocephalic helmet (specifically molded) + Craniosynostosis: limitation of normal growth at one or more cranial sutures due either to a primary defect in brain growth (symmetric small head and brain) or to uterine head constraint and early suture closure; growth is limited and there may be a bony ridge that forms along the synostosis; multiple synostosis may lead to abnormal brain growth and increased intracranial pressure (ICP), and these are major reasons for surgery Disruption—Breakdown of previously normally formed tissue from extrinsic factors (sce below for further discussion/example) + Amnion rupture sequence: Early rupture of the amnion > small amniotic strands > encircle and constrict fetal structures > amputation, limb reductions, clefts, umbili- cal cord compression; diagnosis is made by finding bands of amnion on the placental membranes; majority of cases are idiopathic and sporadic Syndrome—An error in morphogenesis leading to a recognized pattern of multiple malformations Sequence—A single initiating event leading to a pattern of malformation, where the subsequent malformation is related to the formation of the previous malformation + Oligohydramnios sequence (Potter sequence): Defect of fetal urinary output and therefore decreased to absent urine into amniotic cavity (agenesis, dyspla- sia, obstruction) + amniotic fluid leakage > oligohydramnios > fetal compression ~ breech presentation, craniofacial anomalies (Potter facies: inner canthal and infra- orbital skin folds, flat nose and ears), aberrant positioning of the hands and feet with2: Generic AND MeTABoLIC Disease [-— decreased joint mobility and compression of the fetal lungs with delayed development > pulmonary insufficiency (pulmonary hypoplasia = most common cause of death) + Robin sequence: Hypoplasia of the mandible > retrognathia (posterior tongue posi- tioning) > abnormal soft palate (rounded to cleft}; most important issue in first month of life is possibility of airway obstruction; most patients have catch-up of mandibular growth and long-term prognosis is good, + Cleft lip sequence: failure of lip fusion > possible failure of closure of palatal shelves (ie. cleft lip + cleft palate); may have abnormal tooth development and nares closure; may have other malformations (especially in isolated cleft palate); increased incidence of conductive hearing loss and speech problems; most follow pattern of multifactorial inheritance but there are familial patterns of autosomal dominant transmission Association—Nonrandom pattern of malformations that have no clear interrelationship + VACTERL associat bral defects; A, anal atresia; C, cardiovascular defects (most ventricular septal defects [vSDs; single umbilical artery); T-E, fistula with or without esophageal atresia; R, renal defect; L, limb anomaly (most radial defect) + CHARGE association: unknown cause of nonrandom associations of, C, coloboma (Grom iris to retinal); H, heart defect; A, atresia choanae; R, retardation (mental and growth); G, genital hypoplasia in males; E, ear anomalies with or without deafness : sporadic occurrence of nonrandom associations of: V, verte- Table 2.1: Types of Craniosynostosis (major findings) os Eee Coronal eed a =Most common | = Limited forward | ~ Least common = Lateral = Not common; — Biparietal head growth | _ abnormal fetal lie constraint of || significant constraint (brachycephaly) | > constraint of the front of problem with = Head long — Short cranial Paster oes the head brain growth and narrow base and upward | _ Unilateral: ipsilateral | ~Natrow and and increased (olichocephatic) | growth > high | flat occiput and forward- \SACEEEr with prominent | forehead and anterior pinna projecting | - Proptosis, optic Pareheadiandl shallow orbits; | Gisplacement; forehead with | atrophy, visual Bos and lateral bilateral prominent impairment i th > ocular metopic = Ridge from mid | 9° brachycephaly with pI ~ Early surgery aw hypertelorism | small posterior fossa | suture ridge | to reduce ICP sagittal suture | ~Midface — Upsianted and allow brain Geaphocephaly) | hypoplasia, palpebral ‘growth and narrow maxilla fissures and | development hypertelorism ‘Abbreviations: intracranial pressure, 1CP a——| Master tHe Boaros: Peoiatrics Major Malformation Syndromes Chromosomal Table 2.2: Major Chromosomal Malformation Syndromes Doran Pern Dae cae Major Morbidities | Studies Cue Trisomy 21 | Upsianting palpebral Mental deficiency Karyotype; also | Hypotonia (Bown) | fissures, mild microcephaly, | (variable), hearing of parents if | improves with flat occiput, inner loss (conductive, translocation | age; variation in epicanthal folds (not specific | sensorineural, or mixed), mental and social for Down), Brushfield congenital heart disease performance; spots (speckling of iis) (endocardial cushion short stature; small, abnormal ears, defect most common); progressive single palmar crease (not _| gastrointestinal gonadal specific to Down), fifth anomalies deficiency; finger brachydactyly and | (duodenal atresia, major mortality xdactyly, hypotonia; tracheoesophageal early in life is small penis and testicles fistula, Hirschsprung congenital heart disease); atlantoaxial disease instability; leukemia; thyroid disorders Trisomy 13 | IUGR, microcephaly, Most with cardiac Karyotype; also | stillborn or (Patau) | microphthalmia, cleft Ii defect (septal defects | of parents if | death in vast and palate, parietal-occipital_| most common); translocation | majority in first cutis aplasia, finger flexion, | other CNS defects month of life; polydactyly, cryptorchidism | (holoprosencephaly); any survivors with abnormal scrotum, | renal defects have severe single umbilical artery mental defects and failure-to- thrive Trisomy 18 | IUGR, severe mental Cardiac defects (most _ | Karyotype; also | Stillborn or (Edwards) | deficiency, microcephaly, _| are septal defects), of parents if | death in first clenched hand with index | renal defects, bone and_| translocation | week with less finger over the third and | joint abnormalities, surviving over fifth finger over the fourth; | omphalocele first year; severe short sternum, omphalocele mental deficiency cryptorchidism, rocker- and psychomotor bottom feet retardation (continued) a22: GeWeTiCc AND METABOLIC DISEASE Weraeeas Pirin Syndrome | Findings Lee ae ead Cran xO ‘Small stature (may have | Psychomotor and Karyotype in| Some pure XO (Turner) | IUGR) and gonadal neuropsychological | any girl with _| are stillborns; dysgenesis; congenital defects (may have unexplained | higher mosaicism lymphedema, broad chest _| some degree of mental | short stature _| in live-borns, with widely spaced nipples; | retardation); renal or lack of adults at risk for low, abnormal posterior | defects (horseshoe _| pubertal aortic dissection hairline; webbed neck, kidney), cardiac development loose skin at posterior defects (most with | at 13 years of neck, bone and joint bicuspid aortic valve, | age abnormalities (cubitus then coarctation valgus most common) of the aorta; mitral valve prolapse), renovascular hypertension; hypothyroidism; rarely any functional ovarian tissue by adolescence; estrogen therapy is indicated; growth hormone allows for some growth. XXY Tall and thin (decreased | Average IQ mildly —_| Karyotype XXY/_ | Most require (Klinefelter) | ratio of upper to lower decreased (wide XY mosaics have | help with segment due to long lower | range); learning better testicular | learning; limbs); small penis and disabilities, function; other | testosterone testes, gynecomastia behavioral problems; | karyotypes replacement is infertility (decreasing | with more helpful testosterone levels late | profound mental in adolescence) deficiency and behavioral problems Fragile X | Males (carrier females less | Mental retardation, | X chromosome | Normal life span syndrome | affected) with mild to severe | inattention and region of mental retardation; large | hyperactivity, autism; | large number head early and large jaw | mitral valve prolapse, | of repeat after puberty; large ears; | aortic dilation trinucleotide macro-orchidism (especially (cc) > after puberty) molecular analysis Aniridia- |W, Wilms tumor; A, aniridia | More patients with | Most new Mortality related Wilms (and other eye defects); G, | full spectrum develop | mutation of __| to diagnosis and tumor genitourinary anomalies ‘Wilms tumor compared | 11p13 deletion _| treatment of association | (cryptorchidism, hypospadias, | to those with just > molecular | Wilms tumor (WAGR) | others); R, mental retardation | aniridia or GU defect | analysis (moderate to severe) ‘Abbreviations: central nervous system, CNS; intrauterine growth retardation, IUGR 43——| Master tHe Boaros: Peoiatrics Other syndromes Table 2.3: Syndromes with Short Stature ame [ Major Diagnostic Findings and Problems CS leo ets eye aera Cramer) a ea Re ara ERSTE ae ESTATE EE oa Turner syndrome; pectus deformations, small penis and cryptorchidism (normal fertility if descended testes; females are fertile), various bleeding disorders, pulmonic valvular stenosis Williams syndrome | Abnormal gene on the 7th chromosome; mild IUGR and microcephaly; mental retardation and learning disorders; very friendly and talkative; facial dysmorphism, renal anomalies (and renovascular hypertension), supravalvular aortic stenosis; hypercalcemia Table 2.4: Syndromes with Skeletal/Connective Tissue Dysplasias or Hamartoses Baines [ote a eee Achondroplasia___| Abnormal fibroblast gene on chromosome 4; autosomal dominant with almost all cases as new mutations; older paternal age; rhizomelic short stature (shortening in proximal segments of legs) > increased upper to lower segment ratio; large head with short base (may have hydrocephalus if small foramen magnum), prominent. forehead and midface hypoplasia; lumbar lordosis; abnormal vertebral bodies with short intervertebral spaces (spinal compression); intelligence usually normal, later obesity (Note: hypochondroplasia is similar but without significant craniofacial features and without severe spinal abnormalities.) Marfan syndrome | Mutations in the fibrillin gene on chromosome 15; autosomal dominant with wide ‘expression. Marfanoid phenotype: tall (with decreased upper to lower segment ratio because of long legs), thin, arachnodactyly (long spider-like fingers, long arms with arm span > height); joint laxity > hyperextensibility; kyphoscoliosis, pectus deformations, upward lens subluxation (suspensory ligament defect); dilatation of ascending aorta (may have dissecting aneurysm) > aortic insufficiency, mitral valve prolapse Ehlers-Danlos Deficiency of fibrillar collagen; autosomal dominant with wide expression; six syndrome types. Classic (type 1): small stature more common, hyperextensible and fragile skin (and ears) and blood vessels with poor healing; hyperextensible joints; lens dislocation, aortic root dilatation, mitral valve prolapse Homocystinuria | Autosomal recessive; decreased cystathionine synthetase > accumulation ‘of homocystine and methionine and decrease in cystathionine and cystine > interference with crosslinking of collagen; Marfanoid appearance with similar bonefjoint problems; downward lens subluxation; thromboembolism most important morbidity due to degeneration and subsequent fibrosis of elastic arteries 442: GeWeTiCc AND METABOLIC DISEASE Table 2.5: Syndromes with Early Overgrowth Baie’ Con eee ka Beckwith-Wiedemann syndrome (see Chapter 1) balance of gene on chromosome 11; spora let cell hyperplasia > severe hypoglycemia; macrosomia, large tongue, hemihypertrophy, omphalocele, abdominal tumors (Wilms) appearance; problems Sotos syndrome LGA at birth with increased growth velocity through childhood and. advanced bone age; macrocephaly at birth, facial dysmorphism, bone problems, variable mental deficiency; neurodevelopmental and behavioral “Abbreviations: large for gestational age, LGA Table 2.6: Syndromes with Limb Defects Poland sequence Primary defect in development of proximal subclavian ar nipple with rib defects; distal arm hypoplasia, short of dextrocardia if on the left Ben Pon eee kee decreased blood flow to pectoral muscles and limb; most on the right; majority of cases in males; hypoplasia to aplasia of pectoralis major and tery > unilateral F missing fingers; Radial aplasia- Bilateral absent radius, ulnar hypoplasia or aplasia, abnormal humerus; thrombocytopenia thumbs are present; abnormal or absent megakaryocytes > severe syndrome (TAR) thrombocytopenia with hemorrhage (cause of early death); heart and CNS defects ‘Abbrevitions: central nervous system, CNS Table 2.7: Syndromes with Major Facial Detects (and associated with hearing loss) ‘Treacher Collins syndrome | Autosomal dominant with wide expression, most new mi partial or complete absence of lower eyelids, lower li hearing loss Bion Pe eee chromosome 5; down-slanting palpebral fissures, mandibular and malar hypoplasia; scalp hair on lateral cheek, external ear malformations, have early respiratory insufficiency because of a narrow airway; visual and utations; gene on id coloboma; may albinism with white forelock, deafness (severe, bilater with medial flare (may meet in midline) Waardenburg syndrome | Autosomal dominant; gene on chromosome 2; partial oculocutaneous ral), bushy eyebrows 45——| Master tHe Boaros: Peoiatrics Table 2.8: Syndromes with Prominent Brain/Neuromuscular Findings Baten Tot ce eee kar cn Prader-Willi Early-onset childhood obesity (large caloric intake and decreased activity; most syndrome important therapy is dietary regulation and exercise; secondary complications related to morbid obesity including decreased life span); severe hypotonia in infancy; short stature, small hands and feet, mental retardation (most mild to moderate), learning problems, small/hypoplastic external genitalia with cryptorchidism in boys Angelman. ‘Ataxia with jerky arm movements (like a puppet); cerebral atrophy, early seizures, syndrome (Happy | severe mental and motor retardation; very few words to absent speech (may use Puppet syndrome)_| sign language) with laughter paroxysms (brain stem defect) Menkes kinky hair | X-linked recessive inheritance; copper-transporting gene abnormality (low copper syndrome and ceruloplasmin); neurodegeneration beginning in early infancy with death by age 3 years; hair loses pigmentation starting at 6 weeks of age, and becomes sparse, broken, and twisted; abnormally pigmented, thick, dry skin; vascular, skeletal, gastrointestinal and urinary tract abnormalities Table 2.9: Teratogenic Syndromes Syndrome toe nei ee eee oad Fetal alcohol Fetal effects are dose-related intake of alcohol; IUGR and poor postnatal growth; syndrome microcephaly; midface dysmorphism; mild to severe mental retardation with various neurological abnormalities; irritability, hyperactivity; joint abnormalities; VSD, ASD, tetralogy of Fallot Fetal warfarin Use of coumarin derivatives, especially in the first trimester; IUGR with later catch- syndrome up growth; severe mental retardation and seizures; nasal hypoplasia, depressed nasal bridge, groove on nose; short fingers with nail hypoplasia; may have CNS and eye malformations Retinoic acid Isotretinoin (Accutane™) taken subsequent to the 15th day after conception > ‘embryopathy mental deficiency, facial asymmetry, external ear anomalies, small jaw, facial paralysis; flat, depressed nasal bridge, hypertelorism, heart defects (conotruncal lesions); ENS anomalies Fetal hydantoin | Prenatal exposure to phenytoin (also similar effects from valproate, carbamazepine, syndrome phenobarbital; IUGR and poor postnatal growth; may have mild mental deficiency; facial dysmorphism, hypoplasia of distal phalanges with small nails; other findings including CNS, eye, heart, genitourinary, and gastrointestinal Fetal valproate | Prenatal exposure to valproic acid; mental deficiency (less common), midface syndrome hypoplasia, high forehead, epicanthal folds, flat nasal bridge, short nose with anteverted nostrils; cleft lip; long, thin fingers; many types of cardiac defects (conotruncal, hypoplastic left heart); meningomyelocele; bone abnormalities ‘Abbreviations: atrial septal detect, ASD; central nervous system, CNS; intrauterine growrh retardtion, IUGR; venta septal defect, VSD 462: GeWeTiCc AND METABOLIC DISEASE PART TWO: INBORN ERRORS OF METABOLISM Note: Studying the inborn errors is often quite complex, and thorough knowledge of all of the biochemistry and clinical presentations is needed only for subspecialty exams in genetics and metabolism. The following discussion is limited to the most important information and most common clinical presentations of the major metabolic diseases for diagnostic exam questions. As usual, key words to associate with each of the problems are in bold Most inborn errors are due to single-gene defects and are inherited as autosomal recessive disorders. Many present in the neonatal period, but may have a gradual and delayed onset. Presenting findings suggestive of a metabolic problem include: an acute, life-threatening disease in the neonatal period; coma; feeding problems with persistent vomiting and failure-to-thrive; changes in tone with other neurological abnormalities and developmen- tal delay; hepatosplenomegaly with severe liver disease or specific metabolic abnormalities (hypoglycemia, metabolic acidosis, ketosis, hyperammonemia).. ‘The most important initial management is to stabilize the patient: airway, breathing (oxygen, ventilation), circulation, and obtain serum glucose (see later chapters for other considerations). Other labs: complete blood count and differential, cultures (if infection is considered likely), electrolytes, BUN and creatinine, liver enzymes, prothrombin time (PT), partial thromboplastin time (PTT), serum osmolality, serum lactate, plasma ammonia, arterial blood gas, and urinalysis; depending on the results, urine and plasma amino acids and organic acids, + More specifically, to sort out the most common etiologies of a metabolic disease, the following may be used: Obtain a plasma ammonia, blood pH, and serum electrolytes (to calculate the anion gap; see Chapter 3), then: a, Hyperammonemia with no acidosis = urea cycle defect, ’. Normal to high ammonia with an increased anion gap acidosis = organic acidemia ¢. Normal ammonia with a normal anion gap = aminoacidemia or galactosemia Amino-Acid Disorders Phenylketonuria + Most common inborn error that may result in mental retardation; newborn screening is critical to prevent mental retardation, + Deficiency—Phenylalanine (PHE) hydroxylase (PAH) + Biochemistry/testing—With onset of milk feedings > gradual increase of phenyl- Ketones in the urine ~ Increased phenylpyruvic acid > po: green) ~ Increased phenylacetic acid > musty or mousy urine odor - Newborn screen measures increased [PHE] in blood so if there is a positive screen, a serum [PHE] must be drawn. ce urine ferric chloride test (urine turns arMaster THE Boaros: PeDiaTRics 48 + Clinical presentation—Initial feeding problems with vomiting, weight loss, and failure-to thrive; then lethargy, increased muscle tone and deep tendon reflexes, sei- zures, developmental delay, acquired microcephaly and mental retardation; exam may show light complexion and eczema or seborrhea Treatment—Special formulas with decreased PHE; but still need PHE in diet to maintain plasma levels as close to normal as possible Others Most important things to know: + Maple syrup urine disease: Deficiency in enzyme for metabolism of branched chain amino acids (leucine [leu isoleucine [iso], and valine [vall); there is an odor of maple syrup from the breath, urine, and stool; in the classic form, presents in the newborn period with initial poor feeding, vorniting, and progressive lethargy: then alternating hypotonia with hypertonia, opisthotonos, seizures, and coma; survivors with severe motor defects and mental retardation; labs: increased anion gap metabolic acidosis; ketonuria and increased plasma levels of leu, iso, and val. + Hereditary tyrosinemia: Deficiency in last step of tyrosine (tyr) metabolism;an increase in serum tyrosine leads to severe liver, kidney, and peripheral nervous system disease; neonatal screen detects increased tyr in blood (proportional to dietary intake); most present from 2-6 months of life with acute liver disease; also development of Fanconi syndrome (renal proximal tubular disease); high progression to liver failure and later hepatocellular carcinoma, Transient tyrosinemia: delayed maturation of enzyme activity, more common in premature infants; usually normal by 1 month of age with decreased protein intake. + Nonketotichyperglycinemia: Rare defect of glycine (gly) metabolism; severe acute onset of disease in newborn period: hypotonia, decreased reflexes, lethargy, seizures, and coma within the first 2 days of life: significant increase in serum and urine glycine; diagnostic isan increase in cerebrospinal fluid (CSF) glycine out of proportion to that in the serum (ic.,a very large ratio of CSF: plasma gly); increased plasma ammonia but without aci- dosis or ketosis; most die in the neonatal period; transient form: normal by 2 months of age, usually with no long-term problems. Organic Acidemias and Disorders of Fatty-Ac Oxidation and Carnitine Metabolism + Most from methylmalonic and propionic acidemia; also isovaleric acidemia and mul- iple carboxylase deficiency; mostly arise from defects in catabolism of branched-ch: amino acids (iso and val) threonine, methionine, cholesterol, and odd-chain fatty acids. + Hallmarks are metabolic acidosis and encephalopathy. + Newborn disease: feeding problems, vomiting, lethargy, seizures with respiratory distress (severe metabolic acidosis) and hepatomegaly; labs: increased anion gap metabolic acidosis, ketosis and some degree of hyperammonemia; urine shows char- acteristic high amounts of specific metabolites.2: Generic AND MeTABoLIC Disease [-— \sovaleric acidemia + Catabolism of leucine, + Presents basically the same as described above + Baby has a characteristic odor of sweaty feet; blood lab studies show the same, but again the specifi + Definitive diagnosis may be made with cultured skin fibroblasts showing decreased or absent enzymatic activity, or molecular genetic testing can be performed. -reased metabolite in the urine can be identified, Examples of disorders of fatty-acid oxidation + Various acyl-CoA dehydrogenase deficiencies (short, medium, long, and very-long chain deficiencies) + Carnitine transporter defect + Carnitine palmitoyltransferase + Acylcarnitine translocase deficiencies; also defects of ketone metabolism. Abnormalities of fatty-acid oxidation + Especially important with any etiology of decreased caloric intake and with exercise (skeletal muscle). + Main clinical manifestations (medium-chain acyl-CoA dehydrogenase deficiency is, the most common) involve skeletal muscle, liver, and heart, + Presenting findings can be: acute-onset coma and hypoglycemia with mild hepato- megaly (fatty) + Muscle weakness and chronic cardiomyopathy + Particularly symptomatic when the child is old enough to sleep through the night (and. therefore have a long period of fasting). + Labs: hypoglycemia but with low plasma and urinary ketones (hypoketotic hypogly- cemia) and no metabolic acidosis + Increased liver enzymes and abnormal liver function tests. Elevation of specific uri- nary organic acids + Newborn screening can detect abnormal acylcarnitines. Genetic testing can determine the specific mutation. Carnitine + Needed to transport free fatty acids across the inner mitochondrial membrane, where beta-oxidation occurs (ie, in the mitochondria) + Carnitine deficiency (transport defect) leads to abnormal fatty-acid oxidation, + Most present in the first several years of life with progressive muscle weakness and, cardiomyopathy. + Plasma and muscle carnitine levels are very low. Electron transfer defects + Generally produce severe illness in the neonate (acidosis, hypoglycemia, cardiomyopa- thy, and coma) 49Master THE Boaros: PeDiaTRics 50 Defects in ketone synthesis + Generally similar to fatty-acid oxidation, i. fasting hypoketotic hypoglycemia, but without any skeletal or cardiac muscle impairment (with one enzymatic defect) or epi- sodes of severe fasting ketoacidosis (with another) For disorders of very-long chain fatty acids (the peroxisomal disorders), see Chapter 22, Urea-Cycle Defects + Free ammonia, which is toxic, is produced from amino acid catabolism. + Converted to urea in the urea cycle with a series of five enzymes: carbamyl phosphate synthetase (CPS), ornithine transcarbamylase (OTC), argininosuccinate synthetase (AS), argininosuccinate lyase (AL), and arginase. + Most present in the neonatal period within days of normal feeding: feeding problems, hepatomegaly, tachypnea, lethargy, seizures, and coma. + Labs: hyperammonemia, and no acidosis (compare to the organic acidemias). + Mild, transient hyperammonemia may be present in very low birth weight (VLBW) infants for the first 2 months of life; they are asymptomatic and do well + Some premature infants, however, may have significant transient hyperammonemia with very high levels of plasma ammonia, which may be life-threatening. ‘The specific enzyme diagnosis may be sorted out as follows: Hyperammonemia with no acidosis + Obtain plasma amino acids: A specific pattern of elevation will be diagnostic of AS, AL, and arginase deficiencies + Nonspecific pattern (clevated levels of glutamine, alanine, and aspartate) is seen OTC deficiency, CPS deficiency, and transient hyperammonemia of the newborn. To distinguish between these: ~ Obtain urine for orotic acid, High orotic acid concentration is characteristic of OTC deficiency. Normal to low concentration is characteristic of either CPS oF transient hyperammonemia of the newborn. - Obtain a plasma citrulline level. In CPS, it will be low; whereas in transient hyper- atment of acute hyperammonemia is to prevent protein breakdown with adequate calories (glucose, lipids, and minimal amounts of essent {amino acids), to correct dehydration and electrolyte abnormalities, and to remove ammonia (sodium benzo- ate, sodium phenylacetate, and arginine hydrochloride). If the plasma ammonia fails to significantly correct, dialysis is required2: Generic AND MeTABoLIC Disease [-— Defects in Carbohydrate Metabolism Galactosemia ‘The source of galactose is lactose (glucose + galactose), primarily from milkand other dairy products. Galactose has a small contribution to the production of glucose (conversion of galactose-I-phosphate [Gal-1-P] to glucose-1-phosphate [Glu-1-P)) Important in the synthesis of glycolipids, glycoproteins, and glycosaminoglycans. ‘There are three enzyme deficiencies that may lead to galactosemia (see Table 2.10), Table 2.10: Comparison of the Three Enzymatic Deficiencies that Cause Galactosemia PaPeereno ein re unity TD core te a eer CoCr patie) Biochemistry | Cannot convert Gal-1-P to Catalyzes ini Converts UDP-Gal to UDP Glu-1-P; Gal-1-P accumulates _| phosphorylation of Glu; accumulation of cellular in brain, liver, and kidney; galactose; accumulation | UDP-Gal may begin prenatally with of galactose and transplacental galactose galactitol Types Classic complete (or almost- Benign, asymptomatic; complete) deficiency vs. partial diagnosed with neonatal deficiency with milder to screen vs. severe—resembles asymptomatic presentation transferase deficiency Clinical Neonate with vomiting, Asymptomatic except for | A benign form evident presentation | lethargy, failure to gain birth | cataracts only with a positive weight; hepatomegaly, Neonatal screen (deficiency jaundice, liver and renal failure; ‘only in RBCs and WBC), cataracts; increased risk of fora severe form similar Escherichia coli sepsis; if survives to transferase deficiency Untreated, - cirrhosis and and with hypotonia and mental retardation sensorineural deafness ‘Abbreviations: galactose-1-phosphate, Gal-1-P:glucose-1-phosphate, Clu-1-P; ed blood ces, RCs: urdine diphosphate, UDP; white blood cell, WECs Diagnosis and treatment + Urine dipstick with a Clinitest will be positive for reducing substances (ght, gal, fru) but a subsequent Clinistix (glucose oxidase for glucose) will be negative. + Diagnosis is confirmed by assaying the enzyme in RBCs. + Treatment is with a lactose-free diet (elimination of gal from the diet). + With this, all of the findings will regress except for any mental/developmental delays. Fructose deficiencies + Sucrose (fructose + glucose + sorbitol) and free fructose are the dietary sources of fructose, 51Master THE Boaros: PeDiaTRics 52 + Deficiency in fructokinase (conversion of fructose to fructose-1-phosphate) leads to an increased fructose content in the liver and high excretion of fructose in the urine, but this does not lead to problems (benign fructosuria). It usually becomes apparent with ne analysis, where one finds a reducing substance present. icy of fructose 1,6-biphosphate aldolase is called hereditary fructose intoler- ‘There is a toxic accumulation of fructose-1-phosphate (when fructose or suctose is introduced into the diet) that leads to hypoglycemia and features resembling classic galactosemia, Glycogen storage diseases Deficiencies result in abnormalities in the breakdown of glycogen to glucose with accu- mulation of glycogen. There are more than 12 types, and any of the 12 causes prominent liver or muscle problems. The most common types are discussed briefly below: + Von Gierke disease (Type 1): Glucose-6-phosphatase deficiency (little to no activity in liver, kidney, and intestine); problem in conversion of glucose-6-phosphate to glu- cose; most present in first months of life with hypoglycemia (may have seizures), lactic acidosis, and hepatomegaly (with protuberant abdomen); may develop cirthosis and renal failure; characteristic features: short stature with thin extremities and what is described as doll-ike facies; diagnosis with molecular genetic analysis, + Pompe disease (Type II) glycogen in lysosomes (other glycogen storage diseases with glycogen accumm in cytoplasm) with lysosomal glycogen accumulation mostly in skeletal, smooth, and cardiac muscle, Infantile type (with cirrhosis and cardiac failure; huge heart on x-ray) leads to early death, More common presentation: any time from childhood to adult with progression of weakness (more in legs) leading to wheelchair-dependence; there is no severe heart involvement. Labs: increased creatine kinase (CK), lactic acid dehy- drogenase (LADH), and aspartate aminotransferase. Diagnosis is enzyme activity in skin biopsy. + McArdle disease (Type V): Muscle phosphorylase deficiency which leads to glycogen accumulation and decreased production of ATP; presents later in childhood or in the adult with exercise intolerance, cramps, myositis, and rhabdomyolysis, leading to myoglobinuria (during exercise) with acute renal failure. maltase deficiency leads to abnormal breakdown of ion Primary lactic acidosis ‘Caused by defects in gluconeogenesis (e-g., phosphoenolpyruvate carboxylase deficiency) or in the metabolism of pyruvate (during glycolysis or the citric acid cycle). With an unex- plained increased anion gap acidosis, blood should be obtained for pyruvate, lactate, and acylearnitine with urine for organic acids.2: GeWeTiCc AND METABOLIC DISEASE Lactic acidosis from: + Hypoxemia or respiratory chain defects: Serum pyruvate is normal and lactate is significantly increased, therefore there is an increased lactate-pyruvate ratio. + Pyruvate dehydrogenase or gluconeogenesis: Serum pyruvate and lactate are increased, so the lactate-pyruvate ratio is normal. Mucopolysaccharidoses (MPS) Deficiency in enzymes in lysosomes needed to metabolize glycosaminoglycans (primar- ily heparan sulfate); these are complex carbohydrates (with neutral and amino sugars and uronic acid). They are protein-linked for the formation of proteoglycans (in connective tissue and cell/nuclear membranes). With a deficiency in one of the enzymes involve the breakdown of heparan sulfate, fragments accumulate in the lysosomes, which then interfere with cell function. MPS | (spectrum of Scheie to Hurler syndromes) Alpha-L-iduronidase deficiency; depending on the type of mutation, there is variable expression of the disease from the mild Scheie disease to severe Hurler (with an intermedi- ate form); autosomal recessive inheritance; Hurler is severe with death by 10 years of age (respiratory or heart failure); babies are normal at birth but may have inguinal hernias (clue to diagnosis); diagnosis is made thereafter in the first 2 years of life: coarse facies with large tongue and prominent forehead; hepatosplenomegaly, corneal clouding, short stature, joint contractures, skeletal dysplasia (called dysostosis multiplex); patients with Hurler may have cardiomyopathy (with valvular regurgitation and narrowing of the coronary arteries), hydrocephalus, and obstructive airway disease (with repeat infections and deteriorating pulmonary function), MPS II (Hunter disease) Deficiency of iduronate sulfatase; X-linked recessive inheritance, so essentially only in males; wide spectrum of disease; severe disease may look like Hurler, except there corneal cloudiness and there is slower progression of the disease features, with initial findings detected later than Hurler, Most Hunter patients live slightly longer than those with Hurler; may have many Mongolian spots at birth (clue to diagnosis) The other forms of MPS include four types of Sanfilippo disease, two types of Morquio disease, Maroteaux-Lamy disease, Sly disease, and hyaluronidase deficiency. Sphingolipidoses These are lysosomal storage diseases, where deficiency in a hydrolyase leads to accumula tion ofa specific ipid substrate consisting of ceramide, which is the basis for the production of the sphingolipids (essential part of all cell membranes); the sphingolipids are broken down in the nervous system and in visceral organs, RBCs, and WBCs: accumulation of the slycosphingolipids in the CNS results in neurodegenerative disease; systemic findings are present with storage in other organ systems, There is often a broad clinical spectrum of the disease, with various ages of onset, acuity, and severity. Diagnosis is demonstrating 53Master THE Boaros: PeDiaTRics 54 decreased or absent enzyme activity in cultured fibroblasts and with molecular genetic testing to identify the carrier state and for prenatal diagnosis and genetic counseling. In some cases, specific therapies are of value (eg, recombinant enzyme replacement, liver transplantation, bone marrow transplantation, gene therapy), but much of the therapy is supportive. Alll of the following have autosomal recessive inheritance, Tay-Sachs disease and Sandhoff disease (GM, gangliosidosis) + Deficiency: Tay-Sachs: beta-hexosaminidase A only; Sandhoff: beta-hexosaminidose A and B + Accumulation: Lysosomal GM2, especially in CNS + Predilection: Ashkenazi Jews + Key features: Tay-Sachs: infant with motor loss, hyperacusis (with increased startle response), macrocephaly (no hydrocephalus), macular cherry-red spot, seizures and progressive neurodegeneration; death before age 5 years. Sandhoff: similar to Tay- Sachs with prominent hepatosplenomegaly, cardiac involvement, and skeletal abnor- Gaucher disease + Deficiency: Be + Accumulation: Glucosylceramie in reticuloendothelial cells + Pathology: Gaucher cell in the reticuloendothelial system (especially bone marrow): intracytoplasmic inclusions that stain positively + Predilection: The most common of the lipidoses, and Gaucher—not Tay-Sachs. the most prevalent genetic disorder in Ashkenazi Jews. + Key features: Most patients present by adolescence with a non-neuropathic form (infants with an acute, neuropathic form); hepatosplenomegaly (often with huge spleen), bone marrow findings, ic., thrombocytopenia (bruisi ous bleeding), anemia, and bone pain; and skeletal abnormalities with pathologic fractures. mucocutane- Nieman-Pick disease + Deficiency: Acid sphingomyelinase + Accumulation: Sphingomyclin and other lipids in monocytes and macrophages + Key features: Types A and C have neurodegeneration, and type B has systemic mani: festations (pulmonary symptoms in adults; more variable); infants with hepatospleno- megaly, lymphadenopathy, neurodevelopmental regression with severe psychomotor retardation; death by age 3 years Krabbe disease + Deficiency: Galactocerebrosidase + Accumulation: Galactosylceramide (myelin) in neural white matter + Key features: Infant with irritability, hypertonicity, opisthotonos, seizures, severe psy: chomotor retardation, and optic atrophy; death by age 3 years2: Generic AND MeTABoLIC Disease [-— Metachromatic leukodystrophy + Deficiency: Arylsulfatase A + Accumulation: Sulfated glycosphingolipids in neural white matter > demyelination and neurodegeneration + Pathology: Metachromatic neural inclusions that stain positively in white matter + Key features: Most present in first to second year of life with no walking, little or no deep tendon reflexes, hypotonia, and gradual muscle wasting; then nystagmus, loss of any speech, loss of hearing, myoclonic seizures, quadriparesis, and optic atrophy; death in the first 10 years of life. Labs: increased CSF protein, urine sediment meta- chromatic granules, MRI of brain: diffuse symmetric attenuation of white matter Lipoproteins Examples of Hyperlipoproteinemias Familial combined hyperlipidemia + Most common primary lipid disorder; autosomal dominant + Moderate increase in LDL and cholesterol and decreased HDL. + Family history of premature atherosclerotic cardiovascular disease + Dx: two first-degree relative must have either LDL. above the 90th percentile, triglycerides above the 90th percentile, or both + No xanthomas (see below) + Many with metabolic syndrome (see Chapter 16) + Therapy: diet + exercise; consider pharmacotherapy if LDL remains si elevated Familial hypercholesterolemia + Autosomal co-dominant; mutations of LDL receptor (no receptor mutation more severe than defective receptor) + Homozygous (2 gene copies): significant increase in cholesterol, with normal triglycer- ides and small decrease in HDL ~ History of premature cardiovascular disease in first-degree relatives, ~ Poor prognosis: severe atherosclerosis by middle childhood - Xanthomias on tendons (Achilles tendon, hand extensors) or skin = Death during childhood, if untreated Rx: drugs to decrease absorption and synthesis; selective removal of circulating LDL; liver transplant + Heterozygous - Co-dominant with full penetrance > half of first-degree and 25% of second-degree relatives of the affected person will also be affected, ~ Cardiovascular disease symptoms in the 40s for men and 50s for women rst- and second-degree relatives of any child with high cholesterol should be screened ~ Rx: diet modification, pharmacotherapy as above 55Master THE Boarps: Peoiatrics Familial hypertriglyceridemia (Type 1) Autosomal dominant; unknown cause Very high triglyceride levels with or without mildly increased cholesterol and low HDL ‘Mostly presents in adults; less atherogenic; no xanthomas; may present with acute pancreatitis Dx: requires at least one affected first-degree relative Primary Rx is dietary, unless with significant persistent elevations (no fibrates or niacin in children), mostly to prevent pancreatitis