Pediatrics_Nelson

Pediatrics_Nelson. Errors that occur in meiosis during the production of gametes can lead to abnormalities of chromosome structure or number. Syndromes caused by chromosomal abnormalitiesinclude trisomy 21 (Down syndrome or DS), trisomy 13, trisomy 18, Turner syndrome (TS), and Klinefelter syndrome (KS), as well as rarer chromosomal duplications, deletions, or inversions.


Pediatrics_Nelson

Pediatrics_Nelson. Chromosomal abnormalities occur in approximately 8% of fertilized ova but in only 0.6% of liveborn infants. Fifty percent of spontaneous abortuses have chromosomal abnormalities, the most common being 45,X (TS); an estimated 99% of 45,X fetuses are spontaneously aborted. The fetal loss rate for DS, the most viable of the autosomal aneuploidies, approaches 80%. Most other chromosomal abnormalities also adversely affect fetal viability. In newborns and older children, features that suggest the presence of a chromosome anomaly include low birth weight (small for gestational age), failure to thrive, developmental delay, and the presence of three or more congenital malformations. During meiosis or mitosis, failure of a chromosomal pair to separate properly results in nondisjunction. Aneuploidy is a change in the number of chromosomes that results from non-disjunction. A cell may have one (monosomy) or three (trisomy) copies of a particular chromosome. Available @ StudentConsult.com


Pediatrics_Nelson

Pediatrics_Nelson. Available @ StudentConsult.com DS is the most common abnormality of chromosomal number. It occurs in 1 of every 1000 births. Most cases (92.5%)are due to nondisjunction; in 68%, the nondysjunctionalevent occurs in maternal meiosis phase I. As a result ofnondisjunction, there are three copies of chromosome 21(trisomy 21); using standard cytogenetic nomenclature, trisomy 21 is designated 47,XX,+21 or 47,XY,+21. In 4.5%of cases, the extra chromosome is part of a robertsonian translocation, which occurs when the long arms (q) of twoacrocentric chromosomes (numbers 13, 14, 15, 21, or 22)fuse at the centromeres, and the short arms (p), containing copies of ribosomal RNA, are lost. The most commonrobertsonian translocation leading to DS involves chromosomes 14 and 21; standard nomenclature is 46,XX,t(14q21q)or 46,XY,t(14q21q). The parents of DS infants with trans-locations should have a karyotype to exclude a balancedtranslocation.


Pediatrics_Nelson

Pediatrics_Nelson. In approximately 1% to 2% of children with DS, mosaicism occurs. These individuals have two populations of cells: one with trisomy 21 and one with a normal chromosome complement. Mosaicism results from a either a nondisjunctional event that occurs after fertilization and after a few cell divisions, or from trisomic rescue. The loss of this aneuploidy returns the cell to 46,XX or 46,XY. In either case, the individual is referred to as a mosaic for these two populations of cells and is designated 47,XX, +21/46XX or 47,XY,+21/46,XY. Although it is widely believed that individuals with mosaic DS are more mildly affected, there are wide variations in the clinical findings.


Pediatrics_Nelson

Pediatrics_Nelson. Children with DS are most likely diagnosed in the newbornperiod. These infants tend to have normal birth weight andlength, but are hypotonic. The characteristic facial appearance,with brachycephaly, flattened occiput, hypoplastic midface, flattened nasal bridge, upslanting palpebral fissures, epicanthal folds,and large protruding tongue, is apparent at birth. Infants also haveshort broad hands, often with a single transverse palmar crease,and a wide gap between the first and second toes. The severe hypotonia may cause feeding problems and decreased activity. Approximately 50% of children with DS have congenital heart disease, including atrioventricular canal, ventriculoseptal or atrioseptal defects, and valvular disease. Approximately 10% of newborns with DS have gastrointestinal tract anomalies. The three most common defects are duodenal atresia, annular pancreas, and imperforate anus.


Pediatrics_Nelson

Pediatrics_Nelson. Four percent to 18% of infants with DS are found to have congenital hypothyroidism, which is identified as part of the newborn screening program. Acquired hypothyroidism is a more common problem. Thyroid function testing must be monitored periodically during the child’s life. Polycythemia at birth (hematocrit levels >70%) is common and may require treatment. Some infants with DS showa leukemoid reaction, with markedly elevated white blood cellcounts. Although this resembles congenital leukemia, it is a self-limited condition, resolving on its own over the first monthof life. Nonetheless, children with DS also have an increased risk of leukemia, with a 10to 20-fold increase in risk compared with individuals without DS. In children with DS youngerthan 2 year of age, the type is generally acute megakaryoblasticleukemia; in individuals older than 3 years of age, the types ofleukemia are similar to those of other children, with acute lymphoblastic leukemia being the predominant type.


Pediatrics_Nelson

Pediatrics_Nelson. Children with DS are more susceptible to infection, more likely to develop cataracts, and approximately 10% have atlantoaxial instability, an increased distance between the first and second cervical vertebrae that may predispose to spinal cord injury. Many individuals older than 35 years of age develop Alzheimer-like features.


Pediatrics_Nelson

Pediatrics_Nelson. The recurrence risk for parents who have had a child with DS depends on the child’s cytogenetic findings. If the child has trisomy 21, the empiric recurrence risk is 1% (added to the age-specific risk for women up to 40 years of age; after 40, the age-specific risk alone is used for subsequent pregnancies). If the child has a robertsonian translocation, chromosomal analysis of both parents must be performed. In approximately 65% of cases, the translocation is found to have arisen de novo (i.e., spontaneously, with both parents having normal karyotypes), and in 35% of cases, one parent has a balanced translocation. The recurrence risk depends on which parent is the carrier: if the mother is the carrier, the risk is 10% to 15%; if the father is the carrier, the recurrence risk is 2% to 5%.


Pediatrics_Nelson

Pediatrics_Nelson. Trisomy 18 (47,XX,+18 or 47,XY,+18) is the second most common autosomal trisomy, occurring in approximately 1 in 7500 live births. More than 95% of conceptuses with trisomy 18 are spontaneously aborted in the first trimester. Trisomy 18 is usually lethal; fewer than 10% of affected infants survive until their first birthday. Most infants with trisomy 18 are small for gestational age. Clinical features include hypertonia, prominent occiput, micrognathia, low-set and malformed ears, short Head and face Scalp defects (e.g., cutis aplasia) Microphthalmia, corneal abnormalities Cleft lip and palate in 60%–80% of cases Microcephaly Sloping forehead Holoprosencephaly (arrhinencephaly) Capillary hemangiomas Deafness Small and premature appearance Tight palpebral fissures Narrow nose and hypoplastic nasal alae Narrow bifrontal diameter Prominent occiput Micrognathia Cleft lip or palate Available @ StudentConsult.com


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Pediatrics_Nelson. Available @ StudentConsult.com Occurring in 1 in 500 male births, KS is the most commongenetic cause of hypogonadism and infertility in men. It is causedby the presence of an extra X chromosome (47,XXY) (see Chapter 174). The extra X chromosome arises from a nondisjunctionin either the sperm or the egg. About 15% of boys with featuresof KS are found to be mosaic, with 46,XY/47,XXY mosaicismbeing the most common. Before puberty, boys with KS are phenotypically indistinguishable from the rest of the population. The diagnosis is often made when the boy is 15 or 16 years ofage. At that point, the finding of the progressive developmentof pubic and axillary hair in the presence of testes that remaininfantile in volume should alert the clinician to the disorder. Adolescents and young adults with KS tend to be tall, with longlimbs. During adolescence or adulthood, gynecomastia occurs.


Pediatrics_Nelson

Pediatrics_Nelson. Because of failure of growth and maturation of the testes, males with KS have testosterone deficiency and failure to produce viable sperm. Low production of testicular testosterone results in failure to develop later secondary sexual characteristics, such as facial hair, deepening of the voice, and libido. In adulthood, osteopenia and osteoporosis develop. Because of these findings, testosterone supplementation is indicated. Most men with KS are infertile because they produce few viable sperm. Through the use of isolation of viable sperm through testicular biopsy, coupled with in vitro fertilization and intracytoplasmic sperm injection, it is possible for men with KS to father children; all children born to these men using this technology have had a normal chromosome complement. Available @ StudentConsult.com


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Pediatrics_Nelson. Available @ StudentConsult.com TS is the only condition in which a monosomic conceptus survives to term; however, 99% of embryos with 45,X are spontaneously aborted. The most common aneuploidy found in conceptuses (accounting for 1.4%,), 45,X is seen in 13% of first-trimester pregnancy losses. Occurring in 1 in 3200 live-born females, TS is notable for its spectrum of relatively mild physical and developmental findings. Affected women tend to have normal intelligence and life expectancy. Females with TS typically have a characteristic facial appearance with low-set, mildly malformed ears, triangular face, flattened nasal bridge, and epicanthal folds. There is webbing of the neck, with or without cystic hygroma, a shield-like chestwith widened internipple distance, and puffiness of the hands Extremities Overlapping of fingers and toes (clinodactyly) Polydactyly Hypoplastic nails, hyperconvex nails


Pediatrics_Nelson

Pediatrics_Nelson. Extremities Overlapping of fingers and toes (clinodactyly) Polydactyly Hypoplastic nails, hyperconvex nails General Severe developmental delays and prenatal and postnatal growth retardation Renal abnormalities Nuclear projections in neutrophils Only 5% live >6 mo Limited hip abduction Clinodactyly and overlapping fingers; index over third, fifth over fourth Rocker-bottom feet Hypoplastic nails Severe developmental delays and prenatal and postnatal growth retardation Premature birth, polyhydramnios Inguinal or abdominal hernias Only 5% live >1yr ASD, Atrial septal defect; PDA, patent ductus arteriosus; VSD, ventricular septal defect. sternum, rocker-bottom feet, hypoplastic nails, and characteristic clenching of fists—the second and fifth digits overlap the third and fourth digits (Table 49-1).


Pediatrics_Nelson

Pediatrics_Nelson. sternum, rocker-bottom feet, hypoplastic nails, and characteristic clenching of fists—the second and fifth digits overlap the third and fourth digits (Table 49-1). The third of the common trisomies, trisomy 13 (47,XX,+13 or 47,XY,+13) occurs in 1 in 12,000 live births. It is usually fatal in the first year of life; only 8.6% of infants survive beyond their first birthday.


Pediatrics_Nelson

Pediatrics_Nelson. Infants with trisomy 13 have numerous malformations (seeTable 49-1). These infants are small for gestational age and microcephalic. Midline facial defects such as cyclopia (singleorbit), cebocephaly (single nostril), and cleft lip and palate arecommon, as are midline central nervous system anomalies, suchas alobar holoprosencephaly. The forehead is generally sloping,ears are often small and malformed, and microphthalmia oranophthalmia may occur. Postaxial polydactyly of the hands iscommon, as is clubfeet or rocker-bottom feet. Hypospadias andcryptorchidism are common in boys, whereas girls generallyhave hypoplasia of the labia minora. Most infants with trisomy13 also have congenital heart disease. Many infants with thiscondition have a punched-out scalp lesion over the occiputcalled aplasia cutis congenita; when seen in conjunction with polydactyly and some or all of the facial findings, this findingis essentially pathognomonic for the diagnosis of trisomy 13.


Pediatrics_Nelson

Pediatrics_Nelson. and feet. Internal malformations may include congenital heartdefect (in 45%, coarctation of the aorta is the most commonanomaly, followed by bicuspid aortic valve; later in life, poststenotic aortic dilation with aneurysm may develop). Renalanomalies, including horseshoe kidney, are seen in more than50% of patients. Short stature is a cardinal feature of this condition, and acquired hypothyroidism is estimated to occur fivetimes more frequently in women with TS than in the generalpopulation. The presence of streak gonads (gonadal dysgenesis) instead of well-developed ovaries leads to estrogen deficiency, which prevents these women from developing secondary sexual characteristics and results in amenorrhea. Although 10% of women with TS may have normal pubertal development and are even fertile, most affected women require estrogen replacement to complete secondary sexual development.


Pediatrics_Nelson

Pediatrics_Nelson. Infertility in these women is not corrected by estrogen replacement. Assisted reproductive technology using donor ova hasallowed women with TS to bear children. During pregnancy,these women must be followed carefully, because poststenoticdilatation of the aorta, leading to dissecting aneurysm, may occur. Many girls with TS escape detection during the newborn period because phenotypic features are subtle. About 33% of children with TS are diagnosed in the newborn period because of the presence of heart disease and physical features; another 33% are diagnosed in childhood, often during a workup for short stature (and receive growth hormone therapy); the final 33% are diagnosed during adolescence when they fail to develop secondary sexual characteristics.


Pediatrics_Nelson

Pediatrics_Nelson. The karyotypic spectrum in girls with TS is wide. Only 50% have a 45,X karyotype; 15% have an isochromosome Xq [46,X,i(Xq)], in which one X chromosome is represented by two copies of the long arm (leading to a trisomy of Xq and a monosomy of Xp); and approximately 25% are mosaic (45,X/46,XX or 45,X/46,XY). Deletions involving the short (p) arm of the X chromosome (Xp22) produce short stature and congenital malformations, whereas deletions of the long arm (Xq) cause gonadal dysgenesis. Although monosomy X is caused by nondisjunction, TS is not associated with advanced maternal age. Rather, it is believed that the 45,X karyotype results from a loss of either an X or a Y chromosome after conception; that is, it is a postconceptual mitotic (rather than meiotic) nondisjunctional event.


Pediatrics_Nelson

Pediatrics_Nelson. A deletion in the short arm of chromosome 5 is responsible forcri du chat syndrome, with its characteristic catlike cry duringearly infancy, the result of tracheal hypoplasia. Other clinical features include low birth weight and postnatal failure to thrive, hypotonia, developmental disability, microcephaly, andcraniofacial dysmorphism, including ocular hypertelorism,epicanthal folds, downward obliquity of the palpebral fissures,and low-set malformed ears. Clefts of the lip and palate, congenital heart disease, and other malformations may be seen. The clinical severity of cri du chat syndrome depends on thesize of the chromosomal deletion. Larger deletions are associated with more severe expression. Most cases arise de novo;the deletion is usually in the chromosome 5 inherited from thefather. Available @ StudentConsult.com


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Pediatrics_Nelson. Available @ StudentConsult.com Williams syndrome is due to a small deletion of chromosome 7q11.2. Congenital heart disease is seen in 80% of affected children, with supravalvar aortic-valve and pulmonic-valve stenosis and peripheral pulmonic stenosis being the most common anomalies. Although these children often have normal birth weight, they have growth delay, manifesting short stature. They have a distinctive facial appearance (“elfin facies”), with median flare of the eyebrows, fullness of the perioral and periorbital region, blue irides with a stellate pattern of pigment, and depressed nasal bridge with anteversion of the nares. Moderate intellectual disability (average IQ in the 50 to 60 range) is common, but developmental testing reveals strength in personal social skills and deficiencies in cognitive areas. Hypercalcemia is present in neonates.


Pediatrics_Nelson

Pediatrics_Nelson. Individuals with Williams syndrome often have a striking personality. Loquacious and gregarious, they are frequently described as having a cocktail party personality. However, approximately 10% of children with Williams syndrome have features of autism spectrum disorder. Patients occasionally have unusual musical ability (about 20% have absolute or perfect pitch). Most children with Williams syndrome have a de novo deletion. In rare cases, the deletion is inherited from a parent in an autosomal dominant pattern. WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, and mental retardation) is caused by a deletion of 11p13 and is generally a de novo deletion. Genitourinary abnormalities include cryptorchidism and hypospadias. Patients often have short stature, and half may have microcephaly. Wilms tumor develops in 50% of patients with aniridia, genitourinary abnormalities, and mental retardation (see Chapter 159). SEE CHAPTER 47. SEE CHAPTER 47.


Pediatrics_Nelson

Pediatrics_Nelson. SEE CHAPTER 47. SEE CHAPTER 47. Chromosome 22q11.2 Deletion Syndromes Available @ StudentConsult.com Deletions of chromosome 22q11.2 are responsible for a group of findings that have been called by several names, including velocardiofacial syndrome, conotruncal anomaly face syndrome, Shprintzen syndrome, and DiGeorge syndrome. These conditions represent a continuum of findings, virtually all of which are due to the chromosomal deletion.


Pediatrics_Nelson

Pediatrics_Nelson. These conditions represent a continuum of findings, virtually all of which are due to the chromosomal deletion. Although chromosome 22q11.2 deletions can be inherited inan autosomal dominant fashion, most cases arise de novo. Common features include clefting of the palate with velopharyngealinsufficiency; conotruncal cardiac defects (including truncusarteriosus, ventriculoseptal defect, tetralogy of Fallot, and right-sided aortic arch); and a characteristic facial appearance, including a prominent nose and a broad nasal root. Speech and languagedifficulties are common, as is mild intellectual impairment. Morethan 200 additional abnormalities have been identified in individuals with these conditions. About 70% have immunodeficiencies, largely related to T-cell dysfunction. A wide spectrumof psychiatric disturbances, including schizophrenia and bipolardisorder, has been seen in more than 33% of affected adults.


Pediatrics_Nelson

Pediatrics_Nelson. Damage to the third and fourth pharyngeal pouches, embryonic structures that form parts of the cranial portion of thedeveloping embryo, leads to abnormalities in the developingface (clefting of the palate, micrognathia), the thymus gland,the parathyroid glands, and the conotruncal region of the heart.This spectrum of findings, called the DiGeorge malformationsequence, is an important chromosome 22 deletion syndrome. The deletion that occurs in chromosome 22q11 is usually too small to be seen by standard chromosome analysis; either fluorescent in situ hybridization or chromosomal microarray is needed to identify the deletion. A gene called TBX1 is within the deleted sequence. It is believed that deletion of one copy of TBX1 is responsible for many of the features of the various 22q11 deletion syndromes.


Pediatrics_Nelson

Pediatrics_Nelson. Duplications and deletions occur secondary to misalignment and unequal crossing over during meiosis. Small extra chromosomes are found in a small percentage of the population (0.06%). These “marker” chromosomes sometimes are associated with mental retardation and other abnormalities, and other times they have no apparent phenotypic effects.


Pediatrics_Nelson

Pediatrics_Nelson. Chromosome 15 is the most common of all marker chromosomes, and its inverted duplication accounts for almost 40% of this group of chromosomal abnormalities. Features seen in children with 47,XX,+inv dup (15q) or 47,XY,inv dup(15q) depend on the size of the extra chromosomal material present: the larger the region, the worse the prognosis. Children with this disorder tend to have a variable degree of developmental disability and autism spectrum disorders; seizures are common, as are behavior problems. The phenotype shows minimal dysmorphic features, with a sloping forehead, short and downward-slanting palpebral fissures, a prominent nose with a broad nasal bridge, a long and well-defined philtrum, a mid-line crease in the lower lip, and micrognathia.


Pediatrics_Nelson

Pediatrics_Nelson. Named for the iris coloboma that gives patients’ eyes a catlikeappearance, cat eye syndrome is due to a small, supernumerarychromosome with an inversion duplication of 22q11. The twocopies of 22q11 on this extra chromosome plus the two normal copies of chromosome 22 result in four copies of this region.Although the colobomas name the syndrome, they occur infewer than 50% of individuals with the marker chromosome. Other clinical features include mild mental retardation, behavioral disturbances, mild ocular hypertelorism, downward-slanting palpebral fissures, micrognathia, auricular pits and/or tags,anal atresia with rectovestibular fistula, and renal agenesis.


Pediatrics_Nelson

Pediatrics_Nelson. Dysmorphology is the recognition of the pattern of congenital malformations (often multiple congenital malformations) and dysmorphic features that characterize a particular syndrome. Syndromes are collections of abnormalities, including malformations, deformations, dysmorphic features, and abnormal behaviors that have a unifying, identifiable etiology. This etiology may be the presence of a mutation in a single gene, as is the case in Rett syndrome, a disorder that is caused by a mutation in the MECP2 gene on Xq28; by the deletion or duplication of chromosomal material, as is the case in Prader-Willi syndrome, which is caused by the deletion of the paternal copy of the imprinted SNRPN gene on chromosome 15q11.2; or by exposure to a teratogenic substance during embryonic development, as in fetal alcohol spectrum disorder.


Pediatrics_Nelson

Pediatrics_Nelson. Congenital malformations are defined as clinically significant abnormalities in either form or function. They result from localized intrinsic defects in morphogenesis, which were caused by an event that occurred in embryonic or early fetal life. This event may have been a disturbance of development from some unknown cause, but often mutations in developmental genes led to the abnormality. Extrinsic factors may cause disruptions of development by disturbing the development of apparently normal tissues. These disruptions may include amniotic bands, disruption of blood supply to developing tissues, or exposure to teratogens. A malformation sequence is the end result of a malformation that has secondary effects on later developmental events. An example is the Pierre Robin sequence. The primary malformation, failure of the growth of the mandible during the first weeks of gestation, results in micrognathia, which forces the normal-sized tongue into an unusual position. The abnormally placed


Pediatrics_Nelson

Pediatrics_Nelson. malformation, failure of the growth of the mandible during the first weeks of gestation, results in micrognathia, which forces the normal-sized tongue into an unusual position. The abnormally placed tongue blocks the fusion of the palatal shelves, which normally come together in the midline to produce the hard and soft palate; this leads to the presence of a U-shaped cleft palate. After delivery, the normal-sized tongue in the smaller than normal oral cavity leads to airway obstruction, a potentially life-threatening complication. Pierre Robin sequence comprises a triad of anomalies (micrognathia, U-shaped cleft palate, and obstructive apnea) which results from a single malformation, the failure of the jaw to grow at a critical time during gestation. Many children with Pierre Robin syndrome have Stickler syndrome, an autosomal dominant disorder caused by mutations in collagen genes. Stickler syndrome also manifests with ocular and musculoskeletal abnormalities.


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Pediatrics_Nelson. Deformations arise as a result of environmental forces acting on normal structures. They occur later in pregnancy or after delivery. For instance, plagiocephaly (rhomboid shaped head) may result from intrauterine positioning or from torticollis experienced in the newborn period. Deformations often resolve with minimal intervention, but malformations often require surgical and medical management.


Pediatrics_Nelson

Pediatrics_Nelson. Minor malformations, variants of normal that occur in less than 3% of the population, include findings such as single transverse palmar creases, low-set ears, or hypertelorism; when isolated, they have no clinical significance. A multiple malformation syndrome is the recognizable pattern of anomalies that results from a single identifiable underlying cause. It may involve a series of malformations, malformation sequences, and deformations. These syndromes often prompt a consultation with a clinical geneticist. Dysmorphology is the specialty focusing on recognition of patterns of malformations that occur in syndromes (Table 50-1).


Pediatrics_Nelson

Pediatrics_Nelson. An association differs from a syndrome in that in the former, no single underlying etiology explains the recognizable pattern of anomalies that occur together more often than would be expected by chance alone. The VACTERL association (vertebral anomalies, anal atresia, cardiac defects, tracheoesophageal fistula, renal anomalies, and limb anomalies) is an example of a group of malformations that occur more commonly together than might be expected by chance. No single unifying etiology explains this condition, so it is considered an association.


Pediatrics_Nelson

Pediatrics_Nelson. In approximately 50% of children noted to have one or more congenital malformations, only a single malformation is identifiable; in the other 50%, multiple malformations are present. About 6% of infants with congenital malformations have chromosomal defects, 7.5% have a single gene disorder, 20% have conditions that are due to multifactorial effects (an interplay between genetic and environmental factors), and approximately 7% are due to exposure to a teratogen. In more than 50% of cases, no cause can be identified.


Pediatrics_Nelson

Pediatrics_Nelson. The history of the pregnancy and birth can reveal multiple riskfactors that are associated with dysmorphology. Small for gestational age infants may have a chromosome anomaly or may havebeen exposed to a teratogen. Large for gestational age infantsmay be infants of diabetic mothers or have an overgrowth syndrome, such as Beckwith-Wiedemann syndrome. When evaluating an older child with intellectual disabilities, complicationsof extreme prematurity may account for the child’s problems.Postmaturity also is associated with some chromosome anomalies (e.g., trisomy 18) and anencephaly. Infants born from breechpresentation are more likely to have congenital malformations. As a woman gets older there is increased risk of nondisjunction leading to trisomies. Advanced paternal age may be Brachycephaly: Condition in which head shape is shortened from front to back along the sagittal plane; the skull is rounder than normal


Pediatrics_Nelson

Pediatrics_Nelson. Brachycephaly: Condition in which head shape is shortened from front to back along the sagittal plane; the skull is rounder than normal Canthus: The lateral or medial angle of the eye formed by the junction of the upper and lower lids Columella: The fleshy tissue of the nose that separates the nostrils Glabella: Bony midline prominence of the brows Nasal alae: The lateral flaring of the nostrils Nasolabial fold: Groove that extends from the margin of the nasal alae to the lateral aspects of the lips Ocular hypertelorism: Increased distance between the pupils of the two eyes Palpebral fissure: The shape of the eyes based on the outline of the eyelids Philtrum: The vertical groove in the midline of the face between the nose and the upper lip Plagiocephaly: Condition in which head shape is asymmetric in the sagittal or coronal planes; can result from asymmetry in suture closure or from asymmetry of brain growth


Pediatrics_Nelson

Pediatrics_Nelson. Scaphocephaly: Condition in which the head is elongated from front to back in the sagittal plane; most normal skulls are scaphocephalic Synophrys: Eyebrows that meet in the midline Telecanthus: A wide space between the medial canthi Brachydactyly: Condition of having short digits Camptodactyly: Condition in which a digit is bent or fixed in the direction of flexion (a “trigger finger”–type appearance) Clinodactyly: Condition in which a digit is crooked and curves toward or away from adjacent digits Hypoplastic nail: An unusually small nail on a digit Melia: Suffix meaning “limb” (e.g., amelia—missing limb; brachymelia—short limb) Polydactyly: The condition of having six or more digits on an extremity


Pediatrics_Nelson

Pediatrics_Nelson. Melia: Suffix meaning “limb” (e.g., amelia—missing limb; brachymelia—short limb) Polydactyly: The condition of having six or more digits on an extremity Syndactyly: The condition of having two or more digits at least partially fused (can involve any degree of fusion, from webbing of skin to full bony fusion of adjacent digits) associated with the risk of a new mutation leading to an autosomal dominant trait. Maternal medical problems and exposures (medications, drugs, cigarette smoking, and alcohol use) are associated with malformations (see Chapters 47 and 48). An increased amount of amniotic fluid may be associatedwith intestinal obstruction or a central nervous system anomalythat leads to poor swallowing. A decreased amount of fluid maybe the result of a chronic amniotic fluid leak or point to a urinary tract abnormality that results in a failure to produce urine.


Pediatrics_Nelson

Pediatrics_Nelson. A pedigree comprising at least three generations should be constructed, searching for similar or dissimilar abnormalities in firstand second-degree relatives. A history of pregnancy or neonatal losses should be documented. For a more detailed discussion of pedigrees, see Chapter 47. When examining children with dysmorphic features, the following approach should be used. The height (length), weight, and head circumference should bemeasured carefully and plotted on appropriate growth curves.Small size or growth restriction may be secondary to a chromosomal abnormality, skeletal dysplasia, or exposure to toxic orteratogenic agents. Larger than expected size suggests an overgrowth syndrome (Sotos or Beckwith-Wiedemann syndrome)or, in the newborn period, might suggest a diabetic mother.


Pediatrics_Nelson

Pediatrics_Nelson. The clinician should note if the child is proportionate. Limbsthat are too short for the head and trunk imply the presence ofa short-limbed bone dysplasia, such as achondroplasia. A trunkand head that are too short for the extremities suggest a disorderaffecting the vertebrae, such as spondyloepiphyseal dysplasia. Available @ StudentConsult.com Abnormal Head Size, Shape, and Fontanels Careful examination of the head and face is crucial for the diagnosis of many congenital malformation syndromes. Head shape should be carefully assessed; if the head is not normal in size and shape (normocephalic), it may be long and thin (dolichocephalic), short and wide (brachycephalic), or asymmetric or lopsided (plagiocephalic).


Pediatrics_Nelson

Pediatrics_Nelson. Any asymmetry of facial features should be noted. Asymmetry may be due to a deformation related to intrauterine positionor a malformation of one side of the face. The face should be divided into four regions, which are evaluated separately. Theforehead may show overt prominence (achondroplasia) or deficiency (often described as a sloping appearance, which occurs inchildren with primary microcephaly). The midface, extendingfrom the eyebrows to the upper lip and from the outer canthi ofthe eyes to the commissures of the mouth, is especially important. Careful assessment of the distance between the eyes (innercanthal distance) and the pupils (interpupillary distance) mayconfirm the impression of hypotelorism (eyes that are too closetogether), which suggests a defect in midline brain formation, or hypertelorism (eyes that are too far apart). The length of thepalpebral fissure should be noted and may help define whetherthe opening for the eye is short, as is found with fetal


Pediatrics_Nelson

Pediatrics_Nelson. brain formation, or hypertelorism (eyes that are too far apart). The length of thepalpebral fissure should be noted and may help define whetherthe opening for the eye is short, as is found with fetal alcoholsyndrome, or excessively long, as in Kabuki makeup syndrome(short stature, mental retardation, long palpebral fissures witheversion of lateral portion of lower lid).


Pediatrics_Nelson

Pediatrics_Nelson. Other features of the eyes should be noted. The obliquity(slant) of the palpebral fissures may be upward (as seen withDown syndrome) or downward (as in Treacher Collins syndrome). The presence of epicanthal folds (Down syndromeand fetal alcohol syndrome) is also important. Features of the nose—especially the nasal bridge, which can be flattened in Down syndrome, fetal alcohol syndrome, and many other syndromes, or prominent as in velocardiofacial syndrome—shouldbe noted. The malar region of the face is examined next. It extends from the ear to the midface. The ears should be checked for size (measured and checked against appropriate growth charts), shape, position (low-set ears are below a line drawn from the outer canthus to the occiput), and orientation (posterior rotation is where the ear appears turned toward the rear of the head). Ears may be low set because they are small (or microtic) or because of a malformation of the mandibular region.


Pediatrics_Nelson

Pediatrics_Nelson. The mandibular region is the area from the lower portion of the ears bounded out to the chin by the mandible. In most newborns, the chin is often slightly retruded (that is, slightly behind the vertical line extending from the forehead to the philtrum). If this retrusion is pronounced, the child may have the Pierre Robin malformation sequence. In addition, the mouth should be examined. The number and appearance of the teeth should be noted, the tongue should be observed for abnormalities, and the palate and uvula checked for defects. Examination of the neck may reveal webbing, a common featurein Turner syndrome and Noonan syndrome, or shortening, as isseen occasionally in some skeletal dysplasias and in conditions inwhich anomalies of the cervical spine occur, such as Klippel-Feilsyndrome. The position of the posterior hairline also should beevaluated. The size of the thyroid gland should be assessed.


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Pediatrics_Nelson. The chest may be examined for shape (shield-like chest in Noonan syndrome and Turner syndrome) and for symmetry. The presence of a pectus deformity should be noted and is common in Marfan syndrome. The presence of scoliosis should be assessed; it is common in Marfan syndrome and many other syndromes. Many congenital malformation syndromes are associated withanomalies of the extremities. All joints should be examined forrange of motion. The presence of single or multiple joint contractures suggests either intrinsic neuromuscular dysfunction, as insome forms of muscular dystrophy, or external deforming forcesthat limited motion of the joint in utero. Multiple contracturesalso are found with arthrogryposis multiplex congenita and are due to a variety of causes. Radioulnar synostosis, an inability topronate or supinate the elbow, occurs in fetal alcohol spectrumdisorder and in some X chromosome aneuploidy syndromes.


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Pediatrics_Nelson. Examination of the hands is important. Polydactyly (the presence of extra digits) usually occurs as an isolated autosomal dominant trait but also can be seen in trisomy 13.Oligodactyly (a deficiency in the number of digits) is seenin Fanconi syndrome (anemia, leukopenia, thrombocytopenia, and associated heart, renal, and limb anomalies—usuallyradial aplasia and thumb malformation or aplasia), in whichit is generally part of a more severe limb reduction defect, orsecondary to intrauterine amputation, which may occur withamniotic band disruption sequence. Syndactyly (a joining of two or more digits) is common to many syndromes, including Smith-Lemli-Opitz syndrome (see Chapters 199 and201).


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Pediatrics_Nelson. Dermatoglyphics include palmar crease patterns. A transverse palmar crease, indicative of hypotonia during early fetal life, is seen in approximately 50% of children with Down syndrome (and 10% of individuals in the general population). A characteristic palmar crease pattern is also seen in fetal alcohol spectrum disorder. Available @ StudentConsult.com


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Pediatrics_Nelson. Available @ StudentConsult.com Genitalia should be examined closely for abnormalities in structure. In boys, if the penis appears short, it should be measured and compared with known age-related data. Ambiguous genitalia often are associated with endocrinologic disorders, such as congenital adrenal hyperplasia (girls have masculinized external genitalia, but male genitalia may be unaffected), or chromosomal disorders such as 45,X/46,XY mosaicism or possibly secondary to a multiple congenital anomaly syndrome (see Chapters 174 and 177). Although hypospadias, which occurs in 1 in 300 newborn boys, is a common congenital malformation that often occurs as an isolated defect, if it is associated with other anomalies, especially cryptorchidism, there is a strong possibility of a syndrome.


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Pediatrics_Nelson. Chromosome analysis should be ordered for children with multiple congenital anomalies, the involvement of one major organ system and the presence of multiple dysmorphic features, or the presence of mental retardation. In recent years, microarray comparative genomic hybridization has supplanted routine or high-resolution chromosome analysis in most situations. For a complete discussion of chromosome analysis, see Chapter 48. Direct DNA analysis can be performed to identify specific mutations. It is necessary to use Web-based resources to keep up-to-date. An extremely helpful website is www.genetests.org , which provides information about the availability of testing for specific conditions and identifies laboratories performing the testing.


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Pediatrics_Nelson. Radiologic imaging plays an important role in the evaluation of children with dysmorphic features. Individuals found to have multiple external malformations should have a careful evaluation to search for the presence of internal malformations. Testing might include ultrasound evaluations of the head and abdomen to look for anomalies in the brain, kidney, bladder, liver, and spleen. Skeletal radiographs should be performed if there is concern about a possible skeletal dysplasia. The presence of a heart murmur should trigger a cardiology consultation; an electrocardiogram and echocardiogram may be indicated. Magnetic resonance imaging may be indicated in children with neurologic abnormalities or a spinal defect. The presence of craniosynostosis may indicate a computed tomography scan of the head. For those patients for whom testing does not yield a diagnosis, whole-exome sequencing or whole-genome sequencing is becoming a powerful tool.


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Pediatrics_Nelson. For those patients for whom testing does not yield a diagnosis, whole-exome sequencing or whole-genome sequencing is becoming a powerful tool. Although the presence of characteristic findings may make the diagnosis of a malformation syndrome straightforward, in most cases no specific diagnosis is immediately evident. Some constellations of findings are rare, and finding a “match” may prove difficult. In many cases, all laboratory tests are normal, and confirmation relies on subjective findings. Clinical geneticists have attempted to resolve this difficulty by developing scoring systems, cross-referenced tables of anomalies that help in the development of a differential diagnosis, and computerized diagnostic programs. An accurate diagnosis is important for the following reasons: 1. It offers an explanation to the family why their child was born with congenital anomalies. This may help allay guilt for parents, who often believe they are responsible for their child’s problem. 2.


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Pediatrics_Nelson. 2. With well-described natural histories of many disorders, a diagnosis allows anticipation of medical problems associated with a particular syndrome and appropriate screening. It also provides reassurance that other medical problems are no more likely to occur than they might with other children who do not have the diagnosis. 3. It permits genetic counseling to be done to identify the risk to future children and permits prenatal testing to be done for the disorders for which it is available.


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Pediatrics_Nelson. 3. It permits genetic counseling to be done to identify the risk to future children and permits prenatal testing to be done for the disorders for which it is available. Diagnosis enables the clinician to provide the family with educational materials about the diagnosis and facilitate contactwith support groups for particular disorders. The Internet hasbecome an important source for such information. Care shouldbe exercised, as information on the Internet is not subject to editorial control and may be inaccurate. A good site is the NationalOrganization for Rare Disorders ( www.rarediseases.org ), a clearinghouse for information about rare diseases and theirsupport groups. Genetic testing information is available at the Genetests website (www.genetests.org ). This site providesinformation on available clinical and research testing for manydiseases. Brent RL: Environmental causes of human congenital malformations, Pediat rics 113:957–968, 2004


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Pediatrics_Nelson. Brent RL: Environmental causes of human congenital malformations, Pediat rics 113:957–968, 2004 Crissman BG, Worley G, Roizen N, et al: Current perspectives on Down syndrome: selected medical and social issues, Am J Med Genet C Semin Med Genet 142C:127–130, 2006 Encode Project Consortium: An integrated encyclopedia of DNA elements in the human genome, Nature 489:57–74, 2012 Hobbs CA, Cleves MA, Simmons CJ: Genetic epidemiology and congenital malformations: from the chromosome to the crib, Arch Pediatr Adolesc Med 156:315–320, 2002 Holmes LB, Westgate MN: Inclusion and exclusion criteria for malforma tions in newborns exposed to potential teratogens, Birth Defects Research (Part A) 91:807–812, 2011 Kliegman RM, Stanton B, St. Geme J, et al: Nelson Textbook of Pediatrics, 19th ed, Philadelphia, 2011, Saunders . Online Mendelian Inheritance in Man (website): http://www.ncbi.nlm.nih.gov/sites/entrez?db=omim


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Pediatrics_Nelson. Optimal outcomes for children with inborn errors of metabolism (IEMs) depend upon recognition of the signs and symptoms of metabolic disease, and prompt evaluation and referral to a center familiar with their management. Delay in diagnosis may result in end organ damage including progressive neurologic injury or death. With the exception of phenylketonuria (PKU), and medium chain acyl-CoA dehydrogenase (MCAD) deficiency, most metabolic disorders are individually rare, having an incidence of less than 1 per 100,000 births in the United States. When considered collectively, the incidence may approach 1 in 800 to 2500 births (Table 51-1) with the prevalence of a confirmed metabolic disorder detected by newborn screening in 1 in 4000 live births (about 12,500 diagnoses each year) in the United States. This is comparable with the 1 in 1000 infants who have early-onset bacterial sepsis and the 1 in 3000 infants who have invasive group B streptococcal infections.


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Pediatrics_Nelson. IEMs are frequent causes of sepsis-like presentations, mental retardation, seizures, sudden infant death, and neurologic impairment; 20% of admissions to a regional children’s hospital are for genetic disorders. Metabolic disorders can be classified using a variety of schemes based on the clinical presentation, including the age of onset, the tissues or organ systems involved, the defective metabolic pathways, or the subcellular localization of the underlying defect. These classification schemes have differing utility when considering approach to diagnosis, management, and screening strategies. The clinical presentation and longterm prognosis have the most bearing on management of children with genetic metabolic disorders.


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Pediatrics_Nelson. Genetic metabolic disorders result from the deficiency of an enzyme, its cofactors, or biochemical transporters that lead to the deficiency of a required metabolite, the buildup of a toxic compound, or a combination of both processes (Fig. 51-1, Table 51-2). Understanding which of these mechanisms is involved and if the effects are systemic or restricted to the local tissue enables a rational approach to diagnosis, therapy, and management. Available @ StudentConsult.com


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Pediatrics_Nelson. Available @ StudentConsult.com The signs and symptoms of an inborn error are diverse andcan involve any organ system. The presentation varies amongage groups. Inborn errors of metabolism often present a fewhours to weeks after birth, often mimicking late-onset sepsis.Infants who survive the neonatal period without developingrecognized symptoms often experience intermittent illness separated by periods of being well. While pursuing the evaluationof the specific clinical presentations (e.g., the approach to thesick newborn, irritable child, or child with liver dysfunction),the hypoglycemic and intoxicating (encephalopathy) metabolicdisorders should be considered in all neonates presenting withlethargy, poor tone, poor feeding, hypothermia, irritability, orseizures. In most cases these should be evaluated for by assessment of plasma ammonia, blood glucose, and anion gap (Fig. 51-2). Significant ketosis in the neonate is unusual and suggests


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Pediatrics_Nelson. Table 51-1 Estimates of Incidence of Various Classes of Disorders Diagnosed or Followed at Specialized Clinics per 100,000 Population* BRITISH COLUMBIA 1969–1996 WEST MIDLANDS 1999–2003 Amino acid disorders 7.5 (excluding phenylketonuria) Lysosomal storage diseases 7.5 19 Phenylketonuria 7.5 12.5 Peroxisomal disorders 3.5 7.5 Mitochondrial diseases 3 4.5 *Populations in British Columbia, Canada (a predominantly white population), between 1969 and 1996, and in the West Midlands of the United Kingdom (which has a diverse ethnic breakdown) between 1999 and 2003. an organic acid disorder. Similarly specific metabolic disorderspredispose to cardiomyopathy, myopathy, hepatopathy, developmental delay, sepsis and developmental regression; appropriate evaluation should be tailored to the clinical presentation.


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Pediatrics_Nelson. Introduction of new foods or metabolic stress associated with fasting or fever may unmask an inborn error of metabolismduring infancy or in older children. The introduction of fructoseor sucrose in the diet may lead to decompensation in hereditaryfructose intolerance. In older children, increased protein intakemay unmask disorders of ammonia detoxification. Loss of regulation Available @ StudentConsult.com Figure 51-1 Depiction of the basic paradigm in inherited disorders of metabolism. Deficiency of an enzyme complex results in accumula-Altered Mental Status tion of metabolites proximal to the blocked metabolism and deficiency Acidemia of the product of the reaction. Sites of genetic control are indicated. Use of glucose with consequent hypoglycemia oxidation defects Long-chain fatty acid Fat for energy Long-chain fats Use of glucose with consequent hypoglycemia; oxidation defects mitochondrial dysfunction in liver, heart, etc., leading to organ dysfunction


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Pediatrics_Nelson. Long-chain fatty acid Fat for energy Long-chain fats Use of glucose with consequent hypoglycemia; oxidation defects mitochondrial dysfunction in liver, heart, etc., leading to organ dysfunction Glycogen storage disease Glucose to prevent fasting Glycogen resulting in Risk of hypoglycemic brain injury and storage tissue hypoglycemia storage in liver, muscle, heart dysfunction Ketone utilization Fat for energy Ketones Risk of hypoglycemic brain injury; profound metabolic disorders Galactose Elevated galactose leads to severe hepatic dysfunction, neurologic injury, and impaired immune response


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Pediatrics_Nelson. Hyperammonemia in infants Possible inborn error of metabolism Prematurity, respiratory distress early onset Transient hyperammonemia Fatty acid oxidation defects Lactic acidosis Organic aciduria Short, medium and long chain acyl-CoA dehydrogenase deficiencies Carnitine disorders PDH PC Mitochondrial disorders Propionic acidemia Methylmalonic acidemia Isovaleric acidemia Multiple carboxylase deficiency Glutaric acidemia 3-Methyl-3-OH-glutaryl-CoA lyase deficiency Normal or reduced Marked elevation Elevated with ASA in plasma, urine Citrullinemia Argininosuccinic aciduria OTC deficiency Absent, trace No acidosis or ketosis Respiratory alkalosis Low BUN Metabolic acidosis Ketosis Organic aciduria Urea cycle detects Plasma citrulline Plasma arginine Elevated CPS or NAGS deficiency Normal Argininemia Elevated Lysinuric protein intolerance Hyperornithinemia, hyperammonemia, homocitrullinuria syndrome Normal, low Elevated urine lysine, ornithine, arginine Elevated plasma ornithine,


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Pediatrics_Nelson. Argininemia Elevated Lysinuric protein intolerance Hyperornithinemia, hyperammonemia, homocitrullinuria syndrome Normal, low Elevated urine lysine, ornithine, arginine Elevated plasma ornithine, urine homocitrulline Urine orotic acid PDH – pyruvate dehydrogenase deficiency PC – pyruvate carboxylase deficiency ASA – argininosuccinic acid CPS – carbamylphosphate synthase OTC – ornithine transcarbamylase NAGS – N-acetylglutamate synthase


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Pediatrics_Nelson. Figure 51-2 Algorithm for the approach to hyperammonemia infants. ASA, Argininosuccinic acid; BUN, blood urea nitrogen; CPS, carbamylphosphate synthase; NAGS, N-acetylglutamate synthase; OTC, ornithine transcarbamylase; PC, pyruvate carboxylase deficiency; PDH, pyruvate dehydrogenase deficiency.


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Pediatrics_Nelson. The toxic presentation often presents as an encephalopathy.Fever, infection, fasting, or other catabolic stresses may precipitate the symptom complex. A metabolic acidosis, vomiting, lethargy, and other neurologic findings may be present. Diagnostic testing is most effective when metabolites are present in highest concentration in blood and urine at presentation. Abnormal metabolism of amino acids, organic acids, ammonia, or carbohydrates may be at fault. Hyperammonemia is an important diagnostic possibility if an infant or child presents with features of toxic encephalopathy (see Fig. 51-2). Symptoms and signs depend on the underlying cause of the hyperammonemia, the age at which it develops, and its degree. The severity of hyperammonemia may provide a clue to the etiology (Tables 51-3 and 51-4). Available @ StudentConsult.com


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Pediatrics_Nelson. Available @ StudentConsult.com Infants with genetic defects in urea synthesis, transient neonatal hyperammonemia, and impaired synthesis of urea and glutamine secondary to genetic disorders of organic acid metabolism can have levels of blood ammonia (>1000 μmol/L) more than 10 times normal in the neonatal period. Poor feeding, hypotonia, apnea, hypothermia, and vomiting rapidly give way to coma and occasionally to intractable seizures. Respiratory alkalosis is common. Death occurs in hours to days if the condition remains untreated. Available @ StudentConsult.com


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Pediatrics_Nelson. Respiratory alkalosis is common. Death occurs in hours to days if the condition remains untreated. Available @ StudentConsult.com Moderate neonatal hyperammonemia (range, 200 to 400 μmol/L) is associated with depression of the central nervous system, poor feeding, and vomiting. Seizures are not characteristic. Respiratory alkalosis may occur. This type of hyperammonemia may be caused by partial or more distal blocks in urea synthesis and commonly is caused by disorders of organic acid metabolism (producing a metabolic acidosis) that secondarily interfere with the elimination of nitrogen.


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Pediatrics_Nelson. Infants who are affected by defects in the urea cycle may continue to do well while receiving the low-protein intake of breast milk, developing clinical hyperammonemia when dietary protein is increased or when catabolic stress occurs. Vomiting and lethargy may progress to coma. Seizures are not typical. During a crisis, the plasma ammonia level is usually 200 to 500 μmol/L. However, as the ammonia level decreases with decreased protein intake, the condition may go unrecognized for years, especially in the absence of central nervous system symptoms. If a crisis occurs during an epidemic of influenza, the child mistakenly may be thought to have Reye syndrome. Disorders of the urea cycle Lethal hyperammonemia is common Disorders of the propionate Severe hyperammonemia may pathway precede acidosis Disorders of fatty acid catabolism Reye-like syndrome possible and of ketogenesis Transient neonatal Idiopathic, self-limited hyperammonemia


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Pediatrics_Nelson. Disorders of fatty acid catabolism Reye-like syndrome possible and of ketogenesis Transient neonatal Idiopathic, self-limited hyperammonemia Portal-systemic shunting Thrombosis of portal vein, cirrhosis, hepatitis Mitochondrial DNA depletion Typically associated with elevated lactate level Drug intoxication: salicylate, Obtain drug levels valproic acid, acetaminophen Hyperinsulinism/ Clinical hypoglycemia, hyperammonemia syndrome subclinical hyperammonemia Non-metabolic liver disease Ensure evaluation of hepatic including infections such as function and appropriate herpes, cytomegalovirus infectious disease workup All disorders that cause hypoglycemia: Most hepatic glycogen storage diseases Galactosemia, hereditary fructose intolerance Fructose-1,6-bisphosphatase deficiency Disorders of fatty acid beta oxidation Glucose transporter deficiency


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Pediatrics_Nelson. Disorders of the propionate pathway HMG-CoA lyase deficiency Menkes disease Pyruvate carboxylase deficiency (PCD) Maple syrup urine disease Mitochondrial disease: POLG deficiency Iron-sulfur cluster disease Maple syrup urine disease Nonketotichyperglycinemia Diseases producing extreme hyperammonemia: Disorders of the urea cycle Disorders of the propionate pathway Disorders of beta oxidation Congenital lactic acidosis (PCD) HMG-CoA, 3-hydroxy-3-methylglutaryl-CoA. Older children may have neuropsychiatric or behavioral abnormalities (see Fig. 51-2). Available @ StudentConsult.com


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Pediatrics_Nelson. HMG-CoA, 3-hydroxy-3-methylglutaryl-CoA. Older children may have neuropsychiatric or behavioral abnormalities (see Fig. 51-2). Available @ StudentConsult.com Any organ or system can be injured by toxic accumulation of any of the metabolites involved in inborn errors. Symptoms relate to organ-specific or system-specific toxicity and injury. Examples include nervous system (seizures, coma, ataxia), liver (hepatocellular damage), eye (cataracts, dislocated lenses), renal (tubular dysfunction, cysts), and heart (cardiomyopathy, pericardial effusion) (Table 51-5). Disorders whose pathophysiology results in energy deficiency (e.g., disorders of fatty acid oxidation, mitochondrial function/oxidative phosphorylation, or carbohydrate metabolism) may manifest myopathy; central nervous system dysfunction, including mental retardation and seizures; cardiomyopathy; vomiting; hypoglycemia; or renal tubular acidosis. Available @ StudentConsult.com


Pediatrics_Nelson

Pediatrics_Nelson. Acidosis is often found in children without metabolic diseases and may be due to fasting associated with anorexia, vomiting,diarrhea, and dehydration in the course of a viral illness. In thisnormal result of fasting, the blood glucose is relatively low; amild acidosis and ketonuria may be present. Administrationof carbohydrate restores balance. Severe ketosis may also bethe result of disorders of ketone utilization such as ketothiolase deficiency or SCOT (succinyl-CoA:3 ketoacid CoA transferase) deficiency. In these conditions, which frequently present in thecontext of fasting, infection with fever, or decreased intake secondary to vomiting and diarrhea, hypoglycemia may be profound; the ketosis resolves slowly. As ketone bodies accumulate,cyclic vomiting may ensue. Ketotic hypoglycemia is a common condition in which tolerance for fasting is impaired. Symptomatic hypoglycemia with seizures or coma occurs when the childencounters a catabolic stress. The stress may be significant


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Pediatrics_Nelson. is a common condition in which tolerance for fasting is impaired. Symptomatic hypoglycemia with seizures or coma occurs when the childencounters a catabolic stress. The stress may be significant (viralinfection with vomiting) or minor (a prolongation by severalhours of the normal overnight fast). Ketotic hypoglycemia firstappears in the second year of life and occurs in otherwise healthychildren. It is treated by frequent snacks and the provision ofglucose during periods of stress. The pathophysiology is poorlyunderstood (see Chapter 172). Although ketonuria is a normalresponse to prolonged (not overnight) fasting in older infantsand children, it indicates metabolic disease in neonates. A high anion gap metabolic acidosis with or without ketosis suggests a metabolic disorder (Table 51-6). Although ketone productionmay be reduced in some fatty acid oxidation disorders, the presence of ketonuria does not exclude this group of disorders.


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Pediatrics_Nelson. Disorders Associated with Dysmorphic Findings Congenital malformations or dysmorphic features are not intuitively thought of as symptoms and signs of inborn errors. Conditions that cause congenital malformations include carbohydrate-deficient glycoprotein syndrome, disorders of cholesterol biosynthesis (Smith-Lemli-Opitz syndrome), disorders of copper transport (Menkes syndrome, occipital horn syndrome), maternal phenylketonuria syndrome, glutaric aciduria II (also called multiple acyl-coenzyme A [CoA] dehydrogenase deficiency), and several storage diseases. Available @ StudentConsult.com Storage disorders are caused by accumulation of incompletely metabolized macromolecules. This storage often occurs in subcellular organelles, such as lysosomes. The glycogen storage diseases and mucopolysaccharide disorders are examples of storage disorders. Gaucher and Niemann-Pick diseases GSD IV (slowly evolving) Crigler-Najjar disease Rotor, Dubin-Johnson syndromes


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Pediatrics_Nelson. Gaucher and Niemann-Pick diseases GSD IV (slowly evolving) Crigler-Najjar disease Rotor, Dubin-Johnson syndromes GSD, Glycogen storage disease. The assessment begins with a careful history (family and individual) and clinical evaluation. Clinical laboratory testing can define the metabolic derangement (Table 51-7). The results generate a differential diagnosis and a list of more specific laboratory testing to confirm the diagnosis.


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Pediatrics_Nelson. The combination of symptoms and abnormal clinical laboratory findings demands urgent metabolic evaluation. Ametabolic emergency often presents with vomiting, acidosis,hypoglycemia, ketosis (or lack of appropriate ketosis), inter-current infection, anorexia/failure to feed, lethargy proceeding to coma, and hyperventilation or hypoventilation. Clinicalevaluation should focus on the cardiac, renal, neurologic, anddevelopmental assessment as well as looking for changes inmental status, seizures, abnormal tone, visual symptoms,poor developmental progress, global developmental delay,loss of developmental milestones (regression), cardiomyopathy, cardiac failure, cystic renal malformation, and renal tubular dysfunction.


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Pediatrics_Nelson. Clinical laboratory testing should begin with tests that are available in most hospital clinical laboratories. Care in the collection and handling of laboratory specimens is crucial to obtaining accurate results. Plasma measurements oflactate and ammonia are particularly subject to spuriousresults if not handled correctly. Significant ketosis in theneonate is unusual and suggests an organic acid disorder.Ketosis out of proportion to fasting status in an older child occurs in disorders of ketone usage. Lack of severe ketosis in an older child under conditions of metabolic stress is a Arterial blood gas Glucose Electrolytes—anion gap pH Glucose Ketones Ammonia Reducing substances Liver enzymes Organic acids Complete blood count, differential,† Acylglycines and platelet count Orotic acid Lactate, pyruvate Organic acids Amino acids Acylcarnitines Carnitine *Organ-specific evaluation is indicated for specific symptoms (e.g., cranial if nonketotic hyperglycemia is suspected).


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Pediatrics_Nelson. †Thrombocytopenia and neutropenia are seen in organic acidurias; vacuolated lymphocytes and metachromatic granules are seen in lysosomal disorders. feature of fatty acid oxidation disorders. In some disorders,such as urea cycle disorders, ketone utilization disorders,milder forms of fatty acid oxidation defects, and intermittent maple syrup urine disease, the laboratory abnormalitiesmay be present only during an acute presentation. Therefore,normal testing in the well state does not rule out a metabolicdisorder. Mechanisms of Inheritance


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Pediatrics_Nelson. Although all of the classic mechanisms of inheritance are represented, most inborn errors of metabolism are autosomal recessive. Isolation or founder effect may make a specific recessive condition common in some populations (e.g., maple syrup urine disease in the Old Order Mennonite population in Pennsylvania). X-linked conditions exhibit increased presentation in males. In general, carriers of recessive or X-linked (females) diseases are asymptomatic. However, in ornithine transcarbamylase deficiency, females can be symptomatic if they have a low proportion of normal cells in the liver. Most mitochondrial disorders in children are a result of mutations in autosomal genes, although there are X-linked forms. Mutations in the mitochondrial DNA also lead to mitochondrial disease. In this situation the type and severity of the presentation depend on the specific defects and the tissue specific ratio of normal to abnormal copies of the mitochondrial DNA (the degree of heteroplasmy).


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Pediatrics_Nelson. Identification of Molecular Pathology If the molecular basis of an inborn error of metabolism is known (i.e., the gene or genes have been mapped and mutations defined), specific genetic testing may be clinically available. In some disorders, there is a good correlation between specific mutations and clinical outcome. Genetic testing in other at-risk family members can provide important genetic information for them, enabling decision making throughout the rest of the family. Table 51-8 Disorders Identified by Newborn Screening Programs in the United States DISORDER METHODS CONFIRMATORY TESTING AMINO ACID Phenylketonuria (PKU) Guthrie*, MS/MS Plasma phenylalanine, mutation testing Tyrosinemia Guthrie, MS/MS Plasma amino acid profile, urine succinylacetone Maple syrup urine disease (MSUD) Guthrie, MS/MS Plasma amino acid profile, look for alloisoleucine ORGANIC ACID Methylmalonic acidemias MS/MS Urine organic acid profile, plasma amino acid profile, plasma homocysteine


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Pediatrics_Nelson. Methylmalonic acidemias MS/MS Urine organic acid profile, plasma amino acid profile, plasma homocysteine Biotinidase deficiency Enzyme measurement Quantitative biotinidase measurement, DNA mutations Medium-chain acyl-CoA dehydrogenase MS/MS Urine organic acid profile, urine acylglycine profile, plasma deficiency (MCAD) Long-chain 3-hydroxyacyl-CoA MS/MS Urine organic acid profile, urine acylglycine profile, plasma dehydrogenase deficiency (LCHAD) Very long-chain acyl-CoA dehydrogenase MS/MS Urine organic acid profile, urine acylglycine profile, plasma deficiency (VLCAD) Galactosemia GALT enzyme measurement GALT enzyme measurement, DNA mutations, galactose-1-P measurement MS/MS Plasma amino acid profile, DNA mutations


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Pediatrics_Nelson. Galactosemia GALT enzyme measurement GALT enzyme measurement, DNA mutations, galactose-1-P measurement MS/MS Plasma amino acid profile, DNA mutations In the United States the majority of infants diagnosed witha treatable metabolic disorder will be identified as a result of an abnormal newborn screen. Most states use tandem mass spectrometry to screen for a core panel of 29 disorders (Table 51-8). In most states, biotinidase deficiency and galactosemiaare typically screened for by evaluating enzyme function. Strategy of Neonatal Screening


Pediatrics_Nelson

Pediatrics_Nelson. Strategy of Neonatal Screening The purpose of neonatal screening is the early detection and rapid treatment of disorders before the onset of symptoms, thus preventing morbidity and mortality. In most states, infants are tested at 24 to 48 hours (see Chapter 58). A positive test demands prompt evaluation. Specific follow-up testing and treatment of an affected child depends on the disorder. Consistent with most screening tests, a significant proportion of infants who have a positive neonatal screening test do not have a metabolic disorder.


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Pediatrics_Nelson. Neonatal screening is designed to maximize detection ofaffected infants but is not diagnostic. “Cutoff values” for eachtest are established carefully to identify infants with an elevated concentration of the substance or decreased activityof an enzyme with an acceptable number of false-positive results. A positive screening test must be followed by promptclinical assessment as recommended by the screening program and metabolic specialist. In many cases children willalso be provided therapy until the completion of definitive testing.


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Pediatrics_Nelson. A positive screening test result causes anxiety for new parents; management of such anxiety is essential to minimize the harm of the program. In addition, definitive testing must be carried out promptly and accurately. If an inborn error of metabolism is excluded, parents need a thorough explanation of the results and reassurance that the infant is well. Such explanations will frequently require the expertise of a metabolic specialist or genetic counselor in the newborn period but may require reassessment by the primary care physician in the long term. Specialized testing for inherited disorders of metabolism is effective in confirming a diagnosis suspected on the basis of an abnormal newborn screening result or on the basis of clinical suspicion. The tests that are helpful and examples of diagnoses made using these measurements depend on the deficient pathway in the disorder under consideration (Table 51-9).


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Pediatrics_Nelson. Amino acid analysis is performed in plasma, urine, and cerebrospinal fluid. The plasma amino acid profile is most useful inidentifying disorders of amino acid catabolism. Amino acidsin the deficient pathway of the organic acid disorders may beabnormal, but often they are normal or may not be diagnostic. Table 51-9 Specialized Metabolic Testing TEST ANALYTES MEASURED TEST HELPFUL IN IDENTIFYING DISORDERS Plasma amino acid profile Amino acids, including alloisoleucine PKU, urea cycle defects, tyrosinemias, MSUD, homocystinuria Plasma total homocysteine Protein-bound and free homocysteine Homocystinuria, some forms of methylmalonic acidemia Urine amino acid profile Amino acids Disorders of amino acid renal transport Plasma acylcarnitine profile Acylcarnitine derivatives of organic and Organic acid disorders, fatty acid oxidation disorders fatty acid catabolism


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Pediatrics_Nelson. Plasma acylcarnitine profile Acylcarnitine derivatives of organic and Organic acid disorders, fatty acid oxidation disorders fatty acid catabolism Urine acylglycine profile Acylglycine derivatives of organic and Organic acid disorders, fatty acid oxidation disorders fatty acid catabolism Plasma carnitines Free, total, and acylated carnitine Primary and secondary carnitine deficiency; abnormal in many organic acid and fatty acid disorders Urine organic acid profile Organic acids Organic acid, mitochondrial and fatty acid disorders Urine oligosaccharide chromatography Glycosaminoglycans, Lysosomal storage disorders mucopolysaccharides MSUD, Maple syrup urine disease; PKU, phenylketonuria.


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Pediatrics_Nelson. Urine oligosaccharide chromatography Glycosaminoglycans, Lysosomal storage disorders mucopolysaccharides MSUD, Maple syrup urine disease; PKU, phenylketonuria. The urine amino acid profile is helpful in diagnosing primary disorders of renal tubular function, such as Lowe syndrome and cystinuria, as well as secondary disorders of renal tubular function, such as cystinosis and Fanconi syndrome of any cause. The urine amino acid profile is not the test of choice for diagnosing disorders of amino acid or organic acid metabolism.


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Pediatrics_Nelson. Markers of disordered fatty acid oxidation are measuredin urine and plasma. Excessive intermediates of fatty acidoxidation and organic acid catabolism are conjugated withglycine and carnitine. The urine acylglycine profile and the plasma acylcarnitine profile reflect this accumulation. In organic acid disorders and fatty acid oxidation disorders,measurement of plasma carnitine may reveal a secondarydeficiency of carnitine and abnormal distribution of free and acylated carnitine. The plasma free fatty acid profileis helpful in diagnosis of disorders of fatty acid oxidation.Excess 3-OH-butyrate suggests a disorder of ketone metabolism; absence of ketones or decreased amounts of 3-OHbutyrate suggests a fatty acid oxidation disorder. Profiling offatty acid intermediates in cultured skin fibroblasts may beinformative.


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Pediatrics_Nelson. Disorders of organic acid metabolism, such as propionic acidemia and methylmalonic acidemia, have typical urine organic acid profiles. Although analysis of blood and urine usually suggest the specific diagnosis, more targeted testing is typically needed by measuring enzymatic activity in the pathway or establishing DNA changes in the gene.


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Pediatrics_Nelson. Disorders of creatine biosynthesis are reflected by a reduction in creatine in cerebrospinal fluid (CSF) and, in one form, an increase in guanidinoacetic acid in blood and urine. Disorders of purine and pyrimidine metabolism are suggested bythe presence of an abnormal urinary profile of purines, suchas xanthine, hypoxanthine, inosine, guanosine, adenosine, adenine, or succinyladenosine. Similarly, disorders of pyrimidinemetabolism are identified by an abnormal profile of pyrimidines, including uracil, uridine, thymine, thymidine, orotic acid, orotidine, dihydrouracil, dihydrothymine, pseudouridine,N-carbamoyl-β-alanine, or N-carbamoyl-β-aminoisobutyrate, in the urine.


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Pediatrics_Nelson. Storage disorders show abnormalities in urine mucopolysaccharides (glycosaminoglycans, glycoproteins), sialic acid, heparan sulfate, dermatan sulfate, or chondroitin sulfate. Specific enzymology depends on the disorder; tissue can be either white blood cells or cultured skin fibroblasts, depending on assay. In several disorders, CSF is the most helpful specimen, including glycine encephalopathy (CSF amino acid profile when compared to concurrent plasma amino acids), disorders of neurotransmitter synthesis (biogenic amine profile), glucose transporter (GLUT1) deficiency (plasma-to–cerebrospinal fluid glucose ratio), and serine synthesis defect (amino acid profile). In many disorders, an abnormal metabolic profile is consistently present during illness and when the child is well. In some cases, it is only diagnostic during an episode of illness.


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Pediatrics_Nelson. There are several basic principles for treatment of inborn errors of metabolism. Syndromes with toxicity often present with encephalopathy; removal of toxic compounds isthe first goal of therapy. Strategies include hemodialysis,hemovenovenous filtration, and administration of alternate pathway agents (see Chapter 53). A second strategy is toenhance deficient enzyme activity through administration ofenzyme cofactors (e.g., pyridoxine in homocystinuria, tetrahydrobiopterin in PKU). If deficiency of a pathway product plays an important role, providing missing products ishelpful (e.g., tyrosine in the treatment of phenylketonuria).A major principle is to decrease flux through the deficientpathway by restricting precursors in the diet. Examplesinclude the restriction of protein in disorders of ammoniadetoxification and of amino acid precursors in the organicacid disorders.


Pediatrics_Nelson

Pediatrics_Nelson. Many glycogen storage diseases are characterized by hypoglycemia and hepatomegaly (Table 52-1). Glycogen, the storage form of glucose, is found most abundantly in the liver (where it modulates blood glucose levels) and in muscles (where it facilitates anaerobic work). Glycogen is synthesized from uridine diphosphoglucose through the concerted action of glycogen synthetase and brancher enzyme (Fig. 52-1). The accumulation of glycogen is stimulated by insulin. Glycogenolysis occurs through a cascade initiated by epinephrine or glucagon. It results in rapid phosphorolysis of glycogen to yield glucose 1-phosphate, accompanied by, to a lesser degree, hydrolysis of glucose residues from the branch points in glycogen molecules. In the liver and kidneys, glucose 1-phosphate is converted to glucose 6-phosphate through the actions of phosphoglucomutase; glucose-6-phosphatase hydrolyses glucose 6-phosphate to produce glucose. The latter enzyme is not present in muscles. Glycogen storage diseases


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Pediatrics_Nelson. 6-phosphate through the actions of phosphoglucomutase; glucose-6-phosphatase hydrolyses glucose 6-phosphate to produce glucose. The latter enzyme is not present in muscles. Glycogen storage diseases fall into the following four categories: 1.


Pediatrics_Nelson

Pediatrics_Nelson. Diseases that predominantly affect the liver and have a direct influence on blood glucose (types I, VI, and VIII) 2. Diseases that predominantly involve muscles and affect the ability to do anaerobic work (types V and VII) 3. Diseases that can affect the liver and muscles and directly influence blood glucose and muscle metabolism (type III) 4. Diseases that affect various tissues but have no direct effect on blood glucose or on the ability to do anaerobic work (types II and IV)


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Pediatrics_Nelson. Diseases that affect various tissues but have no direct effect on blood glucose or on the ability to do anaerobic work (types II and IV) The diagnosis of type I or type III glycogen storage disease is suggested by an elevated uric acid, lactate, and triglycerides in blood. For all forms, a diagnosis can normallybe confirmed by DNA mutation testing in white blood cells.When this is feasible, invasive procedures, such as muscleand liver biopsy, can be avoided. When mutation testing isnot available or is inconclusive, enzyme measurements intissue from the affected organ confirm the diagnosis. If thediagnosis cannot be established, metabolic challenge andexercise testing may be needed. Treatment of hepatic glycogen storage disease is aimed at maintaining satisfactory


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Pediatrics_Nelson. Type 1a: Glucose-6-Liver, kidney, GI Hypoglycemia, lactic acidosis, Hypoglycemia, Early death from von Gierke phosphatase tract, platelets ketosis, hepatomegaly, lactic acidemia, hypoglycemia, lactic acidosis; hypotonia, slow growth, liver may not be do well with early diagnosis diarrhea, bleeding disorder, enlarged and strict adherence to gout, hypertriglyceridemia, Type V: Muscle Muscle Muscle fatigue beginning in None Good, with sedentary lifestyle McArdle phosphorylase Type VI: Liver phosphorylase Liver Mild hypoglycemia with Usually none Probably good Hers hepatomegaly, ketonuria Type VII: Muscle Muscle Clinical findings similar to None Similar to that of type V Tarui phosphofructokinase Type VIII Phosphorylase kinase Liver Clinical findings similar to type None Good III, without myopathy GI, Gastrointestinal. *Except for one form of hepatic phosphorylase kinase, which is X-linked, these disorders are autosomal recessive.


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Pediatrics_Nelson. GI, Gastrointestinal. *Except for one form of hepatic phosphorylase kinase, which is X-linked, these disorders are autosomal recessive. Figure 52-1 Glycogen synthesis and degradation. (1) Glycogen synthetase, (2) brancher enzyme, (3) debrancher enzyme, (4) phosphoglucomutase, (5) glucose-6-phosphatase. blood glucose levels or supplying alternative energy sourcesto muscle. In glucose-6-phosphatase deficiency (type I), thetreatment usually requires nocturnal intragastric feedings ofglucose during the first 1 or 2 years of life. Thereafter, snacksor nocturnal intragastric feedings of uncooked cornstarchmay be satisfactory; hepatic tumors (sometimes malignant)are a threat in adolescence and adult life. No specific treatment exists for the diseases of muscle that impair skeletalmuscle ischemic exercise. Enzyme replacement early in lifeis effective in Pompe disease (type II), which involves cardiacand skeletal muscle. Available @ StudentConsult.com


Pediatrics_Nelson

Pediatrics_Nelson. Available @ StudentConsult.com Galactosemia is an autosomal recessive disease caused by deficiency of galactose-1-phosphate uridyltransferase (Fig. 52-2).Clinical manifestations are most striking in a neonate who, when fed milk, generally exhibits evidence of liver failure (hyperbilirubinemia, disorders of coagulation, hypoglycemia), disordered renal tubular function (acidosis, glycosuria, aminoaciduria), and cataracts. The neonatal screening test must have a rapid turnaround time because affected infants may die in the first week of life. Affected infants are at increased risk for severe neonatal Escherichia coli sepsis. Major effects on liver and kidney function and the development of cataracts are limited to the first few years of life; older children may have learning disorders despite dietary compliance. Girls usually develop premature ovarian failure despite treatment.


Pediatrics_Nelson

Pediatrics_Nelson. Laboratory manifestations of galactosemia depend on dietary galactose intake. When galactose is ingested (as lactose), levels of plasma galactose and erythrocyte galactose Figure 52-2 Pathway of galactose metabolism. (1) Lactase (intestinal), (2) galactokinase, (3) galactose-1-phosphate uridyltransferase, (4) uridine diphosphoglucose 4-epimerase.


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Pediatrics_Nelson. 1-phosphate are elevated. Hypoglycemia is frequent, and albuminuria is present. Galactose frequently is present in the urine and can be detected by a positive reaction for reducing substances without a reaction with glucose oxidase on urine strip tests. The absence of urinary reducing substances cannot be relied on to exclude the diagnosis. The diagnosis is made by showing extreme reduction in erythrocyte galactose-1-phosphate uridyltransferase activity. DNA testing for the mutations in galactose-1-phosphate uridyltransferase confirms the diagnosis and may be useful in predicting prognosis. Renal tubular dysfunction may be evidenced by a normal–anion-gap hyperchloremic metabolic acidosis. Treatment by the elimination of dietary galactose results in rapid correction of abnormalities, but infants who are extremely ill before treatment may die before therapy is effective.


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Pediatrics_Nelson. Galactokinase deficiency, an autosomal recessive disorder, also leads to the accumulation of galactose in body fluids (see Fig. 52-2), which results in the formation of galactitol (dulcitol) through the action of aldose reductase. Galactitol, acting as an osmotic agent, can be responsible for cataract formation and, rarely, for increased intracranial pressure. These are the only clinical manifestations. Individuals homozygous for galactokinase deficiency usually develop cataracts after the neonatal period, whereas heterozygous individuals may be at risk for cataracts as adults.


Pediatrics_Nelson

Pediatrics_Nelson. Hereditary fructose intolerance, in many ways, is analogous to galactosemia. When fructose is ingested, deficiency of fructose-1-phosphate aldolase leads to the intracellular accumulation of fructose 1-phosphate with resultant emesis, hypoglycemia, and severe liver and kidney disease. Elimination of fructose and sucrose from the diet prevents clinical disease. Fructosuria is caused by fructokinase deficiency, but its deficiency is not associated with clinical consequences.


Pediatrics_Nelson

Pediatrics_Nelson. Disorders of amino acid metabolism are the result of the inability to catabolize specific amino acids derived from protein. Usually a single amino acid pathway is involved. This amino acid accumulates in excess and is toxic to various organs, such as the brain, eyes, skin, or liver. Treatment is directed at the specific pathway and usually involves dietary restriction of the offending amino acid and supplementation with special medical foods (formulas) that provide the other amino acids and other nutrients. Confirmatory testing includes quantitative specific plasma amino acid profiles along with specific mutation testing and sometimes enzymology.


Pediatrics_Nelson

Pediatrics_Nelson. Phenylketonuria (PKU), an autosomal recessive disease, primarily affects the brain and occurs in 1 in 10,000 persons.Classic PKU is the result from a defect in the hydroxylationof phenylalanine to form tyrosine (Fig. 53-1); the activity ofphenylalanine hydroxylase in the liver is absent or greatlyreduced. Affected infants are normal at birth, but if untreated, severe mental retardation (IQ 30) develops in the first year oflife. A positive newborn screening test must be followed up byperforming quantitative plasma amino acid analysis. A plasmaphenylalanine value of greater than 360 μM (6 mg/dL) is consistent with the diagnosis of one of the hyperphenylalaninemiasand demands prompt evaluation and treatment. Untreated,classic PKU is characterized by blood phenylalanine concentrations higher than 600 μM. Milder forms of hyperphenylalaninemia are indicated by values of plasma phenylalanine lowerthan this but higher than 360 μM. A significant percentage ofpremature infants and a few


Pediatrics_Nelson

Pediatrics_Nelson. higher than 600 μM. Milder forms of hyperphenylalaninemia are indicated by values of plasma phenylalanine lowerthan this but higher than 360 μM. A significant percentage ofpremature infants and a few full-term infants have transientelevations in phenylalanine. Short-term follow-up usuallyidentifies these infants promptly. A small percentage of infantsdiagnosed with PKU (≤2% in the United States) have a defectin the synthesis or metabolism of tetrahydrobiopterin, thecofactor for phenylalanine hydroxylase and for other enzymesinvolved in the intermediary metabolism of aromatic aminoacids. Such disorders in biopterin metabolism are diagnosedby measuring dihydrobiopterin reductase in erythrocytes andby analyzing biopterin metabolites in urine. This testing shouldbe carried out in all hyperphenylalaninemic infants.


Pediatrics_Nelson

Pediatrics_Nelson. Treatment is designed to maintain plasma phenylalanine values in the therapeutic range of 120 to 360 mM using a diet specifically restricted in phenylalanine but otherwise nutritionally complete. Since the early 1980s, treatment for life is recommended to reduce the risks of long-term neuropsychiatric problems and reduce the risk of maternal PKU syndrome. Outcome of treatment in classic PKU is excellent. Most infants with classic PKU who are treated within the first Figure 53-1 Metabolism of aromatic amino acids. (1) Phenylalanine hydroxylase, (2) transaminase, (3) p-hydroxyphenylpyruvate oxidase, (4) homogentisate oxidase, (5) maleylacetoacetate isomerase, (6) fumarylacetoacetate hydrolase, (7) dihydrobiopterin reductase, (8) tyrosine hydroxylase, (9) tryptophan hydroxylase. SA, Succinylacetone.


Pediatrics_Nelson

Pediatrics_Nelson. 10 days of life achieve normal intelligence. However, learning problems and problems with executive function aremore frequent than in unaffected peers. The safe concentration of phenylalanine in older children and adults withPKU has not been clearly established. Reversible cognitivedysfunction is associated with acute elevations of plasmaphenylalanine in adults and children with PKU. If the elevated level has been sustained, the dysfunction may not bereversible. Treatment with modified preparation of tetrahydrobiopterin has shown good responses in some individualswith PKU. Females with PKU and their families must be educated on the risks and prevention of “maternal PKU syndrome.” Maternal hyperphenylalaninemia requires rigorous management before conception and throughout pregnancy to prevent fetal brain damage, congenital heart disease, and microcephaly.


Pediatrics_Nelson

Pediatrics_Nelson. Tyrosinemia is identified in neonatal screening programs using tandem mass spectrometry methods to detect elevated tyrosine and/or succinylacetone. Elevated tyrosine levels also occur as a nonspecific consequence of severe liver disease or transient tyrosinemia of the newborn, which responds to ascorbic acid treatment. The inherited disorders of tyrosine metabolism are the target of neonatal screening. Tyrosinemia Type I, which is due to fumarylacetoacetate hydrolase deficiency (see Fig. 53-1), is a rare disease in which accumulated metabolites produce severe liver disease associated with bleeding disorder, hypoglycemia, hypoalbuminemia, elevated transaminases, and defects in renal tubular function. Hepatocellular carcinoma may eventually occur. Quantitative measurement of plasma tyrosine and blood or urine succinylacetone is performed after a positive neonatal screen. The diagnosis of tyrosinemia I is confirmed by an increased concentration of succinylacetone; DNA testing is


Pediatrics_Nelson

Pediatrics_Nelson. tyrosine and blood or urine succinylacetone is performed after a positive neonatal screen. The diagnosis of tyrosinemia I is confirmed by an increased concentration of succinylacetone; DNA testing is available for some mutations. Treatment with nitisinone (NTBC) (an inhibitor of the oxidation of parahydroxyphenylpyruvic acid) effectively eliminates the production of the toxic succinylacetone. A low-phenylalanine, low-tyrosine diet may also play a role. These treatments have obviated the immediate need for liver transplantation in children identified by neonatal screening. Whether they completely eliminate the occurrence of hepatocellular carcinoma is unknown.


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Pediatrics_Nelson. Tyrosinemias II and III are more benign forms of hereditary tyrosinemia. Blocked metabolism of tyrosine at earlier steps in the pathway is responsible, and succinylacetone is not produced. The clinical features include hyperkeratosis of palms and soles and keratitis, which can cause severe visual disturbance. Poor dietary compliance with type II tyrosinemia is associated with mild cognitive impairment. Treatment with a phenylalanineand tyrosine-restricted diet is effective.


Pediatrics_Nelson

Pediatrics_Nelson. Homocystinuria, an autosomal recessive disease (1:200,000 livebirths) involving connective tissue, the brain, and the vascularsystem, is caused by a deficiency of cystathionine β-synthase. In the normal metabolism of the sulfur amino acids, methionine gives rise to cystine; homocysteine is a pivotal intermediate (Fig. 53-2). When cystathionine β-synthase is deficient, homocysteine accumulates in the blood and appears in the urine. Another result is enhanced reconversion of homocysteine to methionine, resulting in an increase in the concentration of methionine in the blood. The neonatal screening test most commonly used measures methionine. An excess of homocysteine produces a slowly evolving clinical syndromethat includes dislocated ocular lenses; long, slender extremities; malar flushing; and livedo reticularis. Arachnodactyly, scoliosis, pectus excavatum or carinatum, and genu valgum are skeletal features. Mental retardation, psychiatric illness, or both may be present. Major


Pediatrics_Nelson

Pediatrics_Nelson. and livedo reticularis. Arachnodactyly, scoliosis, pectus excavatum or carinatum, and genu valgum are skeletal features. Mental retardation, psychiatric illness, or both may be present. Major arterial or venous thromboses are a constant threat.


Pediatrics_Nelson

Pediatrics_Nelson. Confirmation of the diagnosis requires demonstration of elevated total homocysteine in the blood. A plasma amino acid profile reveals hypermethioninemia. Measurement of cystathionine β-synthase is not clinically available, but numerous mutations in the gene are known and can be tested.


Pediatrics_Nelson

Pediatrics_Nelson. There are two clinical forms of homocystinuria. In one form, activity of the deficient enzyme can be enhanced by the administration of large doses of pyridoxine (100 to 1000 mg/day). Folate supplementation is added to overcome folate deficiency if folate is trapped in the process of remethylation of homocysteine to methionine. This pyridoxine-responsive form comprises about 50% of cases and is the more likely form to be missed by neonatal screening because the methionine concentrations are not always above the screening cutoff. The second form is not responsive to pyridoxine therapy. The accumulation of homocysteine is controlled with a methionine-restricted diet and cystine and folate supplementation. The use of supplemental betaine (trimethylglycine), a donor of methyl groups for remethylation of homocysteine to methionine, also has a role in the management of pyridoxine-unresponsive patients. Diet and betaine are sometimes required to control plasma homocysteine, even in


Pediatrics_Nelson

Pediatrics_Nelson. for remethylation of homocysteine to methionine, also has a role in the management of pyridoxine-unresponsive patients. Diet and betaine are sometimes required to control plasma homocysteine, even in pyridoxine-responsive patients. The prognosis is good for infants whose plasma homocysteine concentration is controlled.


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Pediatrics_Nelson. Figure 53-2 Metabolism of methionine and homocysteine. (1) Methionine adenosyltransferase, (2) S-methyltransferase, (3) S-adenosylhomocysteine hydrolase, (4) cystathionine β-synthase, (5) cystathionase, (6) homocysteine methyltransferase, (7) betaine-homocysteine methyltransferase. Maple syrup urine disease (MSUD) is an autosomal recessivedisease, also called branched chain ketoaciduria. A deficiencyof the decarboxylase initiates the degradation of the ketoacid analogs of the three branched chain amino acids—leucine, isoleucine, and valine (Fig. 53-3). Classic MSUD is rare(1:250,000) in the general population but much more commonin some population isolates (Pennsylvania Mennonites 1:150).The American College of Medical Genetics neonatal screeningpanel includes MSUD.


Pediatrics_Nelson

Pediatrics_Nelson. Although MSUD does have intermittent-onset and late-onset forms, clinical manifestations of the classic form typically begin within 1 to 4 weeks of birth. Poor feeding, vomiting, and tachypnea commonly are noted, but the hallmark of the disease is profound depression of the central nervous system, associated with alternating hypotonia and hypertonia (extensor spasms), opisthotonos, and seizures. The urine has the odor of maple syrup. Laboratory manifestations of MSUD include hypoglycemia and a variable presence of metabolic acidosis, with elevation of the undetermined anions; the acidosis is caused, in part, by plasma branched chain organic acids and, inpart, by the usual ketone bodies, β-hydroxybutyrate and acetoacetate. Branched-chain ketoacids in urine (but notβ-hydroxybutyrate or acetoacetate) react immediately with2,4-dinitrophenylhydrazine to form a copious, white precipitate.


Pediatrics_Nelson

Pediatrics_Nelson. The definitive diagnosis of MSUD generally is made by showing large increases in plasma leucine, isoleucine, and valine concentrations and identification of alloisoleucine in the plasma in excess. The urinary organic acid profile is usually abnormal and shows the ketoacid derivatives of the branched chain amino acids. Provision of adequate calories and protein, with restriction of leucine, is crucial for acute and chronic management. Hemodialysis, hemofiltration, or peritoneal dialysis can be lifesaving during acidotic crises in addition to close monitoring and therapy for cerebral edema. Ordinary catabolic stresses, such as moderate infections or labor and delivery in a pregnant mother with MSUD, can precipitate clinical crises. Liver transplantation effectively treats MSUD. Inherited enzymatic deficiencies have been described for each of the steps of urea synthesis (Fig. 53-4). Neonatal screening does not currently detect all of the disorders in the urea cycle.


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Pediatrics_Nelson. Inherited enzymatic deficiencies have been described for each of the steps of urea synthesis (Fig. 53-4). Neonatal screening does not currently detect all of the disorders in the urea cycle. Figure 53-3 Metabolism of the branched chain amino acids. (1) Aminotransferases, (2) α-ketoacid dehydrogenase complex. Figure 53-4 The urea cycle. Site of enzymatic defects: (1) N-acetylglutamate synthase (NAG), (2) carbamoyl phosphate synthetase, (3) ornithine carbamoyltransferase, (4) argininosuccinate acid synthetase, (5) argininosuccinate acid lyase, (6) arginase. Transporters (star). (7) citrin, (8) ornithine translocator (star). AKG, Alpha ketoglutarate. Clinically the two most frequent disorders in the United States are ornithine carbamoyltransferase (OTC) deficiency and argininosuccinate lyase (ASL) deficiency.


Pediatrics_Nelson

Pediatrics_Nelson. Clinically the two most frequent disorders in the United States are ornithine carbamoyltransferase (OTC) deficiency and argininosuccinate lyase (ASL) deficiency. Ornithine carbamoyltransferase (OTC) deficiency is X-linked. Gene mutations include both deletions and point mutations. If the enzyme is nonfunctional, there is no OTC activity in affected males, who are likely to die in the neonatal period. Affected females are heterozygous and, because of lyonization, may have a significant degree of enzyme deficiency and may be clinically affected at any time in life. Clinical manifestations range from lethal disease in the male (coma, encephalopathy) to clinical normalcy in a high percentage of females. Late-onset forms in males also occur. Manifestations in clinically affected females include recurrent emesis, lethargy, seizures, developmental delay, mental retardation, or episodic confusion. Affected females may spontaneously limit their protein intake.


Pediatrics_Nelson

Pediatrics_Nelson. Confirmatory testing for OTC includes a plasma amino acid profile, which may show reduced citrulline and arginine concentrations with increased glutamate and alanine. A urine organic acid profile shows increased excretion of orotic acid after protein loading or with concurrent administration of allopurinol. Mutation testing, deletion testing, and sequencing of the entire coding region of the related genes are available as clinical tests. Argininosuccinate lyase (ASL) deficiency is autosomal recessive, and most children in the United States are detected as a result of an elevated citrulline on newborn screening. The diagnosis is confirmed by the detection of elevated argininosuccinic acid in the urine. Treatment of Hyperammonemia


Pediatrics_Nelson

Pediatrics_Nelson. Treatment of Hyperammonemia During episodes of symptomatic hyperammonemia, proteinintake is reduced, and intravenous glucose is given in sufficient quantity to suppress catabolism of endogenous protein. Ammonia can be eliminated by use of the alternate pathway agents, sodium benzoate and sodium phenylacetate, which are excreted in the urine as conjugates of glycine andglutamine. Arginine, which is usually deficient, is supplied.When ammonia levels are very high (>1000 µM) or refractory to therapy, direct removal of ammonia using hemodialysis or hemofiltration, but not peritoneal dialysis, is required.The neurologic status must be followed closely and cerebraledema treated promptly. Despite successful management ofhyperammonemic crises, the long-term outcome for males with severe neonatal OTC deficiency and all children with severe ASL deficiency is guarded. Early liver transplantationhas increased survival, especially in males with severe OTC deficiency.


Pediatrics_Nelson

Pediatrics_Nelson. Restriction of dietary protein intake to daily needs is the mainstay of ongoing treatment for urea cycle defects. Crystalline essential amino acids can be supplied in amounts just sufficient to support protein synthesis. Arginine is an essential amino acid when arginine synthesis via the urea cycle is grossly impaired; thus arginine must be supplied except in the case of arginase deficiency. Citrulline needs to be supplied for some urea cycle disorders. For OTC deficiency and carbamoyl phosphate synthase deficiency, treatment with phenylbutyrate (which is metabolized to phenylacetate) prevents accumulation of ammonia.