BRS – Pediatrics: Genetic Disorders and Inborn Errors of Metabolism
I. Inheritance Patterns
A. Mendelian inheritance (Figure 5-1). The classic patterns of inheritance seen in single-gene disorders
1. Dominant inheritance
a. Autosomal dominant mode of inheritance is observed when an abnormal copy of a gene is located on one of the autosomes (chromosomes 1–22). Males and females have the same chance of being affected. If one parent is affected, the risk of having an affected child is 50% in each pregnancy.
b. X-linked dominant mode of inheritance is observed when an abnormal gene is located on one X chromosome. An affected father will transmit disease to 100% of his female offspring and none of his male offspring, whereas an affected mother has a 50% chance of transmitting disease to any of her offspring.
2. Recessive inheritance
a. Autosomal recessive mode of inheritance is observed when there are no normal copies of a gene. If both parents are carriers, offspring will have a 25% chance of being affected. It is often seen in only one generation in a pedigree. Parental consanguinity increases the risk for autosomal recessive conditions.
b. X-linked–recessive mode of inheritance is observed when there are no normal copies of the gene. Disease occurs when a son inherits the abnormal copy from his mother. There is no male-to-male transmission. Daughters who inherit one abnormal copy of the gene are usually asymptomatic, but some may be affected if there is skewed X-inactivation. For example, because one random X chromosome is inactivated in all cells of females, if the X chromosomes with the normal gene are disproportionately inactivated relative to the X chromosomes with the abnormal gene, the female may be affected. A female who inherits two abnormal copies will always be affected. A carrier mother has a 50% chance of having an affected son.
B. Mitochondrial inheritance is observed when a mutation occurs in one of the genes in the mitochondrial genome. The mitochondrial genome is housed separately from the nuclear genome and is only inherited from the mother. In a pedigree, offspring of an affected mother can show signs of disease, but an affected father will never have affected offspring.
C. Multifactorial inheritance occurs when a combination of genetic and environmental factors determines whether or not a disorder will manifest. The disorder will be seen in a particular family with increased frequency compared with that of the general population. Examples of multifactorial inheritance include cleft lip and palate, neural tube defects, developmental dysplasia of the hip, and pyloric stenosis.
FIGURE 5.1 Pedigrees of different Mendelian inheritance patterns.
Adapted with permission from Sakala EP. BRS Obstetrics and Gynecology. 2nd Ed. Philadelphia: Lippincott Williams & Wilkins, 2000:52.
II. Types of Genetic Tests
A. Karyotype analysis is used to determine the number and structure of chromosomes. This may be used to diagnose a chromosomal trisomy, sex chromosome disorders, translocations, and larger deletions or duplications.
B. Microarray is currently the preferred first line test used to diagnose microdeletion/microduplication syndromes, such as 22q11.2 deletion syndrome [see section IV.D.1].
C. Fluorescence in situ hybridization (FISH) is a targeted test that may be also used to look for the presence of a specific sequence of DNA on a chromosome.
D. Methylation studies are performed to help diagnose specific imprinting disorders (e.g., Prader–Willi syndrome). When methyl groups are added to DNA, the activities of the DNA segment can change. This physiologic process plays a role in X chromosome inactivation and imprinting [see section IV.E.1.a], but also plays a role in pathologic processes such as aging, carcinogenesis, and the development of imprinting disorders such as Prader–Willi.
E. Gene sequencing is performed to look for mutations in a specific gene (e.g., fibrillin 1 sequencing to diagnose Marfan syndrome).
F. Exome sequencing looks for potential diseases causing mutations in the protein coding regions (exons) of nearly the entire genome. It is useful when there is a broad differential diagnosis of genetic conditions.
III. Fetal Evaluation and Prenatal Diagnosis
A. Maternal serum markers
1. α-Fetoprotein (AFP) is elevated with fetal neural tube defects, multiple gestation pregnancies, underestimated gestation age, ventral abdominal wall defects, fetal demise, or fetal edema or skin defects. Low AFP levels are associated with overestimated gestation age, trisomies 18 and 21, and intrauterine growth retardation.
2. Triple/quadruple markers are used in conjunction with ultrasound findings as a noninvasive method to assess the fetus for the possibility of trisomy syndromes. The three classic second-trimester screening markers are AFP, unconjugated estriol (uE3), and the β-subunit of human chorionic gonadotropin (β-HCG). More recently, the use of inhibin-A has been introduced to increase the detection rate of Down syndrome.
a. Trisomy 21 is suggested by findings of low AFP and uE3 and high β-HCG and inhibin-A.
b. Trisomy 18 is suggested by low levels of AFP, uE3, and β-HCG
B. Ultrasound is used to assess gestation age and fetal growth and to evaluate for major fetal anomalies. The finding of increased nuchal translucency may indicate the presence of trisomies 13, 18, and 21 and Turner syndrome, as well as structural anomalies such as congenital heart disease.
C. Genetic evaluation of the fetus
1. Chorionic villus sampling (CVS) is the use of villus tissue from the chorion of the trophoblast that is collected at 10–13 weeks’ gestation. Karyotype, gene sequencing, and enzyme analyses from CVS can be used to assess for genetic and metabolic disorders.
2. Amniocentesis is the use of amniotic fluid containing sloughed fetal cells collected at 16– 18 weeks’ gestation. This technique can be used to assess for the same genetic diseases as CVS.
3. Percutaneous umbilical blood sampling involves obtaining a sample of fetal blood to assess for hematologic abnormalities, genetic disorders, infections, and fetal acidosis. It can also be used to administer medications or blood transfusions to the fetus.
4. Noninvasive prenatal testing (NIPT) involves the isolation of fetal cells extracted from a cell-free DNA sample of maternal blood. It is used for assessment of fetal trisomies 13, 18, and 21, and has the potential to replace more invasive forms of sampling for all genetic tests in the future.
IV. Common Genetic Disorders
A. Terminology
1. Malformations are defects that result from the intrinsically abnormal development of a structure or set of structures (e.g., anencephaly, congenital heart disease).
2. Deformations occur when extrinsic (mechanical) forces impinge on the development of otherwise normal tissue (e.g., clubfoot).
3. Disruptions occur when normal tissue is irreparably destroyed, altering the subsequent formation of the structure (e.g., amniotic bands).
4. Syndromes are recognizable patterns of symptoms or abnormalities that suggest a specific underlying disorder.
B. Trisomy syndromes
1. Trisomy 21 (Down syndrome) is the most common chromosomal disorder. The incidence is about 1:700 live births. The risk increases in advanced maternal age, with a sharper rise in prevalence rates seen every year after the age of 35 years.
a. Clinical features. See Table 5-1 and Figure 5-2.
b. Diagnosis is on the basis of clinical features and genetic testing that demonstrates three copies of chromosome 21. Note that about 3–4% of individuals have Down syndrome due to a translocation. A karyotype is needed to distinguish full trisomy 21 from a translocation. If a parent carries a translocation, the recurrence risk for subsequent children with Down syndrome is higher.
2. Trisomy 18 (Edwards syndrome)
a. Clinical features include severe intellectual disability, prominent occiput, low-set ears, micrognathia, congenital heart disease, rocker-bottom feet, and clenched hands with overlapping digits.
b. Prognosis is poor, as 90% of children die by 1 year of age.
3. Trisomy 13 (Patau syndrome)
a. Clinical features include severe intellectual disability, cutis aplasia, microphthalmia, coloboma, congenital heart disease, polydactyly, and midline defects such as agenesis of the corpus callosum and cleft lip and palate.
b. Prognosis is poor, as 50% die by 1 month of age and 90% die by 1 year of age.
C. Sex chromosome syndromes
1. Turner syndrome (XO) occurs in females with complete or partial absence of a second X chromosome.
a. Epidemiology
1. Monosomy X is found in 45% of affected individuals, whereas the remainder of cases are due to either a structural abnormality of the second X chromosome or mosaicism.
2. The incidence is 1:2500–3000 female live births.
b. Clinical features
1. Short stature is present in 95% of individuals with Turner syndrome. Growth hormone can be used to increase final height.
2. Webbed neck with low posterior hairline
3. Broad chest with widely spaced nipples (shield chest)
4. Congenital lymphedema. May have swelling of the hands and/or feet at birth
5. Cardiac defects: coarctation of the aorta, bicuspid aortic valve, hypoplastic left heart
6. Ovarian dysgenesis leads to primary amenorrhea and lack of secondary sex characteristics in most patients. Estrogen therapy can be used to promote
secondary sex characteristics.
7. Most individuals have normal intelligence.
8. Renal malformations, hypothyroidism, diabetes, and hearing loss are also associated with Turner syndrome.
2. Klinefelter syndrome (XXY) is the most common genetic cause of male infertility.
a. Epidemiology
1. The incidence is 1:500–1000 male live births.
2. Risk increases with advancing maternal age.
b. Clinical features
1. Tall stature, thin, with relatively long legs, and gynecomastia
2. Hypogonadism results in small testicles, underdeveloped secondary sex characteristics, oligo- or azoospermia, and decreased bone density.
3. Learning disabilities are common, especially in the areas of verbal comprehension and reading. There is an increased risk of psychosocial and behavioral problems.
4. There is also an increased risk for developing mediastinal germ cell tumors (starting in adolescence) and breast cancer.
3. XYY males may be taller than average but have normal sexual development. Intelligence is usually normal, but there is increased risk for learning disabilities and behavioral problems.
D. Chromosomal (micro) deletion syndromes
1. 22q11.2 deletion syndrome (DiGeorge, velocardiofacial syndrome) occurs when a portion of the q arm of chromosome 22 is missing. The deletion can be de novo or inherited. The mnemonic CATCH-22 can be used to remember the findings of this disorder (Cardiac defects, Abnormal facies, Thymic hypoplasia, Cleft palate, Hypocalcemia, and deletion on chromosome 22)
a. Epidemiology.
1. The incidence of 22q11.2 deletion syndrome is about 1 in 4000 live births.
b. Clinical features
1. Cardiac: congenital heart disease, especially conotruncal malformations (tetralogy of Fallot, ventricular septal defect)
2. Palatal abnormalities: velopharyngeal incompetence, cleft palate, submucous cleft, and bifid uvula
3. Abnormal facies: hooded eyelids, hypertelorism, overfolded or squared off helices, prominent nasal root, bulbous nasal tip, and micrognathia
4. Thymic hypoplasia can result in immunodeficiency. Parathyroid hypoplasia can result in severe hypocalcemia, and therefore, calcium should be monitored in any newborn with suspected 22q11.2 deletion.
5. Intellectual and learning disability
6. Other associations include renal anomalies, hearing loss, and gastrointestinal anomalies.
2. Williams syndrome results from a deletion on chromosome 7 (7q11.23) that includes the elastin gene.
a. Epidemiology.
1. The incidence of Williams syndrome is about 1 in 20,000 births.
b. Clinical features
1. Distinctive facial features (“Elfin facies”) include prominent forehead, widely spaced eyes, upturned and full nasal tip, long philtrum, distinctive wide mouth, and stellate/lacy iris pattern.
2. Cardiovascular disease (elastin arteriopathy): Supravalvar aortic stenosis is
the most common location.
3. Abnormalities of connective tissue may result in a hoarse voice or hernias.
4. Intellectual disability, with a very friendly personality
5. Endocrine problems include hypocalcemia, hypercalcuria, and hypothyroidism.
3. Cri du chat syndrome results from a deletion of the short arm of chromosome 5 (5p). It is characterized by catlike cry in infancy, microcephaly, downslanting palpebral fissures, developmental delay, and intellectual disability.
E. Imprinting disorders
1. Key concepts
a. Genomic imprinting results in differences in gene expression depending on whether the gene is inherited from the mother or father. Disease occurs when the copy from the appropriate parent cannot be expressed. An example occurs in an imprinted region of chromosome 11q. Angelman syndrome occurs when there is a deletion or other mechanism that causes a missing maternal copy of the region, and Prader–Willi syndrome occurs if there is a missing paternal copy of the region. The mnemonic “P is for Prader–Willi and paternal deletion” may be used to remember the molecular basis of these conditions.
b. Uniparental disomy (UPD) occurs when both copies of one chromosome come from the same parent.
2. Prader–Willi syndrome
a. Clinical features
1. In infancy, patients demonstrate hypotonia and feeding difficulties, usually resulting in failure to thrive. In childhood, patients develop hyperphagia leading to obesity.
2. Almond-shaped eyes, strabismus, down-turned mouth, hypopigmentation, small hands and feet, short stature, and hypogonadism
3. Behavioral problems, intellectual disability, and learning disabilities
b. The most common cause is a deletion in a region within the paternally inherited chromosome 15. The second most common cause is maternal UPD of chromosome 15.
c. Diagnosis is by methylation analysis.
3. Angelman syndrome
a. Clinical features
1. Severe developmental delay, speech impairment, and happy demeanor with inappropriate laughter and smiling.
2. Jerky movements and ataxic gait is sometimes described as “puppetlike.”
3. Microcephaly, seizures, large mouth, widely spaced teeth, and prognathia (prominent mandible)
b. The most common cause is a deletion in a region within the maternally inherited chromosome 15.
4. Diagnosis is by methylation analysis.
5. Beckwith–Wiedemann syndrome
a. Clinical features
1. Overgrowth disorder characterized by macrosomia, macroglossia, and visceromegaly
2. Can have hemihyperplasia, ear creases/pits, and omphalocele
3. Increased risk for embryonal tumors (Wilms tumor, neuroblastoma, etc.)
b. This syndrome has several different etiologies, all of which affect imprinting on chromosome 11p15.5.
c. Diagnosis can be established by clinical criteria, methylation studies, microarray, or specific gene sequencing.
6. Russell–Silver syndrome
a. Clinical features
1. Intrauterine growth retardation/small for gestational age (SGA), short stature, normal head circumference, and asymmetry (limb, body, or face)
2. Triangular facies, frontal bossing, or prominent forehead. The patient can also have café-au-lait macules.
b. It has been associated with hypomethylation of a region that regulates expression of insulin-like growth factor 2.
c. Diagnosis is largely based on clinical characteristics.
F. Triplet repeat expansion disorders. Certain genes are sensitive to increasing (expanding) the number of nucleotide repeats in a specific gene segment. The number of repeats can increase with each generation, but the disorder only occurs once the number of nucleotide repeats in a gene expands beyond a specific threshold. Once the threshold is reached, this expansion can become even larger, causing earlier onset and more severe symptoms, which is a phenomenon known as anticipation.
1. Fragile X syndrome
a. This is caused by expansion of the number of CGG repeats in the FMR1 gene on the X chromosome. It has an X-linked recessive mode of inheritance. Full
mutation = >200 repeats
b. Clinical features
1. Developmental delay and mild to severe intellectual disability. Behavioral abnormalities including autism and attention deficit/hyperactivity disorder
2. Macrocephaly, long face, prominent jaw, protruding ears. Macroorchidism
develops in adolescence.
3. Females with full mutation may have behavioral problems and developmental delays, but most have normal intelligence quotient (IQ).
2. Myotonic dystrophy
a. Genetic mechanism
1. The severe form is caused by expansion of the number of CTG repeats in the
DMPK gene.
2. Expansion of the repeats occurs much more frequently in mothers.
b. Clinical features
1. Progressive muscular weakness starting at any time during childhood
2. Other features include cataracts and cardiac conduction abnormalities.
G. Connective tissue disorders
1. Marfan syndrome
a. An autosomal dominant disorder caused by mutations in the gene that codes for
fibrillin. Mutations can either be inherited or sporadic.
b. Clinical features. Characteristic findings involve the ocular, skeletal, and cardiovascular systems.
1. Myopia, lens dislocation, and retinal detachment
2. Tall stature with long extremities, long fingers (arachnodactyly), pectus deformity, scoliosis, pes planus, decreased upper-to-lower segment ratio, increased arm span-to-height ratio
3. Aortic root dilatation, mitral valve prolapse, and valvular regurgitation. Note: Patients with aortic root dilatation are at increased risk for aortic dissection. β-blockers +/− angiotensin receptor blockers are prescribed to help prevent or slow progressive aortic enlargement.
4. Patients are at risk for spontaneous pneumothorax.
2. Ehlers–Danlos syndrome, classic type
a. An autosomal dominant disorders caused by mutations in genes that code for type V collagen. Mutations can be inherited or sporadic.
b. Clinical features. Characterized by skin hyperextensibility, abnormal wound healing, and joint hypermobility. Skin may be described as soft and/or velvety in texture, with bruising caused by fragile blood vessels. Tissue fragility and poor wound healing results in widened atrophic scars.
H. Skeletal disorders
1. Achondroplasia
a. An autosomal dominant disorder caused by mutations in FGFR3. The majority of cases result from a sporadic mutation. Advanced paternal age (>45 years old) increases the risk of having an affected child.
b. Achondroplasia is the most common cause of disproportionate short stature.
c. Clinical features
1. Craniofacial findings include macrocephaly, prominent forehead, low nasal bridge, and midface hypoplasia.
2. Characteristic skeletal findings:
a. Rhizomelic (proximal limb) shortening of the limbs, bowed legs, and
trident appearance of the hands.
b. Lumbar gibbus deformity (structural, sharp-angled kyphosis resulting in a prominent “hump” on the back) in infancy that resolves once the patient starts walking. Lumbar lordosis then develops.
3. Normal intelligence with delayed acquisition of motor milestones
4. Recurrent middle ear dysfunction and obstructive sleep apnea
5. Increased risk for foramen magnum stenosis and compression of the craniocervical junction. Patients should therefore be monitored for signs of hydrocephalus and spinal cord compression.
2. Osteogenesis imperfecta (OI)
a. Most cases are due to autosomal dominant mutations in genes that encode for chains of type I collagen. Type I is the most common and the mildest form of OI. Patients with Type II OI are the most severely affected, and rarely survive beyond the first weeks of life. Type III is the most severe type among those who survive the neonatal period.
b. Clinical features of Type I OI
1. Characterized by blue sclera and frequent fractures after minimal or no trauma. Easy bruising. Fractures usually heal without resulting deformity.
2. Normal stature or slightly shorter than the rest of the family
3. May have yellow or grayish brittle teeth (dentinogenesis imperfecta) which are at increased risk for breakage.
4. Progressive hearing loss in adulthood
I. Additional disorders
1. Noonan syndrome
a. Autosomal dominant disorder caused by mutations in certain genes involved in the RAS/MAPK pathway.
b. Clinical features
1. Characterized by short stature, congenital heart defect, pectus deformity, and characteristic facies
2. Craniofacial findings are most prominent in infancy and include low-set, posteriorly rotated ears, wide-spaced eyes (hypertelorism), eyelid ptosis, and
downslanting palpebral fissures.
3. Pulmonary valve stenosis is the most common cardiac defect. All patients are at risk for developing hypertrophic cardiomyopathy during their lifetime.
4. Patients can have short, webbed neck with low posterior hairline, and broad chest with widely spaced nipples. Affected females are sometimes initially misdiagnosed with Turner syndrome (which is associated with left-sided heart defects vs. Noonan syndrome with right-sided heart defects).
5. Patients may have developmental delay and/or intellectual disability.
2. VACTERL (VATER) association
a. A group of malformations generally observed as a sporadic occurrence in an otherwise healthy family. The etiology is unknown. Clinical findings overlap with those seen in Fanconi anemia, which should be ruled out in anyone presenting with VACTERL.
b. Clinical features
1. V—vertebral defects
2. A—anal atresia
3. C—cardiac defects
4. TE—tracheoesophageal (TE) fistula
5. R—renal dysplasia
6. L—limb/radial defects
3. CHARGE Syndrome
a. An autosomal dominant disorder most often caused by a spontaneous mutation
b. Clinical features
1. C—colobomas of the iris or retina. Usually results in impaired vision
2. H—heart defects such as conotruncal defects and aortic arch abnormalities
3. A—choanal atresia or stenosis
4. R—retarded growth and development
5. G—genital abnormalities, including genital hypoplasia
6. E—ear anomalies, including abnormal outer ear shape, hearing loss, and ossicular and temporal bone abnormalities
7. Cranial nerve dysfunction is another important feature.
4. Cornelia de Lange syndrome
a. Generally observed as a sporadic occurrence in an otherwise healthy family. Autosomal dominant and X-linked mutations have been found.
b. Clinical features
1. Characteristic facies include synophrys (single eyebrow resulting from both eyebrows growing into one another), long eyelashes, small upturned nose, and microcephaly.
2. SGA, failure to thrive, and small stature
3. Hirsutism
4. Upper limb malformations
5. Developmental delay, intellectual disability, and behavioral problems
5. Neurofibromatosis type 1 (see also Chapter 19, Table 19-3)
a. Autosomal dominant disorder caused by mutations in NF1. Half of the cases are inherited, and the remainder are spontaneous mutations.
b. Clinical features
1. Characteristic findings include multiple café-au-lait macules, axillary and inguinal freckling, cutaneous and/or plexiform neurofibromas, iris hamartomas (Lisch nodules), and osseous dysplasia.
2. Increased risk for malignant peripheral nerve sheath tumors (PNETs), optic
nerve gliomas, and central nervous system (CNS) gliomas
3. Learning disabilities are seen in half of patients.
6. Potter syndrome
a. A deformation sequence that results from compressive forces exerted on a developing fetus subjected to prolonged oligohydramnios. The oligohydramnios may have resulted from bilateral renal agenesis, other urinary tract defects, or a chronic leak of amniotic fluid.
b. Clinical features include lung hypoplasia, abnormal limb positioning, and characteristic “Potter facies” (compressed facial appearance, with large ears flattened against the head).
7. Pierre Robin sequence
a. A sequence that can be seen as an isolated finding or as part of a specific multiple malformation syndrome. Clinical findings result from mandibular hypoplasia, which leads to a cascade of other features.
b. Clinical features include micrognathia, glossoptosis (posterior displacement of the tongue), and cleft palate (often a U-shaped cleft).
8. Amniotic band syndrome occurs when rupture of the amniotic sac during pregnancy results in small strands of amnion wrapping around areas of the fetus’s body, causing deformation and/or amputation.
J. Syndromes caused by teratogens(Table 5-2)
1. Diabetic embryopathy
a. Increased risk for congenital malformations occurs in infants born to mothers with type 1 or type 2 diabetes, especially when the Hgb A1C level is >12 just before conception and/or in the early first trimester.
b. The infant may have isolated or multiple malformations, including caudal regression syndrome (sacral agenesis), neural tube defects, renal malformations, cardiac defects, or craniofacial abnormalities.
2. Fetal alcohol syndrome (FAS)
a. FAS is caused by maternal alcohol consumption during pregnancy. Prenatal exposure to alcohol can cause a wide range of findings, with FAS being the most severe. No amount of alcohol is considered safe, but the risk for FAS is higher with binge drinking or chronic alcohol consumption during pregnancy.
b. Clinical features
1. Microcephaly, short palpebral fissures, smooth philtrum, and thin upper lip
2. Developmental delay, intellectual disability, and attention deficit hyperactivity disorder
3. Infants may be SGA.
4. Cardiac defects may occur (ventricular septal defects are most common).
3. Fetal hydantoin syndrome
a. Infants born to mothers taking phenytoin during pregnancy are at increased risk for specific malformations.
b. Clinical features
1. Microcephaly, wide anterior fontanelle, hypertelorism, short nose, wide mouth
2. Low hairline, short neck, hypoplastic nails
3. Developmental delays
Table 5-1
Clinical Features and Complications Associated with Down Syndrome, with Recommendations for Screening
Craniofacial features Atlantoaxial instability (1–2%)
Brachycephaly Anemia
Epicanthal folds
Check hemoglobin annually
Upslanting palpebral fissures Leukemia (1% of patients but more common than the general population)
Brushfield spots (speckled irides)
Protruding tongue Celiac disease (5%)
Hypotonia Early onset Alzheimer disease
Intellectual disability Obstructive sleep apnea (50–75%)
Sleep study by 4 years of age
Musculoskeletal features Hearing problems (75%)
Clinodactyly
Hearing screens needed every 1–2 years
Single palmar creases Thyroid disease
Wide space between first and second toes (sandal gap)
Annual TSH screening
Gastrointestinal features Cataracts, glaucoma, and refractive errors
Duodenal atresia
Annual ophthalmologic examinations
Hirschsprung disease and omphalocele
Pyloric stenosis
Cardiac defects (40%)
Endocardial cushion defects (most common)— echocardiogram at birth
TSH = thyroid-stimulating hormone.
FIGURE 5.2 Clinical features of Down syndrome.
Table 5-2
Teratogens and Associated Anomalies
Drugs Associated Anomalies
Alcohol Microcephaly; short palpebral fissures; long, smooth philtrum; variable intellectual disability; and
congenital heart disease
Cigarette
smoking Small for gestational age
Cocaine Premature birth
Diethylstilbestrol
(DES) Increased risk of vaginal adenocarcinoma and genitourinary anomalies
Isotretinoin Small low-set ears, micrognathia, depressed nasal bridge, cardiac defects, thymic hypoplasia, and central
nervous system malformations
Lithium Ebstein anomaly
Phenytoin Wide anterior fontanelle, short nose, wide mouth, microcephaly, low hairline, hypoplastic nails, and
developmental delay
Thalidomide Phocomelia (malformed extremities resulting in flipperlike appendages)
Valproic acid Neural tube defects
Warfarin Hypoplastic nose with depressed nasal bridge, stippled epiphyses, and hypoplastic nails
V. General Concepts of Inborn Errors of Metabolism (IEM)
A. IEM are a heterogeneous group of diseases that can present in a variety of ways. Individually, each disease is rare but causes significant morbidity and mortality.
B. Disorders occur when a specific step in a metabolic pathway is disrupted in some way (defective enzyme, receptor problem, etc.), resulting in the accumulation of toxic metabolites.
C. Each individual disorder may have several subtypes that can vary in level of severity. Unless otherwise stated, the severe/classic form of each disorder is discussed below.
D. An overview of different categories of IEM, including examples of conditions within each category, is summarized in Figure 5-3.
E. Clinical features (Table 5-3)
1. IEM should be considered in patients with the following clinical presentations.
a. An otherwise healthy newborn who develops an acute severe illness within the first few hours to weeks of life
b. Acute and recurrent episodes of altered mental status, vomiting, acidosis, organ failure, or ataxia
c. Chronic and progressive symptoms such as developmental delay or regression of developmental milestones, intellectual disability, or seizures
2. Age of onset. Age of onset is variable depending on the type of IEM. Some disorders that present in infancy have less severe forms that can present later in infancy, childhood, adolescence, or even adulthood.
3. Family history
a. Most IEM are inherited in an autosomal recessive fashion, but several are X-linked recessive. A history of parental consanguinity may be seen in patients with autosomal recessive disorders.
b. There might be a family history of neonatal death.
c. For recessive conditions, there may be an affected sibling, and for X-linked disorders, there may be an affected brother or maternal uncle.
4. Key point: Sepsis is much more common than metabolic disease. However, it is important to keep in mind that the presenting symptoms of IEM may be similar to those of sepsis, and patients with IEM are vulnerable to sepsis.
F. Laboratory evaluation and management(Table 5-4) depends on presenting features and clinical status of patient (acute episode or stable between episodes). Newborn screening programs can diagnose several IEM before symptoms develop; however, the specific disorders that are screened differ from state to state.
FIGURE 5.3 Summary chart of inborn errors of metabolism. MELAS = mitochondrial encephalopathy, lactic acidosis, and strokelike episodes; MERRF = myoclonic epilepsy and ragged-red fibers.
Table 5-3
Typical Clinical Features of Inborn Errors of Metabolism (IEM)
General symptoms:
Lethargy or coma
Poor feeding
Intractable hiccups
Unusual odor (especially when acutely ill):
Odor: IEM:
Mousy/musty Phenylketonuria
Sweet maple syrup Maple syrup urine disease
Sweaty feet Isovaleric or glutaric acidemia
Boiled cabbage Tyrosinemia type I
Neurologic:
Hypotonia
Unexplained developmental delay
Unexplained and difficult to control seizures
Ophthalmologic:
Cherry-red macula, cataracts, or corneal clouding
Gastrointestinal:
Unexplained vomiting
Hepatomegaly
Splenomegaly
Metabolic:
Hypoglycemia may be associated with fatty acid oxidation disorders or carbohydrate disease
Elevated NH3 without acidosis is suggestive of urea cycle defects
Elevated NH3, metabolic acidosis, and elevated anion gap are suggestive of organic acidemias
Urinary ketones in a newborn are unusual and may indicate an IEM such as maple syrup urine disease
NH3 = ammonia.
Table 5-4
Initial Evaluation for Inborn Errors of Metabolism
Test Reason for Test
Initial studies
Serum glucose
Rule out hypoglycemia
CBC with differential
Some organic acidemias may cause pancytopenia
Urinalysis
Assess for ketones:
Presence of ketones is especially suspicious in newborns, because they do not normally produce ketones well
Arterial blood gas and serum electrolytes
In older children, absence of ketones with hypoglycemia is suspicious for fatty acid oxidation defect
Assess for urine-reducing substances:
Positive reducing substances with a negative dipstick for glucose is suggestive of galactosemia
Assess for anion gap metabolic acidosis
Plasma NH3
Rule out urea cycle defects or organic acidemias Mild elevations can be nonspecific
If metabolic acidosis is present:
Serum lactate and pyruvate
Rule out lactic acidemias or organic acidemias
Urine organic acids
Rule out organic acidemias
If increased ammonia is present:
Plasma amino acids
If elevated, then suspect aminoacidopathies
Urine organic acids
If elevated, suspect organic acidemias. If elevated orotic acid, suspect ornithine transcarbamylase deficiency
CBC = complete blood count; NH3 = ammonia.
VI. Defects in Amino Acid Metabolism
The characteristics of phenylketonuria (PKU), tyrosinemia type 1, and maple syrup urine disease are summarized in Table 5-5. Other examples of defects of amino acid metabolism are described in this section.
A. Homocystinuria. An autosomal recessive disorder caused by cystathionine β-synthase deficiency, resulting in increased levels of homocysteine and methionine
1. Clinical features
a. Marfanoid body habitus (tall, slender), scoliosis, and pes planus
b. Myopia. High risk for lens dislocation. Note that in Marfan syndrome, the lens more often dislocates superiorly, whereas in homocystinuria, the lens more often dislocates inferiorly.
c. Developmental delay, with variable intellectual disability
d. Thromboembolism can occur in any vessel, increasing the risk of stroke and systemic thrombosis, as well as developmental delay.
e. Key point: If a patient is developmentally delayed and has a marfanoid habitus, perform screening tests for homocystinuria. Homocystinuria screening should also be performed in patients who test negative for Marfan syndrome.
2. Diagnosis
a. Plasma amino acids
1. Increased homocysteine in plasma
2. Increased methionine in plasma
b. Genetic testing confirming homozygous mutations
3. Management
a. Special diet (methionine restricted, cystine enhanced)
b. Betaine therapy (lowers homocysteine levels and reduces risk for thromboembolism)
c. Some patients are responsive to treatment with vitamin B6.
B. Urea cycle disorders (UCDs). They result from deficiencies in one of the enzymes involved in the urea cycle. The urea cycle is responsible for the metabolism of excess nitrogen into urea. Defects in the urea cycle result in accumulation of ammonia, which is toxic, especially to the nervous system. The age of onset and severity of the different UCDs varies. All of the UCDs are autosomal recessive, except ornithine transcarbamylase (OTC) deficiency, which has X- linked recessive inheritance.
1. OTC deficiency
a. Epidemiology: the most common of the UCDs
b. Clinical features: Male infants become symptomatic in first 48 hours of life with poor feeding, hypotonia, and hyperventilation, which can rapidly progress to lethargy, coma, and seizures.
c. Diagnosis of OTC deficiency
1. Initial labs usually include a blood gas showing respiratory alkalosis due to hyperventilation.
2. Plasma ammonia concentration >200 µmol/L
3. Low or absent plasma citrulline and high urine ototic acid level
d. Management of OTC deficiency includes a low-protein diet and modalities to decrease ammonia levels. Medications can “scavenge” ammonia (e.g., sodium benzoate binds with ammonia and provides an alternative pathway to excrete nitrogen). For severe episodes of hyperammonemia, hemodialysis and/or liver transplant may be indicated.
e. Prognosis of OTC deficiency is variable, depending on the severity of hyperammonemic episodes. In most cases, at least some degree of developmental delay and intellectual disability will be present.
2. Transient hyperammonemia of the newborn is a self-limited disease that may present in premature infants within the initial 24–48 hours of life. Symptoms are nonspecific and can be similar to those of a UCD. Aggressive treatment of hyperammonemia is required to prevent neurologic sequelae.
C. Organic acidemias. The most common organic acidemias are caused by abnormal amino acid catabolism of branched-chain amino acids, and are characterized by urinary excretion of nonamino organic acids.
1. Propionic aciduria (PA) and methylmalonic aciduria (MMA) typically present after the first few days of life with vomiting, poor feeding, hypotonia, and other neurologic symptoms, which will progress if left untreated. Laboratory studies show metabolic acidosis, hyperammonemia, and ketotic hypoglycemia. Hyperammonemia results from inhibition of one of the urea cycle enzymes, and measurement of urine organic acids will diagnose the disorders.
2. Isovaleric acidemia. Presentation is similar to PA and MMA. Patient may also have an
odor of sweaty feet.
3. Glutaric acidemia type I. This diagnosis should be considered in any infant with macrocephaly, basal ganglia changes on magnetic resonance imaging (MRI), and a movement disorder exacerbated by intercurrent illness.
Table 5-5
Characteristics of Selected Defects in Amino Acid Metabolism
Phenylketonuria (PKU) Maple Syrup Urine Disease Tyrosinemia Type I
Inheritance
Autosomal recessive
Autosomal recessive
Autosomal recessive
Clinical features
Developmental delay Infantile hypotonia Mousy or musty odor
Progressive mental retardation Eczema
Decreased pigment (light eyes and hair)
Mild PKU may present in early childhood with developmental delay, hyperactivity
Progressive vomiting and poor feeding
Lethargy, hypotonia, and coma
Developmental delay Maple syrup odor in urine Hypoglycemia and severe acidosis during episodes
Episodes of peripheral neuropathy
Chronic liver disease Odor of rotten fish or cabbage
Renal tubular dysfunction
Diagnosis
↑ Phenylalanine: Tyrosine ratio in serum
↑ Serum and urine branched- chain amino acids
Succinylacetone in urine
Management
Phenylalanine-restricted diet
Dietary protein restriction
Dietary restriction of phenylalanine, tyrosine, NTBC Liver transplant
Prognosis
Near-normal intelligence if diet restriction begun < 1 month of age
Protein restriction within 2 weeks of life may avert neurologic damage
Death by 1 year of age if disease begins in infancy
Increased risk of hepatocellular carcinoma and cirrhosis
NTBC = 2-2 nitro-4-trifluoromethylbenzoyl 1,3-cyclohexanedione.
VII. Defects of Carbohydrate Metabolism
A. Galactosemia is an autosomal recessive disorder caused by galactose-1-phosphate uridyltransferase (GALT) deficiency.
1. Clinical features. Patients are unable to metabolize galactose and are therefore unable to tolerate lactose. Symptoms start in newborns after ingesting lactose in breast milk or milk- based formulas.
a. Feeding problems, failure to thrive, vomiting, and diarrhea
b. Jaundice, hypoglycemia, hepatomegaly, liver failure, renal failure, and bleeding
c. Patients are at increased risk of developing Escherichia coli sepsis.
d. Developmental delay
e. Cataracts
f. Even treated patients may have long-term effects:
1. Intellectual disability and neurologic defects, including ataxia
2. Ovarian failure in females
2. Diagnosis
a. Increased red blood cell (RBC) galactose-1-phosphate in blood
b. Absent or markedly decreased GALT activity in RBCs
c. Urinary reducing substances (a nonspecific finding)
3. Management includes restricting galactose intake and a lactose-free diet.
4. Prognosis varies depending on the severity of initial symptoms before diagnosis and compliance with treatment. Even with treatment, patients may demonstrate speech defects and learning disabilities.
B. Glycogen storage diseases (GSDs). A group of autosomal recessive disorders of glycogen metabolism that result in glycogen accumulation in various organs.
1. GSD type I (von Gierke disease) is most commonly caused by glucose-6-phosphatase deficiency.
a. Clinical features
1. Often presents by 3–4 months of age with hypoglycemia, lactic acidosis, hepatomegaly, hyperuricemia, hyperlipidemia, short stature, and cherubic facies.
2. Patients may develop hepatic adenomas that are at increased risk for malignant transformation to hepatocellular carcinoma.
b. Management includes frequent feedings with complex carbohydrates and cornstarch to avoid hypoglycemia.
2. GSD type II (Pompe disease) is caused by a deficiency of the lysosomal enzyme α- glucosidase.
a. Clinical features
1. Often presents in the first two months of life.
2. Should be considered in the differential diagnosis of a profoundly hypotonic infant with failure to thrive, cardiomegaly, and macroglossia (large tongue).
3. Additional findings include hepatomegaly, wide QRS complex, and elevated blood creatine kinase levels.
b. Management includes supportive care for symptoms and enzyme replacement therapy.
C. Hereditary fructose intolerance is an autosomal recessive disorder caused by aldolase B deficiency that affects the ability to digest fructose.
1. Clinical features
a. Symptoms typically develop after fructose- and sucrose-containing foods are
introduced into the diet.
b. Symptoms include diarrhea, bloating, and abdominal pain.
c. Continued fructose ingestion can result in failure to thrive, as well as liver and kidney disease.
2. Management involves avoidance of fructose-containing foods and beverages.
VIII. Fatty Acid Oxidation Disorders
Fatty acid oxidation is a major source of energy and ketone generation. Fatty acid oxidation defects can have variable effects on different tissues and organ systems, but typically affected children present with hypoketotic hypoglycemia at different ages. Medium-chain acyl-CoA dehydrogenase deficiency (MCAD) is the most common disorder.
A. Clinical features of MCAD.
1. Usually presents between 4 months to 4 years of age after a period of fasting or during an illness that caused vomiting.
B. Presenting signs and symptoms of MCAD include hypoglycemia, encephalopathy and liver dysfunction. MCAD may resemble Reye syndrome and accounts for 5% of cases of sudden infant death.
C. Diagnosis of MCAD is made by the presence of abnormal urine organic acids and an abnormal acylcarnitine profile. Plasma amino acids are normal.
IX. Lysosomal Storage Diseases
A. Mucopolysaccharidoses (MPSs) are caused by defects in enzymes required to break down glycosaminoglycans, resulting in accumulation of molecules in various organs. Patients are usually normal at birth but will show features of this disorder in the first few years of life. Common features include short stature, intellectual disability, hepatosplenomegaly, and skeletal abnormalities. X-rays may show dysostosis multiplex (a constellation of bony abnormalities that include a J-shaped sella turcica; malformed, ovoid, or beaklike vertebrae; short and thickened clavicles; and oar-shaped ribs). Most MPSs are inherited in an autosomal recessive manner, with the exception of Hunter syndrome that is X-linked.
1. Hurler syndrome (MPS type I) is an autosomal recessive disorder caused by α-l- iduronidase deficiency.
a. Clinical features
1. Hepatosplenomegaly, short stature, and corneal clouding
2. Progressive coarsening of facial features, large tongue, umbilical hernia, hearing loss, and cardiomyopathy
3. Kyphosis, stiff joints, and joint contractures
4. Severe classic forms have developmental regression and death in childhood.
b. Diagnosis may be made by increased urinary glycosaminoglycans, by enzyme assays, and by genetic testing.
c. Management includes enzyme replacement therapy, bone marrow transplant, and supportive care.
2. Hunter syndrome (MPS type II) is an X-linked recessive disorder caused by a deficiency of idurontate-2-sulfatase.
a. Clinical features overlap with those seen with Hurler syndrome, except that there is no corneal clouding (“a hunter needs to see clearly!). In severe classic forms of the disease, death usually occurs by later adolescence.
b. Diagnosis is by a urine mucopolysaccharide spot test, by an enzyme assay, and by genetic testing.
c. Management includes enzyme replacement therapy and supportive care.
B. Sphingolipidoses. A group of autosomal recessive disorders caused by defects in lipid metabolism. The following three disorders have high carrier frequency in the Ashkenazi Jewish population. Diagnosis is based on demonstration of deficient enzyme activity and/or by genetic testing.
1. Gaucher disease type I is caused by β-glucocerebrosidase deficiency and is the most common lysosomal storage disease. Clinical features include hepatosplenomegaly, cytopenias (anemia, thrombocytopenia, and leukopenia), and bone disease (osteopenia, lytic lesions, and fractures). Bleeding and complaints of “growing pains” may be presenting complaints. Bony disease results in an Erlenmeyer flask appearance of the distal femur on radiographs. Gaucher cells (foamy macrophages) are found on bone marrow biopsy. Management includes enzyme replacement therapy. More severe patients are classified as type II or III and have CNS manifestations.
2. Tay–Sachs disease is a neurodegenerative disorder caused by hexosaminidase A deficiency. Symptoms are usually apparent by 6 months of age. Clinical features include an increased startle reflex, hypotonia, loss of developmental milestones, hearing loss, cherry-red spot on the macula, and macrocephaly. As the disorder progresses, patients develop blindness, seizures, and autonomic dysfunction. Death usually occurs by 5 years of age.
3. Niemann–Pick disease types A and B are neurodegenerative disorders caused by acid
sphingomyelinase deficiency. Symptoms are usually noted by 3 months of age. There is a wide range of clinical features, but hepatosplenomegaly and progressive neurologic deterioration are constant features. A cherry-red spot may also be seen. Death usually occurs by 3 years of age.
X. Mitochondrial Disorders
These disorders affect multiple organ systems and may arise from mutations in the mitochondrial DNA (present in multiple copies per cell) or the nuclear DNA. Examples of mitochondrial DNA disorders include Kearns–Sayre syndrome (ophthalmoplegia, pigmentary degeneration of the retina, hearing loss, heart block, and neurologic degeneration) and MELAS (mitochondrial encephalopathy, lactic acidosis, and strokelike episodes). Diagnosis is based on clinical features, laboratory studies and genetic testing. Management is predominantly supportive but depends on the specific disorder.
XI. Disorders of Metal Metabolism
A. Wilson disease is an autosomal recessive disorder of copper metabolism that results in copper accumulation in various tissues, including the liver, brain, and cornea.
1. Clinical features
a. Hepatic dysfunction. Symptoms may include jaundice, hepatomegaly, hepatic failure, and cirrhosis.
b. Neurologic findings include changes in intellect and behavior, dystonia, dysarthria, basal ganglia symptoms (Parkinson-like), seizures and dementia. Wilson disease should be considered in a child who presents with new-onset behavior problems and difficulty learning.
c. Kayser–Fleischer rings are dark rings that encircle the iris due to copper deposition in Descemet’s membrane.
2. Diagnosis
a. Decreased serum ceruloplasmin and increased serum copper
b. Increased urine copper excretion
c. Increased copper deposition on liver biopsy
3. Management includes copper chelating agents such as penicillamine and avoidance of copper-containing foods.
B. Menkes disease is a progressive neurodegenerative X-linked recessive disorder caused by a defect of copper transport. Symptoms generally present at around 2–3 months of age with hypotonia, loss of developmental milestones, seizures, and failure to thrive. Physical features include hair that is sparse, lightly pigmented, and/or kinky. Diagnostic studies include low serum copper and ceruloplasmin, as well as low copper in tissues.
Review Test
1. A 1-week-old male infant is brought to the emergency department because of vomiting and decreased feeding for 3 days. On examination, you find that he is jaundiced and has hepatomegaly. The infant is admitted to the neonatal intensive care unit, but later he dies of Escherichia coli sepsis. Urine-reducing substances are positive. Which of the following is the most likely diagnosis?
A. Gaucher disease
B. Galactosemia
C. Glycogen storage disease type 1
D. Hurler disease
E. Niemann–Pick disease
2. The parents of a 15-year-old boy consult you because they are concerned that their son has been acting strangely for the past 6 months. The boy has developed ataxia, tremors, and seizures. His father reports that his son seems to have developed a different personality. On examination, you note that the boy has brown rings at the edge of his corneas bilaterally. Which of the following is the best serum laboratory screen for the most likely diagnosis?
A. Aluminum
B. Lead
C. Porphobilinogen
D. Zinc
E. Ceruloplasmin
3. A 6-year-old girl is brought to the clinic for a routine health maintenance visit. Her growth was normal until 2 years of age, when her height started to fall off the growth curve, steadily decreasing to below the fifth percentile. On examination, she has a webbed neck with a normal range of motion, a shield chest with widely spaced nipples, and scoliosis. Past medical history is significant for repaired coarctation of the aorta at 3 years of age. Which of the following is the most likely diagnosis?
A. Noonan syndrome
B. Achondroplasia
C. Turner syndrome
D. Russell–Silver syndrome
E. Marfan syndrome
4. The mother of a 6-year-old boy brings her son to the office for a second opinion regarding her child’s developmental delay. Your nurse takes the initial history and reports that he was adopted from another country. He was born at term by normal spontaneous vaginal delivery and seemed normal at birth, but has not been meeting his developmental milestones. After assessing his vital signs, your nurse pulls you aside and states, “That mother has no control over her child! He is hyperactive, still in diapers, and he stinks!” You walk into the examination room and immediately notice a mousy, musty smell. Which of the following is the most likely diagnosis?
A. Phenylketonuria
B. Tyrosinemia type I
C. Maple syrup urine disease
D. Homocystinuria
E. Cystinuria
5. During a health maintenance visit, the parents of a 9-month-old infant note that their infant is unable to sit alone or roll over and startles very easily to sound. On examination, you note a cherry-red macula and poor eye contact. Which of the following is correct regarding the likely
diagnosis?
A. Hearing loss is a common complication of this condition.
B. Radiography of the lower extremity reveals an Erlenmeyer flask–shaped distal femur.
C. Radiography of the extremities reveals dysostosis multiplex.
D. Mild developmental delay is expected.
E. Microcephaly should be apparent.
6. A 5-day-old male infant is brought to the emergency department in coma. The infant’s diaper has a sickly sweet smell. Laboratory results reveal no acidosis, hypoglycemia, or hyperammonemia, but there are significant amounts of ketones in the urine. Maple syrup urine disease is in the differential diagnosis. Which of the following statements regarding the acute management of this patient is correct?
A. Antibiotics are not indicated because the infant likely has an inborn error of metabolism.
B. Intravenous glucose should be administered.
C. Total parenteral nutrition with protein and lipids should be started.
D. Sodium benzoate should be administered.
E. Enteral feeds with a soy-based formula should be given.
7. A 14-year-old boy with mental retardation has been referred to you. The underlying cause of his mental retardation has never been identified. On physical examination, you note that he has large ears and large testes. Which of the following syndromes is associated with mental retardation and these physical findings?
A. Klinefelter syndrome
B. Down syndrome
C. Prader–Willi syndrome
D. Williams syndrome
E. Fragile X syndrome
8. A 4-month-old male infant has been brought to your office for a routine health maintenance evaluation. You note that his height is below the third percentile, yet his head circumference is at the 75th percentile. Facial findings include a prominent forehead and hypoplasia of the midface region. He also has trident-shaped hands and bilateral short femurs and upper arms. Which of the following is a potential complication of this patient’s likely disorder?
A. Lumbar kyphosis in late childhood
B. Atlantoaxial instability
C. Spinal cord compression
D. Aortic dissection
E. Delayed puberty
9. The mother of a 5-year-old boy is very concerned and shows you a note from his kindergarten teacher. The boy is very active, easily distracted, and unable to perform skills at the same level as others in his class, and the teacher expresses concern and wonders whether the boy could have a severe learning problem. On examination, you note that the boy’s height and weight are at the 50th percentile, but his head appears very small. In addition, he has short palpebral fissures and a long, smooth philtrum with a thin upper lip. The remainder of the examination is normal. Which of the following is the most likely diagnosis?
A. Angelman syndrome
B. Down syndrome
C. Fetal phenytoin syndrome
D. Fetal alcohol syndrome
E. Prader–Willi syndrome
10. A 12-year-old boy is brought to the office for a routine health maintenance visit by his parents. They report that he has struggled in school, requiring some special educational assistance since kindergarten, but has been otherwise healthy. Examination reveals that the boy is very
tall (>95th percentile) with long, thin arms with fingers of normal size. Mild scoliosis is evident. On auscultation, a murmur consistent with mitral regurgitation is audible. Based on the likely diagnosis, which of the following would you also expect to find on further evaluation?
A. Increased upper-to-lower segment ratio
B. Downward lens subluxation
C. Aortic root dilatation
D. Joint laxity
E. Hypogonadism
11. You are called to the newborn nursery to evaluate a 1-day-old female infant with unusual physical findings. On examination, you note that the neonate’s hands are clenched with overlapping digits and her lower extremities are extended and crossed. You also note the presence of rocker bottom feet and delicate, small facial features. Which of the following chromosomal abnormalities is the most likely cause of the patient’s features?
A. Trisomy 13
B. Trisomy 18
C. Trisomy 21
D. Deletion on chromosome 7
E. Absence of a region on paternally derived chromosome 15
The response options for statements 12–14 are the same. You will be required to select one answer for each statement in the following set.
A. Ehlers–Danlos syndrome
B. Cri du chat syndrome
C. Osteogenesis imperfecta
D. Williams syndrome
E. Angelman syndrome
F. Hurler syndrome
G. Hunter syndrome
H. Tay–Sachs disease
I. Gaucher disease
J. Homocystinuria
For each patient, select the most likely genetic condition.
1. Six-year-old boy with coarsened facial features, stiff joints, and a cloudy cornea
2. Four-year-old boy with microcephaly, hypertelorism, mental retardation, and a deletion on the short arm of chromosome 5
3. Fourteen-year-old girl with joint laxity, easily bruisable skin, and a defect in type V collagen
Answers and Explanations
1. The answer is B [VI.A]. Galactosemia should always be considered in the differential diagnosis of any newborn who develops hypoglycemia and has hepatomegaly. Infants with galactosemia develop vomiting and diarrhea after feeding with either breast milk or cow’s milk–based formulas, because both types of feeding contain galactose. Soy milk does not contain galactose, which means that an infant who is fed a soy formula will not be symptomatic, which delays the diagnosis. Infants with galactosemia are vulnerable to Escherichia coli sepsis, and if the condition is not diagnosed, they may die in early infancy. Children with Gaucher disease present with neurodegeneration, splenomegaly, and bony changes (the most characteristic of which is an Erlenmeyer flask–shaped distal femur). After the first year of life, individuals with Hurler disease present with developmental delay, coarse facies, corneal clouding, and dysostosis multiplex. Individuals with with Niemann–Pick disease may present with hepatomegaly and seizures, but hypoglycemia and E. coli sepsis are not typical features of these diseases. Patients with glycogen storage disease type 1 may have hepatomegaly and hypoglycemia, but they will not have urine-reducing substances, and they do not have a special propensity to get E. coli sepsis.
2. The answer is E [XI.A.2]. Wilson disease should always be considered in a patient with personality changes, ataxia, and seizures. The patient’s signs and symptoms are suggestive of Wilson disease, which is caused by a defect in copper excretion leading to copper deposition in the brain, eyes, and liver. Kayser–Fleischer rings, which represent copper deposition in Descemet’s membrane, are pathognomonic for Wilson disease. The most commonly used screening test for Wilson disease is a low serum ceruloplasmin, which is very suggestive of the disorder. None of the other answer choices are associated with the signs and symptoms present in this patient. Aluminum, zinc, or lead does not cause the signs and symptoms seen in this patient. Serum porphobilinogen, while not addressed given the scope of this text, is elevated in acute intermittent porphyria, which may present with weakness, abdominal pain and autonomic instabilty.
3. The answer is C [III.C.1]. Girls with Turner syndrome are usually diagnosed in childhood after an evaluation for short stature, or during adolescence after an evaluation for delayed puberty. Patients with Turner syndrome classically have a webbed neck with a low posterior hairline, a shield chest with widely spaced nipples, and transient swelling of the hands and feet during the newborn period. Noonan syndrome can occur in females and has similar physical findings, but affected patients usually have right-sided heart lesions (e.g., pulmonary stenosis). Patients with Turner syndrome have left-sided heart lesions (e.g., coarctation of the aorta). Patients with achondroplasia are short from birth with shortening of the proximal long bones (rhizomelic short stature), those with Russell–Silver syndrome have short stature with skeletal asymmetry, and those with Marfan syndrome are tall, not short.
4. The answer is A [Table 5-5]. Patients with mild phenylketonuria (PKU) may present in childhood with developmental delay, hyperactivity, and a classic mousy or musty odor. Although newborn screening identifies the vast majority of cases, patients who are born in countries without newborn screening can present with untreated PKU. Patients with tyrosinemia type I present with peripheral neuropathy and renal and liver disease, and may produce an odor of rotten fish or cabbage. Children with mild maple syrup urine disease may also present with developmental delay, but their urine has a sweet maple syrup odor. Neither homocystinuria nor cystinuria has a peculiar odor as a feature; however, patients with homocystinuria may have developmental delay as a result of strokes from their hypercoagulable state.
5. The answer is A [IX.A.1]. The infant has infantile Tay–Sachs disease, a devastating
progressively neurodegenerative disease caused by hexosaminidase A deficiency. The onset of disease is in early infancy when the infant presents with a hyperactive startle and loses eye contact. Classic features include a cherry-red macula, enlarging head circumference, neurodegeneration with severe developmental delay, progressive blindness, and seizures.
Death usually occurs by 5 years of age. An Erlenmeyer flask–shaped distal femur is a feature of Gaucher disease and not Tay–Sachs disease. Dysostosis multiplex (bony abnormalities that include a thickened skull, malformed vertebrae, and abnormal ribs and clavicle) is found in patients with mucopolysaccharidoses (e.g., Hunter and Hurler syndromes).
6. The answer is B [IV.C]. In general, the acute management of an inborn error of metabolism involves supplying a source of energy that can be used, removing toxic metabolites, and preventing continued exposure to the offending substance. Glucose is a basic energy source that can be used in any patient, regardless of the inborn error of metabolism, and should be administered intravenously in a patient who is markedly hypoglycemic and in coma or shock. Sodium benzoate is a scavenger agent that would be useful to facilitate ammonia excretion, but this patient does not have hyperammonemia. Although the patient’s condition is likely to be an inborn error of metabolism (maple syrup urine disease, given the diaper odor consistent with the odor of maple syrup), sepsis is more common and can present in a similar fashion. Therefore, initial management should include intravenous antibiotics. Patients with maple syrup urine disease cannot adequately metabolize branched-chain amino acids; therefore, offering parenteral nutrition with protein would continue the toxic exposure. Soy formulas, while appropriate for galactosemia, still contain a full amount of branch-chain amino acids, and similar to regular formulas would overwhelm the patient’s ability to metabolize the branched chain amino acids, resulting in toxic exposure as well.
7. The answer is E [III.C.2]. The characteristic physical features of fragile X syndrome include large ears, macrocephaly, and large testes. Klinefelter syndrome is characterized by tall stature, gynecomastia, and a small penis and testes; Down syndrome, by characteristic facial features, endocardial cushion defects, duodenal atresia, mental retardation, single palmar creases, and a wide space between the first and second toes; Prader–Willi syndrome, by infantile hypotonia, hypogonadism, short stature, and obesity and hyperphagia later in childhood; and Williams syndrome, by a loquacious very friendly personality, supravalvular aortic stenosis, and hypercalcemia. Testes are unaffected in Down syndrome and in Williams syndrome.
8. The answer is C [III.D.2.c]. This patient’s physical features are consistent with achondroplasia, the most common skeletal dysplasia. Potential complications of this disorder include cord compression caused by foramen magnum stenosis, obstructive sleep apnea, and orthopedic problems such as genu varum and back pain caused by lumbar lordosis during late childhood. Atlantoaxial instability (a complication of Down syndrome), aortic dissection (a complication of Marfan syndrome), or delayed puberty is not associated with achondroplasia.
9. The answer is D [IV.E.3]. This patient’s physical characteristics, along with learning problems and attention deficit/hyperactivity disorder, are consistent with fetal alcohol syndrome. Angelman syndrome is associated with severe mental retardation and a small head, although a puppetlike gait and inappropriate bouts of laughter are also characteristic. Down syndrome is also associated with mental retardation; however, the facial characteristics include upslanting palpebral fissures, epicanthal skin folds, and a protruding tongue. Fetal phenytoin syndrome is associated with mental retardation, nail and digit abnormalities, and cardiac defects. Prader–Willi syndrome is associated with hypogonadism, almond-shaped eyes, short stature, and hyperphagia with obesity during childhood.
10. The answer is B [V.A]. The clinical features of homocystinuria and Marfan syndrome overlap considerably; however, this patient most likely has homocystinuria based on the presence of cognitive delay and a marfanoid body habitus with fingers of normal length (i.e., no
arachnodactyly). All of these features are seen in homocystinuria but are not expected to be seen in Marfan syndrome. In addition, patients with homocystinuria usually have downward lens subluxation (upward lens subluxation is found in Marfan syndrome) and large, stiff joints (joint laxity is found in Marfan syndrome). Patients with both disorders have a decreased upper-to-lower segment ratio. Hypogonadism is absent in both disorders.
11. The answer is B [III.B.2]. The findings of scissoring of the lower extremities, clenched hands with overlapping digits, rocker bottom feet, and delicate small facial features are consistent with the diagnosis of trisomy 18, the second most common trisomy syndrome after trisomy 21. Trisomy 21 is the cause of Down syndrome and is associated with hypotonia, prominent epicanthal folds, upslanting palpebral fissures, and single palmar creases. Trisomy 13 is associated with midline defects of the brain and forebrain. Features include microphthalmia, holoprosencephaly, and cleft lip and palate. Absence of a region on the paternally derived chromosome 15 is the cause of Prader–Willi syndrome, a disorder associated with neonatal hypotonia, hypogonadism, almond-shaped eyes, and short stature. A deletion on chromosome 7 causes Williams syndrome, characterized by elfin facies and a loquacious personality.
12. The answers are F [IX.B.1], B [III.A.14], and A [III.A.6], respectively. Hurler syndrome, a mucopolysaccharidosis in which glycosaminoglycans deposit in various tissues causing a progressive clinical picture, is characterized by corneal clouding, changes to the bone termed dysostosis multiplex, organomegaly, and progressively coarsened facies, including frontal bossing, widened nasal bridge, and thickening of the nasopharyngeal tissues. Hunter syndrome is similar but does not have corneal clouding.
Cri du chat syndrome, caused by a partial deletion on the short arm of chromosome 5, is characterized by slow growth, microcephaly, mental retardation, hypertelorism, and a classic catlike cry.
Ehlers–Danlos syndrome is caused by a defect in type V collagen that results in hyperextensible joints, fragile blood vessels that cause easily bruised skin, tissue paper–thin scars, and cardiovascular complications (e.g., mitral valve prolapse and aortic root dilatation that can lead to dissection).