Secrets – Pediatric: Genetics
CLINICAL ISSUES
1. Which disorders with ethnic and racial predilections most commonly warrant maternal screening for carrier status?
See Table 8-1.
Table 8-1. Maternal Screening According to Ethnic and Racial Predilections
DISORDER ETHNIC OR RACIAL GROUP
SCREENING TEST
Tay-Sachs disease Ashkenazi Jewish, French, French Canadian Decreased serum hexosaminidase A concentration, DNA studies
Familial dysautonomia Ashkenazi Jewish DNA
Gaucher disease Ashkenazi Jewish DNA
Canavan disease Ashkenazi Jewish DNA
Bloom syndrome Ashkenazi Jewish DNA
Fanconi anemia Ashkenazi Jewish DNA
Niemann-Pick disease (type A) Ashkenazi Jewish DNA
Mucolipidosis IV Ashkenazi Jewish DNA
Cystic fibrosis Pan ethnic DNA
Sickle cell anemia Black, African, Mediterranean, Arab, Indian, Pakistani Presence of sickling in hemolysate followed by confirmatory hemoglobin electrophoresis
DNA ¼ Deoxyribonucleic acid.
2. Why are mitochondrial disorders transmitted from generation to generation by the mother and not the father?
Mitochondrial deoxyribonucleic acid (DNA) abnormalities (e.g., many cases of ragged red fiber myopathies) are passed on from the mother because mitochondria are present in the cytoplasm of the egg and not the sperm. Transmission to males or females is equally likely; however, expression
is variable because mosaicism with normal and abnormal mitochondria in varying proportions is very common.
McFarland R, Taylor RW, Turnbull DM: A neurological perspective on mitochondrial disease, Lancet Neurol
9:829–840, 2010.
Johns DR: Mitochondrial DNA and disease, N Engl J Med 333:638–644, 1995.
3. What is genetic imprinting?
It is a genetic mechanism by which genes are selectively expressed from the maternal or paternal allele on a chromosome. As a consequence, depending on the gene, either the maternal or the paternal allele only is expressed. The inactive allele is epigenetically marked by histone modification, DNA (cytosine) methylation or both. The imprint is maintained throughout the life of the individual. However, imprints
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are erased during early development of the male and female germ lines and then reset before germ cell maturation. Imprinted genes play crucial roles in growth, development, and tumor control.
Imprinted genes can cause disease when the maternal/paternal gene that is usually expressed is mutated, silenced, or deleted. In humans about 50 genes are known to be imprinted. Classic examples of human diseases linked to imprinting defects are transient neonatal diabetes, Russell-Silver syndrome, Beckwith-Wiedemann syndrome, Prader-Willi syndrome, Angelman syndrome, and Albright hereditary osteodystrophy.
4. What is uniparental disomy?
Uniparental disomy occurs when a fetus receives two copies of a chromosome, or portions of a chromosome, from only one parent with no copies from the other parent. In most instances, this is not significant. However, the concept of genetic imprinting does have a role here. Because some essential genes undergo genetic imprinting, if a fetus lacks those imprinted genes from one parent, there can be a loss of gene function, which can lead to the diseases noted in question 3.
Patten MM, Ross L, Curley JP, et al: The evolution of genomic imprinting: theories, predictions and empirical tests, Heredity (Edinb) 113:119–128, 2014.
5. What is the etiology of arthrogryposis congenita? Arthrogryposis congenita (AC) refers to nonprogressive, congenital joint contractures (single or multiple) that generally result from lack of fetal movements in utero.
Any condition, intrinsic to the fetus or secondary to environmental/maternal factors, that decreases fetal movements can lead to arthrogryposis congenita. Decreased fetal movement leads to increased connective tissue around the joint(s), skin dimpling over the immobilized joint(s), and disuse atrophy of the muscles that mobilize the joint (Fig. 8-1). Etiologies include muscle disease, central nervous system (CNS) disorders, connective tissues disorders, maternal illness (e.g., myasthenia, myotonic dystrophy,
hyperthermia (fever >39 °C), and a host of specific genetic disorders. Specific genetic conditions associated with arthrogryposis congenita are fetal akinesia syndrome, amyoplasia (classical
arthrogryposis), distal arthrogryposis type 1, congenital contractural arachnodactyly (Beal syndrome), multiple pterygium syndromes, and cerebro-oculo-facial-skeletal syndrome (COFS). Inheritance varies depending on the specific type.
Hall JG: Arthrogryposis (multiple congenital contractures): Diagnostic approach to etiology, classification, genetics and general principles, Eur J Med Gen 57:464–472, 2014.
Figure 8-1. A 1-month-old girl with the quadrimelic form of arthrogryposis. (From Staheli LT, Song KM: Pediatric Orthopedic Secrets, ed 3. Philadelphia, 2007, ELSEVIER, pp 494–498.)
6. How common are genetic causes of hearing loss in childhood?
Hearing loss significant enough to affect speech and language development affects 2 to 3 of every 1000 births in the United States. About 50% of cases are due to genetic causes. Inheritance can be autosomal dominant, recessive, X-linked, or mitochondrial. More than 400 genetic syndromes include hearing loss as a feature including Waardenburg syndrome (pigmentary anomalies), Pendred syndrome (enlarged vestibular aqueduct), branchio-oto-renal syndrome (branchial arch and renal anomalies), Treacher-Collins syndrome, and Usher syndrome (retinitis pigmentosa).
Alford RL, Arnos KS, Fox M, et al: American College of Medical Genetics and Genomics guideline for the clinical evaluation and etiologic diagnosis of hearing loss, Genet Med 16:347–355, 2014.
7. What is the most common genetic mutation in infants with prelingual hearing loss?
Prelingual hearing loss is hearing loss detected before speech development. All congenital hearing loss, by definition, is prelingual. The GJB2 gene (gap junction β-2) is the most common site for a mutation. In patients with congenital nonsyndromic deafness, about 75% are due to mutations in that gene. The GJB2 gene encodes the protein connexin 26, which is critical for gap junctions between cochlear cells. Connexin mutations are usually autosomal recessive. Another mutation classified as 167delT is found exclusively in the Ashkenazi Jewish population.
Chan DK, Chang KW: GJB2-associated hearing loss: systematic review of worldwide prevalence, genotype, and auditory phenotype, Laryngoscope 124: e34–e53, 2014.
8. What are the genetic causes of microcephaly?
Microcephaly, defined as an occipital-frontal circumference below the 3rd percentile or 3 standard deviations below the mean, can be associated with more than 500 genetic syndromes. Chromosome defects, single gene disorders, or environmental causes can be responsible for microcephaly. Genetic diagnostic investigations can include karyotype, chromosomal microarray, and FISH testing. Research is focusing on the role of genetic disease associated with (and perhaps causative of) abnormalities in the centrosomes, the organelles that serve as the main microtubule organizing center of the cell. Centrosomal proteins control the mitotic spindle, which is essential for normal cell mitotic proliferation. Abnormalities of the centrosomes could be a central pathway in the development of microcephaly with abnormal neuronal production.
Gilmore EC, Walsh CA: Genetic causes of microcephaly and lessons for neuronal development, Wiley Interdiscip REV DEV Biol 2:461–478, 2013.
9. Are older fathers at increased risk of having a child with a genetic disease? Advanced paternal age is well-documented to be associated with new dominant mutations. The assumption is that the increased mutation rate is the result of the accumulation of new mutations from many cell divisions. The more cell divisions, the more likely an error (mutation) will occur. The mutation rate in fathers who are older than 50 years is five times higher than the mutation rate in fathers who are younger than 20 years. Autosomal dominant new mutations have been mapped and identified, including achondroplasia, Apert syndrome, and Marfan syndrome.
10. What is the most common genetic lethal disease? Cystic fibrosis (CF). A genetic lethal disease is one that interferes with a person’s ability to reproduce as a result of early death (before childbearing age) or impaired sexual function. CF is the most common autosomal recessive disorder in whites, occurring in 1 in 1600 infants (1 of every 20 individuals is a carrier for this condition) (Fig. 8-2). CF is characterized by widespread dysfunction of exocrine glands, chronic pulmonary disease, pancreatic insufficiency, and intestinal obstructions. Males are azoospermic. The median survival is about 29 years.
Cystic Fibrosis Foundation: www.cff.org. Accessed on Dec. 3, 2014.
I
II
c
III
Figure 8-2. Risk for cystic fibrosis (CF) in offspring of a mother with no family history of CF and a healthy father whose brother has CF. (1) Because IIa is affected with CF, both his parents must be carriers. (2) The chance of IIb being a carrier is 2 out of 3 because we know that he is not affected by CF. (3) The risk of IIc being a carrier is 1 in 20 (the population risk). (4) The chance of IIIa being affected is calculated as follows: father’s carrier risk× mother’s carrier risk× chance that both will pass on their
recessive CF gene to their child¼ 2/3 × 1/20 × 1/4 ¼ 1/120.
11. What are the syndromes associated with macrosomia (large baby syndromes)?
• Prader-Willi (obesity, hypotonia, small hands and feet)
• Beckwith-Wiedemann (macrosomia, omphalocele, macroglossia, ear creases)
• Sotos (macrosomia, macrocephaly, large hands and feet)
• Weaver (macrosomia, accelerated skeletal maturation, camptodactyly)
• Bardet-Biedl (obesity, retinal pigmentation, polydactyly)
• Infants of diabetic mothers
12. What is the “H3O” of Prader-Willi syndrome?
Hyperphagia, hypotonia, hypopigmentation, and obesity. About 70% of Prader-Willi patients will have a deletion of an imprinted gene SNPRN on the long arm of paternally derived chromosome 15; in about 20% of these patients, both copies of the chromosome are maternally derived. The phenomenon in which a child inherits two complete or partial copies of the same chromosome from only one parent is referred to as uniparental disomy. The maternal uniparental disomy for chromosome 15 results in Prader-Willi syndrome, just as does a deletion of the paternal copy of the chromosome.
13. A child with supravalvular aortic stenosis, small and abnormally shaped primary teeth, low muscle tone with joint laxity, and elevated calcium noted on testing is likely to have what syndrome?
Williams syndrome, also known as Williams-Beuren syndrome. The genetic abnormalities result from microdeletions on chromosome 7 in an area that codes for the gene elastin. The loss of this gene is thought to contribute to the cardiac and musculoskeletal features found in Williams syndrome. Other characteristic features include frequent ear infections, hyperacusis (sensitivity to loud noises), failure to thrive at a younger age, and personality traits of a strong social orientation (“cocktail party personality”) combined with anxiety problems.
Prober BR: Williams-Beuren syndrome, N Engl J Med 362:239–252, 2010.
Waxler JL, Levine K, Pober BR: Williams syndrome: a multidisciplinary approach to care, Pediatr Ann 38:456–463, 2009.
14. What are the two most common forms of dwarfism that are recognizable at birth?
• Thanatophoric dwarfism: This is the most common, but it is a lethal chondrodysplasia that is characterized by flattened, U-shaped vertebral bodies; telephone receiver–shaped femurs; macrocephaly; and redundant skinfolds that cause a puglike appearance. Thanatophoric means death loving (an apt description). The incidence is 1 in 6400 births.
• Achondroplasia: This is the most common viable skeletal dysplasia, occurring in 1 in 26,000 live births. Its features are small stature, macrocephaly, depressed nasal bridge, lordosis, and a trident hand.
15. What chromosomal abnormality is found in cri-du-chat syndrome?
Cri-du-chat syndrome is the result of a deletion of material from the short arm of chromosome 5 (i.e., 5p-), which causes many problems, including growth retardation, microcephaly, and severe mental retardation. Patients have a characteristic catlike cry during infancy, from which the syndrome derives its name. In 85% of cases, the deletion is a de novo event. In 15%, it is due to malsegregation from a balanced parental translocation.
16. Is there a “Catch-22” to the Catch-22 syndrome?
Unlike the Heller novel, this puzzle does have solutions, both genetic and acronymal. The acronym has been used to describe the salient features of DiGeorge/velocardiofacial syndrome:
• Congenital heart disease (e.g., ventricular septal defect [VSD], truncus arteriosus, tetralogy of Fallot, aortic arch anomalies)
• Abnormal face (e.g., ear anomalies, wide-set eyes, long face, nasal abnormalities; Fig. 8-3)
• Thymic aplasia or hypoplasia
• Cleft palate
• Hypocalcemia (secondary to hypoparathyroidism)
• 22: Microdeletion of chromosome 22q11
Kobrynski LJ, Sullivan KE: Velocardiofacial syndrome, DiGeorge syndrome: the chromosome 22q11.2 deletion syndromes,
Lancet 370:1443–1452, 2007.
Figure 8-3. Two-year-old with CATCH-22/DiGeorge syndrome. Facial dysmorphisms include hypertelorism, low-set ears, micrognathia, small fishlike mouth, short philtrum, malformed nose and down-slanting palpebral fissures. Cardiac defect was truncus arteriosus. (From Perloff JK: Clinical recognition of congenital heart disease, Clinical Recognition of Congenital Heart Disease, 41:492–504, 2012.)
17. For what condition are patients with isolated limb hypertrophy at risk?
Embryonal cell tumors, including Wilms tumor, adrenal tumors, and hepatoblastoma. The risk in patients with isolated hemihypertrophy is about 6%; in patients with Beckwith-Wiedemann syndrome, it is 7.5%. Surveillance with abdominal ultrasound and α-fetoprotein measurements every 3 months is recommended until the child is at least 5 years old. In patients with Beckwith-Wiedemann syndrome, facial appearance is also affected (Fig. 8-4).
Figure 8-4. Facial shape in Beckwith-Wiedemann syndrome, illustrated from birth to adolescence in a single person. In infancy and early childhood, the face is round with prominent cheeks and relative narrowing of the forehead. Note that by adolescence the trend is toward normalization. (From Allanson JE: Pitfalls of genetic diagnosis in the adolescent: the changing face, Adolesc Med State Art Rev 13:257–268, 2002.)
18. After Down syndrome, what are the next most common autosomal trisomies in live-born children?
Trisomy 18 and trisomy 13. (See Table 8-2.)
Support Organization for Trisomy (SOFT) 18, 13 and Related Disorders: www.trisomy.org. Accessed on Dec. 3, 2014. Trisomy 18 Foundation: www.trisomy18.org. Accessed on Dec. 3, 2014.
Table 8-2. Differences Between Trisomy 18 and Trisomy 13
TRISOMY 18 TRISOMY 13
Edwards syndrome (described in 1960) Patau syndrome (described in 1960)
~1:8000 live births ~1:20,000 live births
Clinical features: IUGR, elfin appearance Clinical features: CNS malformations
failure to thrive, cardiac and kidney defects (holoprosencephaly), heart defects, genitourinary
severe mental deficiency, micrognathia, anomalies, growth retardation, polydactyly, cleft
microcephaly, posterior heel prominence lip/palate, nasal malformation
prominent occiput, overlapping fingers
Poor prognosis: 40% survive to 1 month; 5% survive to 1 year Poorer prognosis: Only 50% survive >1 week; 5%
to 6 months
80% female Slight female predominance
Advanced maternal age: “”risk Advanced maternal age: “risk
CNS ¼ Central nervous system; IUGR ¼ intrauterine growth restriction.
19. What are the reasons that a condition might be genetically determined but the family history would be negative?
• Autosomal recessive inheritance
• X-linked recessive inheritance
• Genetic heterogeneity (e.g., retinitis pigmentosa may be transmitted as autosomal recessive or dominant or X-linked recessive)
• Spontaneous mutation
• Nonpenetrance (i.e., not all disease-causing genes or genetic mutations exhibit clinical expression)
• Expressivity (i.e., variable expression)
• Extramarital paternity
• Phenocopy (i.e., an environmentally determined copy of a genetic disorder)
Juberg RC: .. .but the family history was negative, J Pediatr 91:693–694, 1977.
20. What online resources are available for a pediatrician who suspects a child has a genetic syndrome or would like additional information about a patient already diagnosed with a genetic problem?
Two sites are particularly useful.
Online Mendelian Inheritance in Man (OMIM; www.omim.org): This site is a comprehensive com- pendium of human genes and genetic phenotypes. It is now edited primarily under the auspices of Johns Hopkins University School of Medicine.
GeneTests (www.ncbi.nlm.nih.gov/books/NBK1116): This site provides a wealth of genetic information, including peer-reviewed articles (GENEREVIEWS) with disease descriptions, including diagnosis and management information. It is sponsored by the University of Washington at Seattle.
DOWN SYNDROME
21. What are the common physical characteristics of children with Down syndrome?
• Upslanted palpebral fissures with epicanthal folds
• Small, low-set ears with overfolded upper helices
• Short neck with excess skinfolds in newborns
• Prominent tongue
• Flattened occiput
• Exaggerated gap between first and second toe
• Hypotonia See Fig. 8-5.
National Down Syndrome Society: www.ndss.org. Accessed on Mar. 24, 2015.
Figure 8-5. Characteristic facies seen in Down syndrome. The child’s posture is due to hypotonia. (From Lissauer T, Clayden G: Illustrated Textbook of Paediatrics, ed 4. Philadelphia, 2012, ELSEVIER, p 115–132.)
22. Are Brushfield spots pathognomonic for Down syndrome? No. Brushfield spots are speckled areas that occur in the periphery of the iris (Fig. 8-6). They are seen in about 75% of patients with Down syndrome, but they also are found in up to 7% of normal newborns.
Figure 8-6. Brushfield spots (arrows) consisting of depigmented foci along the circumference of the iris in a child with Down syndrome. (From Gatzoutis MA, Webb GD, Baubeney PEF, editors: Diagnosis and Management of Adult Congenital Heart Disease, ed 2. Philadelphia, 2011, Saunders, pp 29–47.)
23. What is the chance that a newborn with a simian crease has Down syndrome? A single transverse palmar crease (Fig. 8-7) is present in 5% of normal newborns. Bilateral palmar creases are found in 1%. These features are twice as common in males as they are in females. However, about 45% of newborn infants with Down syndrome have a single transverse crease. Because Down syndrome occurs in 1 in 800 live births, the chance that a newborn with a simian crease has Down syndrome is only 1 in 60.
Figure 8-7. Simian crease. (From Clark DA: Atlas of Neonatology, Philadelphia, 2000, WB Saunders, p 31.)
24. Why is an extensive cardiac evaluation recommended for newborns with Down syndrome?
About 40% to 50% have congenital heart disease, but most infants are asymptomatic during the newborn period. Defects include atrioventricular canal (most common, 60%), VSD, and patent ductus arteriosus.
Down Syndrome: Health Issues. www.ds-health.com. Accessed on Mar. 23, 2015.
25. What proportion of infants with Down syndrome has congenital hypothyroidism? About 2% (1 in 50), compared with 0.025% (1 in 4000) for all newborns, have congenital hypothyroidism. This emphasizes the importance of the state-mandated newborn thyroid screen. However, children with Down syndrome can become hypothyroid at any age.
26. Infants with Down syndrome are at increased risk for a number of conditions during early infancy. What are they?
• Gastrointestinal malformations, including duodenal atresia and tracheoesophageal fistula
• Cryptorchidism
• Lens opacities and cataracts
• Strabismus
• Hearing loss, both sensorineural and conductive
Down Syndrome Research Foundation: www.dsrf.org. Accessed on Mar. 23, 2015.
KEY POINTS: INCREASED RISKS FOR PATIENTS WITH DOWN SYNDROME DURING THE NEWBORN PERIOD AND EARLY INFANCY
1. Congenital heart disease: Atrioventricular canal defects, ventricular septal defects (VSD)
2. Gastrointestinal malformations: duodenal atresia, tracheoesophageal atresia
3. Congenital hypothyroidism
4. Lens opacities and cataracts
5. Hearing loss
6. Cryptorchidism
27. What is the most common malignancy in an infant with Down Syndrome? Leukemia. Its frequency in these individuals is 50-fold higher for younger children (0 to 4 years old) and 10-fold higher for individuals 5 to 29 years old, for a 20-fold increase in lifetime risk. Before leukemia becomes apparent, children with Down syndrome are at increased risk for other unusual white blood cell problems, including transient myeloproliferatiVE disorder (a disorder of marked leukocytosis, blast cells, thrombocytopenia, and hepatosplenomegaly that spontaneously resolves) and a leukemoid reaction (markedly elevated white blood cell count with myeloblasts without splenomegaly, which also spontaneously resolves).
Seewald L, Taub JW, Maloney KW, et al: Acute leukemias in children with Down syndrome, Mol Genet Metab
107:25–30, 2012.
28. What is the genetic basis for Down syndrome?
The syndrome can be caused by trisomy of all or part of chromosome 21:
• Full trisomy 21: 94%
• Mosaic trisomy 21: 2.4%
• Translocation: 3.3%
29. What chromosomal abnormalities are related to maternal age?
All trisomies and some sex chromosomal abnormalities (except 45,X and 47,XYY) are related to maternal age.
30. How does the risk for having an infant with Down syndrome change with advancing maternal age?
See Table 8-3. Most cases of Down syndrome involve nondisjunction at meiosis I in the mother. This may be related to the lengthy stage of meiotic arrest between oocyte development in the fetus until ovulation, which may occur as much as 40 years later.
Table 8-3. Approximate Risk for Down Syndrome (Live Births) by Maternal Age
MATERNAL
AGE
(YR) APPROXIMATE RISK FOR DOWN SYNDROME
All ages 1 in 650
20 1:1500
30 1:1000
35 1:385
40 1:110
45 1:37
From Lissauer T, Clayden G: Illustrated Textbook of Paediatrics, ed 4. Philadelphia, 2012, ELSEVIER, pp 115–132.
31. Who was Down of Down syndrome? John Langdon Down was a British physician. He originally described the condition that would later bear his name in 1866 based on measurements of the diameters of the head and palate and, in pioneering fashion, a series of clinical photographs taken in hospitals. His descriptions classified “mentally subnormal” patients on the basis of “ethnic classification” from which the widely used term “Mongolism” originated. It was not until 1961 that the term Down’s syndrome came into vogue at the urging of genetic experts. Eponymous diseases no longer carry the possessive form and the condition is more properly referred to as Down syndrome.
Ward OC: John Langdon Down: the man and his message, Downs Syndr Res Pract 6:19–24, 1999.
DYSMORPHOLOGY
32. What is the clinical significance of a minor malformation? The recognition of minor malformations in a newborn may serve as an indicator of altered morphogenesis or as a valuable clue to the diagnosis of a specific disorder. The presence of several minor malformations is unusual and often indicates a serious problem in morphogenesis. For example, when 3 or more minor malformations are discovered in a child, the risk for a major malformation also being present is >90%.
The most common minor malformations involve the face, ears, hands, and feet. Almost any minor defect
may occasionally be found as an unusual familial trait.
33. Do infants with the LEOPARD syndrome have spots?
This autosomal dominant condition is also known as multiple lentigines syndrome. Yes, infants with this syndrome have multiple lentigines (darkly pigmented macules). See Fig. 8-8. Other features include:
• Electrocardiogram abnormalities
• Ocular hypertelorism
• Pulmonic stenosis
• Abnormal genitalia
• Retarded growth
• Deafness
Figure 8-8. Multiple lentigines in a 13-year-old with LEOPARD syndrome. (From Cohen BA: Pediatric Dermatology, ed 4. Philadelphia, 2013, Saunders
ELSEVIER, p 151.)
34. Which is correct: CHARGE syndrome or CHARGE association? CHARGE syndrome, formerly CHARGE association, is correct. A syndrome refers to a condition in which the underlying genetic cause has been identified. An association has signs and symptoms in combination greater than expected by chance alone, but without a known genetic etiology. It is now known that CHARGE syndrome is an autosomal dominant condition, and almost all cases are due to de novo mutations in the CHD7 gene. Rare familial cases have been reported. CHD7 (chromodomain helicase DNA-binding protein 7) is the only gene currently known to be affected in CHARGE syndrome. In 70% of CHARGE syndrome patients, a mutation can be identified in this gene.
35. What is the proper way to test for low-set ears?
The designation is made when the upper portion of the ear (helix) meets the head at a level below a horizontal line drawn from the lateral aspect of the palpebral fissure. The best way to measure is to align a straight edge between the two inner canthi and determine whether the ears lie completely below this plane (Fig. 8-9). In normal individuals, about 10% of the ear is above this plane.
Figure 8-9. How to test for low-set ears. (From Feingold M, Bossert WH: Normal VALUES for selected physical parameters: an aid to syndrome delineation. In Bergsma D, editor: The National Foundation—March of Dimes Birth Defects Series 10:9, 1974.)
36. How is hypertelorism distinguished from telecanthus?
Hypertelorism is wide spacing of the eyes in which the interpupillary distance is increased. Hypertelorism can be a normal variant or may be seen in cranial abnormalities, DiGeorge syndrome, and multiple other syndromes. Telecanthus occurs when the inner canthi are laterally displaced but the interpupillary distance is normal. Telecanthus can be seen in fetal alcohol syndrome and Waardenburg
Normal distance of pupil to midline
Normal
Hypertelorism
Telecanthus Figure 8-10. Normal versus hypertelorism versus telecanthus. (From Goldbloom RB: Pediatric Clinical Skills, ed 4. Philadelphia, 2011, ELSEVIER Saunders, p 63.)
syndrome (Fig. 8-10). The eyes appear widely spaced but are not. Hypotelorism (not shown in figure) is a shortening of the interpupillary distance. Standard distances are found in various reference sources.
37. What is the inheritance pattern of cleft lip and palate? Most cases of cleft lip and palate are inherited in a polygenic or multifactorial pattern. The male-to-female ratio is 3:2, and the incidence in the general population is about 1 in 1000. Recurrence risk after one affected child is 3% to 4%; after two affected children, it is 8% to 9%.
38. Which syndromes are associated with colobomas of the iris?
Colobomas (defects) of the iris (Fig. 8-11) are the result of abnormal ocular development and embryogenesis. They are frequently associated with chromosomal syndromes (most commonly trisomy 13, 4p-, 13q-) and triploidy. In addition, they may be commonly found in patients with the CHARGE syndrome, Goltz syndrome, and Rieger syndrome. Whenever iris colobomas are noted, chromosome analysis is recommended. The special case of complete absence of the iris (aniridia) is associated with the development of Wilms tumor and may be caused by an interstitial deletion of the short arm of chromosome 11.
Figure 8-11. Left iris coloboma. (From Zitelli BJ, DAVIS HW: Atlas of Pediatric Physical Diagnosis, ed 4. St. Louis, 2002, Mosby, p 674.)
GENETIC PRINCIPLES
39. Identify the common symbols used in the construction of a pedigree chart
See Fig. 8-12.
Figure 8-12. Symbols used in the construction of a pedigree chart.
40. How can the same genotype lead to different phenotypes?
Separated Divorced
Multiple marriages Birthrank unknown No offspring
Illegitimate offspring
Monozygotic twins
Dizygotic twins Zygosity unknown
In parental imprinting (an area of the regulation of gene expression that is incompletely understood), the expression of an identical gene is dependent on whether the gene is inherited from the mother or the father. For example, in patients with Huntington disease, the clinical manifestations occur much earlier if the gene is inherited from the father rather than the mother. Modification of the genes by methylation of the DNA during development has been hypothesized as one explanation of the variability.
41. When a geneticist says they are going “FISH”ing, what does that mean? Fluorescence in situ hybridization (FISH) is a molecular cytogenetic technique that is used to identify abnormalities of chromosome number or structure using a single-stranded DNA probe (for a known piece of DNA or chromosome segment). The probe is labeled with a fluorescent tag and targeted to a
single-strand DNA that has been denatured in place on a microscope slide. The use of fluorescent microscopy enables the detection of more than one probe, each of which is labeled with a different color. FISH is commonly used for the rapid prenatal diagnosis of trisomies with the use of amniotic fluid or chorionic villi using interphase cells from cultured specimens and probes for the most common chromosomal abnormalities (13, 18, 21, X, and Y). Although interphase FISH for prenatal diagnosis has low false-positive and false-negative rates, it is considered investigational and is used only in conjunction with standard cytogenetic analysis.
42. What is currently the best method for detecting small chromosome deletions and duplications?
Single nucleotide polymorphism microarray (SNP microarray) is currently the best method of detecting DNA copy number variations (CNVs). This test scans the whole genome for variations in DNA copy numbers. Standard chromosome analysis can detect chromosomal imbalances that are at least 5 Mb in size, whereas SNP-array is able to detect cryptic changes (deletions and duplications) that are not visible on standard chromosome analysis. It has become the method of choice for infants and children with multiple congenital anomalies and/or developmental delays. Five percent of such children have visible abnormalities on routine chromosome analysis, but an additional 10% to 15% will have an abnormality when screened with SNP array. It will eventually replace the current FISH analysis for detection of conditions such as DiGeorge syndrome and Williams syndrome. It is important to note that not all CNVs are deleterious; some are polymorphisms that are frequently carried by one parent. Parental studies are thus important in interpreting the comparative genomic hybridization, a molecular cytogenetic method for analyzing the CNV results, when the results are not clear.
Shaffer LG, Bejjani BA: Using microarray-based molecular cytogenic methods to identify chromosome abnormalities,
Pediatr Ann 38:440–447, 2009.
Veltman JA: Genomic microarrays in clinical diagnosis, Curr Opin Pediatr 18:598–603, 2006.
INBORN ERRORS OF METABOLISM
43. What types of inherited metabolic conditions are routinely screened by most states?
Inherited metabolic disorders/inborn error of metabolism (IEM): organic acidemias, amino acid disorders, fatty acid oxidation defects, homocystinuria, galactosemia and biotinidase deficiency. Some states screen for Krabbe and X-linked adrenoleukodystrophy as well.
Endocrine disorders: congenital adrenal hyperplasia and hypothyroidism
Hemoglobinopathies: sickle cell disease and thalassemias
Congenital immunodeficiencies Cystic fibrosis
Bennett MJ: Newborn screening for metabolic diseases: saving children’s lives and improving outcomes, Clin Biochem
47:693–694, 2014.
Levy HL: Newborn screening conditions: what we know, what we do not know, and how we will know it, Genet Med
12(Suppl):S213–S214, 2010.
44. In what settings should inborn errors of metabolism be suspected?
• Onset of symptoms correlating with dietary changes
• Loss or leveling of developmental milestones
• Patient with strong food preferences or aversions
• Parental consanguinity
• Unexplained sibling death, mental retardation, or seizures
• Unexplained failure to thrive
• Unusual odor
• Hair abnormalities, especially alopecia
• Microcephaly or macrocephaly
• Abnormalities of muscle tone
• Organomegaly
• Coarsened facial features, thick skin, limited joint mobility, hirsutism
45. What are the main categories of specialized laboratory testing to detect an IEM?
• Plasma amino acids
• Plasma acylcarnitines
• Urine organic acids
• Carnitine analysis
• Enzymatic assays for specific disorders
• Molecular testing for specific disorders
46. What are the main principles of treatment for IEM?
• Removal of the offending compound
• Use of special diets and supplements (medical foods) to provide appropriate nutrition, to keep offending compounds at minimum, and to avoid deficiencies
• Use of medication that helps eliminate toxic compounds (i.e., ammonia scavengers) or to block the production of toxic compounds (such as in tyrosinemia type I)
• Use of enzyme replacement therapies available for specific conditions (e.g., lysosome storage disorders)
• Bone marrow/hematopoietic stem cell transplant for selected disorders
Saudubray JM, Berghe G, Walter JH, editors: Inborn Metabolic Diseases: Diagnosis and Treatment, ed 5. Berlin Heidelberg, 2012, Springer Verlag, pp 103–109.
47. What are the main features of phenylketonuria (PKU)?
PKU is a defect in the hepatic enzyme phenylalanine hydroxylase, which results in an inability to metabolize one amino acid (phenylalanine) to another (tyrosine). Phenylalanine accumulates with toxic consequences. Untreated infants will develop microcephaly, early developmental delay, and later seizures. Clinical clues include musty-smelling infant sweat (due to phenylacetate, a phenylalanine breakdown product) and albinism (light colored skin and hair due to tyrosine deficits, a component of melanin. PKU is the most frequent IEM with an incidence of about 1:12,000. Inheritance is autosomal recessive. Carriers are asymptomatic. Treatment involves dietary manipulation to limit phenylalanine exposure, supplementation with other amino acids, and occasional pharmacotherapy to reduce serum phenylalanine levels. Early identification, as through newborn screening, and early treatment result in an excellent prognosis, but treatment is for life.
Greene CL, Longo N: National Institutes of Health (NIH) review of evidence in phenylalanine hydroxylase deficiency (phenylketonuria) and recommendations/guidelines from the American College of Medical Genetics (ACMG) and Genetics Metabolic Dietitians International (GMDI), Mol Genet Metab 112:85–86, 2014.
48. What are the main characteristics of a patient with glycogen storage disease type 1 (GSD 1)?
Glycogen storage diseases, of which there are 11 types, involve defects in glycogen synthesis or breakdown in multiple organs, including muscles and liver. Type I (von Gierke disease), the most common, and others are listed in Table 8-4.
• The cardinal feature of the disease is fasting hypoglycemia.
• The main defect is in the enzyme glucose-6-phosphatase that allows glucose to be released from the glycogen molecule in the liver to other areas of the body.
• Additional laboratory markers are lactic acidemia, increased uric acid, and triglycerides.
• Clinical features include growth retardation, short stature, hepatomegaly, prominent abdomen, developmental delay/intellectual disability (if not treated) and acute symptoms associated with hypoglycemia (i.e., tremors, sweating, tachycardia, lethargy, seizures, coma, etc.).
• Treatment is based on adequate supply of glucose: continuous feedings, frequent meals, uncooked cornstarch, and overnight feedings.
• Outcome is good with proper treatment.
Vanier MT: Lysosomal diseases: biochemical pathways and investigations, Handb Clin Neurol 113:1695–1699, 2013.
49. What are the main features of a patient with mucopolysaccharidosis? Mucopolysaccharidoses are examples of storage diseases of lysosomes, which are intracellular organelles that degrade structural macromolecules. If enzymes are deficient, metabolites accumulate
Table 8-4. Most Common Glycogen Storage Disorders
TYPE
Enzyme deficiency MAIN FEATURES LABORATORY TREATMENT
I: Type Ia Truncal obesity, hepatomegaly, “doll face”, Hypoglycemia after short fasting Avoidance of fasting using
(Von Gierke) glucose-6-phosphatase nephromegaly, short stature, failure to thrive (3-4 hours), acidosis, elevated frequent meals, overnight
lactate, uric acid and continuous feeds and
triglycerides uncooked cornstarch
I: Type Ib
Glucose-6-phosphate transporter Same as type Ia + neutropenia, leukocyte dysfunction, bacterial infections, diarrhea, immflamatory bowel disease (IBD) Same as type Ia + neutropenia and leukocyte dysfunction Same as type Ia + granulocyte colony growth factor
II (Pompe)
α-glucosidase (acid maltase) Infantile: cardiomyopathy, hypotonia, failure to thrive. JUVENILE/ADULT: progressive muscle weakness No hypoglycemia Enzyme replacement therapy (ERT): aglucosidase. High protein diet
III (Cori)
debranching enzyme Type IIIa: same as type Ia, but less hypoglycemia, normal kidneys, myopathy, cardiomyopathy
Type IIIb: only liver Hypoglycemia, normal lactate and uric acid Avoidance of fasting using frequent meals, overnight continuous feeds and uncooked cornstarch
IV (Andersen) Classic: failure to thrive, hepatomegaly, No hypoglycemia Liver transplant
Branching enzyme progressive liver disease (liver failure, cirrhosis).
Neuromuscular form: myopathy and
cardiomyopathy
VI (Hers)
Liver phosphorylase Hepatomegaly, mild hypoglycemia, often asymptomatic Mild hypoglycemia, elevated lactate and liver enzymes Avoidance of fasting using frequent meals and uncooked cornstarch
IX Phosphorylase kinase (X-linked) Hepatomegaly, mild hypoglycemia, often asymptomatic Mild hypoglycemia, elevated lactate and liver enzymes Avoidance of fasting using frequent meals and uncooked cornstarch
predominantly in the tissues that are primarily responsible for their degradation (e.g., heparin sulfate in the CNS, dermatan sulfate in bone and liver). All disorders are autosomal recessive except for type II (Hunter syndrome), which is X-linked recessive. Patients are normal at birth. Subsequent clinical features include progressive facial and skin changes (“connective tissue”), progressive skeletal deformities including growth restriction, bone dysplasia and contractures, and hepatomegaly. Depending on the type, there may be progressive psychomotor retardation with loss of acquired skills and intellectual disability. Treatment, when available, may involve enzyme replacement therapy and hematopoietic stem cell transplantation. Diagnosis is based on analysis of glycosaminoglycans (mucopolysaccharides) in urine, enzyme analysis, and molecular testing. See Table 8-5.
Vanier MT: Lysosomal diseases: biochemical pathways and investigations, Handb Clin Neurol 113: 1695–1699, 2013.
50. An 8-month-old presents with vomiting, lethargy, hypoglycemia and no ketones on urinalysis. What condition is likely?
Medium-chain acyl-CoA dehydrogenase deficiency (MCAD). Disorders of fatty-acid oxidation or a deficiency of carnitine (the principal transporter of fatty acids into mitochondria) can result in maladaptation to the fasting stress that often accompanies an intercurrent illness. Hypoketotic hypoglycemia results from the inability to utilize fatty acids, which are the primary source of ketones. Screening for this condition, which is more common in families of Northern European ancestry, is included in most mandatory newborn screening panels. The clinical presentation varies, including no symptoms, but a presentation can be dramatic with severe vomiting, encephalopathy, coma,
and death.
51. What features should raise suspicion of mitochondrial disease?
Most mitochondrial diseases are progressiVe and multisystemic. Suspicion about a mitochondrial disorder should be raised if (1) the patient has either muscle disease and involvement of two additional organ systems (one of which may be the CNS) or (2) the CNS plus two other systems, or (3) multisystem disease (at least 3 systems) including muscle and/or the CNS. Organ systems affected are those with high energy demand such as skeletal and cardiac muscle, endocrine organs, kidney, retina, and the CNS. Any infant with unexplained failure to thrive, weakness, hypotonia, and a metabolic acidosis (particularly lactic acidosis) should be evaluated for a possible mitochondrial disorder.
Haas RH, Parikh S, Falk MJ, et al: Mitochondrial disease: a practical approach for primary care physicians, Pediatrics
120:1326–1333, 2007.
United Mitochondrial Disease Foundation: www.umdf.org. Accessed on Mar. 23, 2015.
52. What is the most common presentation of childhood-onset mitochondrial disease?
Leigh syndrome. This is a progressive neurodegenerative condition that involves developmental regression, pyramidal signs, and brainstem dysfunction (e.g., dystonia, strabismus, nystagmus, swallowing problems), hypotonia, and lactic acidosis. It is also known as subacute necrotizing encephalomyelopathy. Etiology can be due to mutation in the mitochondrial DNA (mtDNA), autosomal recessive mutations (SURF1; a nuclear gene), or X-linked (PDHA1) mutations. The prognosis is poor.
Haas RH, Parikh S, Falk MJ, et al: Mitochondrial disease: a practical approach for primary care physicians, Pediatrics
120:1326–1333, 2007.
53. When you are rounding in the well newborn nursery, one of the infants has an unusual odor. What are the typical body and urine odors associated with inherited metabolic disorders?
• Musty, mildewy: PKU
• Maple syrup: maple syrup urine disease (MSUD)
• Sweaty feet: isovaleric aciduria (IVA), glutaric aciduria type II
Table 8-5. Most Common Mucopolysaccharidoses
TYPE
Enzyme deficiency CLINICAL FEATURES DIAGNOSIS MANAGEMENT
Type I (Hurler: severe) Onset first year of life; coarse facial features, corneal Increased dermatan and heparan Enzyme replacement (ERT) for non-
α-L-Idurodinase clouding, failure to thrive, recurrent upper respiratory sulfate in urine. Enzymatic assay. SNC features. BMT/HSCT below
infections, developmental delay, cardiac disease, Molecular testing (IDUA gene) 2½ years to treat ALL features
hepatosplenomegaly including SNC
Type I (Sheie: milder) Onset in adolescence and adulthood; normal Increased dermatan and heparan Symptomatic; ERT
α-L-Idurodinase intelligence, mostly normal height, mild skeletal sulfate in urine. Enzymatic assay.
deformities, degenerative joint disease, corneal Molecular testing (IDUA gene)
clouding, cardiac valve disease
Type II (Hunter) Iduronate-2-sulphatase Joint contractures, obstructive and restrictive airway disease, cardiac disease, skeletal deformities, cognitive decline. Mild form (adult onset). X-linked. Normal corneas. Increased dermatan and heparan sulfates. Enzymatic assay. Molecular testing (IDS gene) ERT for non-SNC features. Possible BMT or HSCT
Type III (Sanfilippo)
4 enzymes of the heparan sulphate metabolism Encephalopathy with mild organ involvement; development/language delay, behavioral problems, sleep deprivation, hyperactivity, intellectual disability, seizures, neuro-degeneration. Increased heparan sulphate in urine. Enzymatic assay. Molecular testing (4 different genes) Symptomatic.
Type IV (Morquio)
2 enzymes of keratan sulphate metabolism Normal intelligence. Short stature. Skeletal deformities, short neck, scoliosis, joint contractures, Atlanta-axial instability Increased keratan sulphate in urine. Abnormal skeletal x-rays. Enzyme assays. Molecular testing for 2 genes. Symptomatic. ERT
Type VI (Maroteaux-Lamy disease) arylsulphatase-B Normal intelligence, skeletal deformities similar to Type I (Hurler). Often macrocephaly at birth. Increased dermatan sulphate in urine. Enzymatic assay.
Molecular testing (ARSB gene) ERT
BMT ¼ bone marrow transplant; HSCT ¼ hematopoietic stem cell transplant.
• Cat urine: 3-methylcrotonylglycinuria, multiple carboxylase deficiency
• Cabbage: tyrosinemia type 1
• Rancid butter: tyrosinemia type 1
• Sulphur: cystinuria, tyrosinemia type 1
• Fish-like: trimethylaminuria, dimethylglycinuria
54. Which inborn errors of metabolism can result in fetal hydrops?
• Lysosomal disorders: MPS type VII, sialidosis, mucolipidosis type II (I-cell disease), sphingolipidosis (Niemann-Pick type A, Gaucher, Farber, GM1, etc.), lipid storage disorders (Niemann-Pick type C), sialic storage disorders
• Sterol synthesis disorders: Smith-Lemli-Opitz syndrome, mevalonic aciduria
• Peroxisomal disorders: Zellweger
• Glycogen storage disease type IV (Anderson disease)
• Glycosylation disorders
• Primary carnitine deficiency
• Mitochondrial disorders
• Neonatal hemochromatosis
55. Which metabolic disorders can present as sudden unexpected death syndrome (SUDS)?
• Fatty acid oxidation defects
• Some organic acidemias
• Defects of aldosterone and glucocorticoid metabolism
• McArdle syndrome (myophosphorylase deficiency)
• Mitochondrial defects (e.g., Leigh syndrome)
56. One of the infants in your care dies from a suspected IEM. What postmortem investigations are key?
• Serum and plasma: Centrifuge several milliliters immediately, freeze in separate fractions.
• Dried blood spot: Obtain on filter paper card.
• Urine: Freeze immediately; consider bladder wash with saline.
• Bile: Obtain spot on filter card for acylcarnitine analysis.
• DNA: Obtain 3 to 10 mL whole blood in EDTA tube; if necessary freeze without centrifuging.
• Culture fibroblasts: skin biopsy, may be obtained up to 24 hours postmortem.
• Cerebrospinal fluid (CSF): Obtain several 1-mL fractions; freeze immediately, if possible at 70 °C.
• Muscle biopsy: DNA, histology, histochemistry, enzymatic studies (energy metabolism)
• Liver biopsy: histochemistry, enzymatic assays
SEX-CHROMOSOME ABNORMALITIES
57. Does the Lyon hypothesis refer to the “king of beasts”?
The Lyon hypothesis states that, in any cell, only one X chromosome will be functional. Any other X chromosomes present in that cell will be condensed, late replicating, and inactive (called the Barr body). The inactive X may be either paternal or maternal in origin, but all descendants of a particular cell will have the same inactive parentally derived chromosome.
58. What are the features of the four most common sex-chromosome abnormalities?
See Table 8-6.
Table 8-6. Most Common Sex Chromosome Disorders
47,XXY (KLINEFELTER) 47,XYY 47,XXX 45,X (TURNER)
Frequency of live births (males) 1 in 1000 1 in 1000 — —
Frequency of live births (females) — — 1 in 1000 1 in 2000
Maternal age association + — + —
Phenotype Tall, eunuchoid habitus, underdeveloped secondary sexual characteristics, gynecomastia (XXY) Tall, severe acne, indistinguishable from normal males (XYY) Tall, indistinguishable from normal females (XXX) Short stature, webbed neck, shield chest, pedal edema at birth, coarctation of the aorta (45,X)
IQ and behavior problems 80-100; behavioral problems (XXY) 90-110; behavioral problems; aggressive behavior (XYY) 90-110; behavioral problems (XXX) Mildly deficient to normal intelligence; spatial-perceptual difficulties (45,X)
Reproductive function Extremely rare (XXY) Common (XYY) Common (XXX) Extremely rare (45,X)
Gonad Hypoplastic testes; Leydig cell hyperplasia, Normal-size testes, Normal-size ovaries, Streak ovaries with deficient
Sertoli cell hypoplasia, seminiferous tubule normal testicular normal ovarian follicles (45,X)
dysgenesis, few spermatogenic precursors histology (XYY) histology (XXX)
(XXY);
From Donnenfeld AE, Dunn LK: Common chromosome disorders detected prenatally, Postgrad Obstet Gynecol 6:5, 1986.
59. Of the four most common types of sex-chromosome abnormalities, which is identifiable at birth?
Only infants with Turner syndrome have physical features that are easily identifiable at birth (See Fig. 8-13).
Figure 8-13. Newborn with Turner syndrome with (A) short, webbed neck with low posterior hairline, shield chest with widespaced nipples, micrognathia and (B and C) lymphedema of hands and feet, including toes. Lymphedema of the toes can lead to nail hypoplasia. (From Zitelli BJ, McIntire SC, Nowalk AJ, editors: Atlas of Pediatric Physical Diagnosis, ed 6.
Philadelphia, 2012, Saunders, p 15.)
Loscalzo ML: Turner syndrome, Pediatr REV 29:219–227, 2008.
KEY POINTS: TURNER SYNDROME
1. Majority: 45,X
2. Newborn period: Only sign may be lymphedema of feet and/or hands
3. Adolescence: Primary amenorrhea due to ovarian dysplasia
4. Short stature often prompts initial workup
5. Normal mental development
6. Classic features: Webbed neck with low hairline, broad chest with wide-spaced nipples
7. Increased risk for congenital heart disease: Coarctation of the aorta
60. What are the differences between Noonan syndrome and Turner syndrome?
See Table 8-7.
Table 8-7. Differences Between Turner Syndrome and Noonan Syndrome
TURNER SYNDROME NOONAN SYNDROME
Affects females only Affects both males and females
Chromosome disorder Normal chromosomes
(45,X) Autosomal dominant disorder
Near-normal intelligence Mental deficiency
Coarctation of aorta is the most common Pulmonary stenosis is the most common
Amenorrhea and sterility due to ovarian dysgenesis Normal menstrual cycle in females
61. What is the second most common genetic form of mental retardation? Fragile X syndrome (with Down syndrome being the most common). It affects an estimated 1 in 1000 males and 1 in 2000 females. About 2% to 6% of male subjects and 2% to 4% of female subjects with unexplained mental retardation will carry the full fragile X mutation.
FRAXA Research Foundation: www.fraxa.org. Accessed on Dec. 3, 2014. National Fragile X Foundation: www.fragilex.org. Accessed on Dec. 3, 2014.
62. What are the characteristic facial features of fragile X syndrome? Typical features include a long face, long everted ears, prominent mandible and large forehead. These tend to be more evident in affected adults. In younger children, the prominent features are prominent ears (Fig. 8-14).
Figure 8-14. A child with Fragile X. At this age, the main feature is often the prominent ears. (From Lissauer T, Clayden G: Illustrated Textbook of Paediatrics, ed 4. Philadelphia, 2012, ELSEVIER, p 115–132.)
63. What is the nature of the mutation in fragile X syndrome? Expansion of trinucleotide repeat sequences. When the lymphocytes of an affected male are grown in a folate-deficient medium and the chromosomes examined, a substantial fraction of X chromosomes demonstrate a break near the distal end of the long arm. This site—the fragile X mental retardation-1 gene (FMR1)—was identified and sequenced in 1991. At the center of the gene is a repeating trinucleotide sequence (CGG) that, in normal individuals, repeats 6 to 45 times. However, in carriers, the sequence expands to 50 to 200 copies (called a premutation). In fully affected individuals, it expands to 200 to 600 copies.
Bagni C, Oostra BA: Fragile X syndrome: from protein function to therapy, Am J Med Genet A 161A:2809–2821, 2013.
64. What are the associated medical problems of fragile X syndrome in males?
Flat feet (80%), macroorchidism (80% after puberty), mitral valve prolapse (50% to 80% in adulthood), recurrent otitis media (60%), strabismus (30%), refractive errors (20%), seizures (15%), and scoliosis
(>20%).
Lachiewicz AM, Dawson DV, Spiridigliozzi GA: Physical characteristics of young boys with fragile X syndrome: reasons for difficulties in making a diagnosis in young males, Am J Med Genet 92:229–236, 2000.
65. What is the outcome for girls with fragile X?
Heterozygous females who carry the fragile X chromosome have more behavioral and developmental problems (including attention deficit hyperactivity disorder), cognitive difficulties (50% with an IQ in the mentally retarded or borderline range), and physical differences (prominent ears, long and narrow face). Cytogenetic testing is recommended for all sisters of fragile X males.
Visootsak J, Hipp H, Clark H, et al: Climbing the branches of a family tree: diagnosis of fragile X syndrome, J Pediatr
164:1292–1295, 2014.
Hagerman RJ, Berry-Kravis E, et al: Advances in the treatment of fragile X syndrome, Pediatrics 123:378–390, 2009.
KEY POINTS: FRAGILE X SYNDROME
1. Most common cause of inherited mental retardation
2. Prepubertal: Elongated face, flattened nasal bridge, protruding ears
3. Pubertal: Macroorchidism
4. Heterozygous females: 50% with IQ in the borderline or intellectually disabled range
5. First recognized trinucleotide repeat disorder
TERATOLOGY
66. Which drugs are known to be teratogenic?
Most teratogenic drugs exert a deleterious effect in a minority of exposed fetuses. Exact malformation rates are unavailable because of the inability to perform a statistical evaluation on a randomized, controlled population. Known teratogens are summarized in Table 8-8.
Table 8-8. Known Teratogens
DRUG MAJOR TERATOGENIC EFFECT
Thalidomide Limb defects
Lithium Ebstein tricuspid valve anomaly
Aminopterin Craniofacial and limb anomalies
Methotrexate Craniofacial and limb anomalies
Phenytoin Facial dysmorphism, dysplastic nails
Trimethadione Craniofacial dysmorphism, growth retardation
Valproic acid Neural tube defects
Diethylstilbestrol M€ullerian anomalies, clear cell adenocarcinoma
Androgens Virilization
Tetracycline Teeth and bone maldevelopment
Streptomycin Ototoxicity
Warfarin Nasal hypoplasia, bone maldevelopment
Penicillamine Cutis laxa
Accutane (retinoic acid) Craniofacial and cardiac anomalies
67. Describe the characteristic features of the fetal hydantoin syndrome
Craniofacial: Broad nasal bridge, wide fontanel, low-set hairline, broad alveolar ridge, metopic ridging, short neck, ocular hypertelorism, microcephaly, cleft lip and palate, abnormal or low-set ears, epicanthal folds, ptosis of eyelids, coloboma, and coarse scalp hair
Limbs: Small or absent nails, hypoplasia of distal phalanges, altered palmar crease, digital thumb, and dislocated hip
About 10% of infants whose mothers took phenytoin (Dilantin) during pregnancy have a major malformation; 30% have minor abnormalities.
68. A pregnant female sommelier asks you what amount of Chateauneuf Du Pape is safe to ingest during pregnancy.
How much alcohol is safe to consume during pregnancy is unknown. The full dysmorphologic manifestations of fetal alcohol syndrome are associated with heavy intake. However, most infants will not display the full syndrome. For infants born to women with lesser degrees of alcohol intake during pregnancy and who demonstrate more subtle abnormalities (e.g., cognitive and behavioral problems), it is more difficult to ascribe risk because of confounding variables (e.g., maternal illness, pregnancy weight gain, other drug use [especially marijuana]). Furthermore, for reasons that are unclear, it appears that infants who are prenatally exposed to similar amounts of alcohol are likely to have different consequences. Because current data (including a 2014 meta-analysis) do not support the concept that any amount of alcohol is safe during pregnancy, the American Academy of Pediatrics recommends abstinence from alcohol for women who are pregnant or who are planning to become pregnant.
Sowell SR, Charness ME, Riley EP: Pregnancy: no safe level of alcohol, Nature 513(7517):172, 2014.
Flak AL, Su S, Bertrand J, et al: The association of mild, moderate, and binge prenatal alcohol exposure and child neuropsychological outcomes: a meta-analysis, Alcohol Clin Exp Res 38:214–226, 2014.
69. What are the frequent facial features of the fetal alcohol syndrome?
The three facial dysmorphisms found most characteristically are short palpebral fissures, thin vermillion border, and smooth philtrum. Additional features include:
• Skull: Microcephaly, midface hypoplasia
• Eyes: Epicanthal folds, ptosis, strabismus
• Mouth: Prominent lateral palatine ridges, retrognathia in infancy, micrognathia or relative prognathia in adolescence
• Nose: Flat nasal bridge, short and upturned nose (Fig. 8-15)
Figure 8-15. Patient with fetal alcohol syndrome. A, Note bilateral ptosis, short palpebral fissures, smooth philtrum, and thin upper lip. B, Short palpebral fissures are sometimes more noticeable in profile. Head circumference is second percentile. (From SEAVER LH: ADVERSE ENVIRONMENtal exposures in pregnancy: teratology in adolescent medicine practice, Adolesc Med State Art Rev 13:269–291, 2002.)
Hoyme HE, May PA, Kalberg WO, et al: A practical clinical approach to diagnosis of fetal alcohol spectrum disorders: clarification of the 1996 Institute of Medicine criteria, Pediatrics 115:39–47, 2005.
KEY POINTS: FETAL ALCOHOL SYNDROME
1. Growth deficiencies: Prenatal and postnatal
2. Microcephaly with neurodevelopmental abnormalities
3. Short palpebral fissures
4. Smooth philtrum
5. Thin upper lip
70. What happens to children with fetal alcohol syndrome when they grow up?
Follow-up studies of adolescents and adults revealed that relative short stature, poorly developed philtrum, thin upper lip, and microcephaly persisted, but other facial anomalies became more subtle. Persistent mental handicaps (including intellectual disabilities), problematic academic functioning (particularly in mathematics), limited occupational options, and dependent living were major sequelae. Intermediate or significant maladaptive behavior was also a very common finding. Severely unstable family environments were common.
Spohr HL, Willms J, Steinhausen HC: Fetal alcohol spectrum disorders in young adulthood, J Pediatr 150: 175–179, 2007.
Streissguth AP, Aase JM, Clarren SK, et al: Fetal alcohol syndrome in adolescents and adults, JAMA 265: 1961–1967, 1991.
National Organization on Fetal Alcohol Syndrome: www.nofas.org. Accessed on Mar. 23, 2015.
Acknowledgment
The editors gratefully acknowledge contributions by Drs. Elain H. Zackai, JoAnn Bergoffen, Alan E. Donnenfeld, and Jeffrey E. Ming that were retained from the first three editions of Pediatric Secrets.
BONUS QUESTIONS
71. What syndromes with a genetic basis should be considered in a patient with ambiguous genitalia?
• Congenital adrenal hyperplasia
• Smith-Lemli-Opitz syndrome
• Campomelic dysplasia
• WAGR syndrome: Wilms tumor, aniridia genitourinary anomalies, mental retardation
• Drash syndrome or Wilms tumor and pseudohermaphroditism
• Frasier syndrome
• 5-alpha-reductase deficiency
• 17-beta-hydroxysteroid dehydrogenase deficiency
• Partial androgen insensitivity syndrome
• Deletion of 9p24.3 or 10q26
Ohnesorg T, Vilain E, Sinclair AH: The genetics of disorders of sex development in humans, Sex DEV 8:262–272, 2014.
72. What is the genetic basis of Angelman syndrome?
Angelman syndrome is a syndrome characterized by developmental delay, cognitive deficits, seizures, and a particularly happy demeanor with frequent laughter or smiling. About 70% of cases are due to deletions of an imprinted gene, UBE3A (E6-associated protein ubiquitin-protein ligase gene), which resides on the long arm of the maternally derived chromosome 15. About 25% of cases are due to UBE3A mutations, and a small percentage of cases are due to unipaternal disomy of chromosome 15. (Both copies of chromosome 15 are derived from the father.)
73. Why are patients with Marfan syndrome at risk for sudden cardiac death?
A mutation in the fibrillin gene located on chromosome 15 in patients with Marfan syndrome results in abnormal cross-linking of collagen and elastin. Degeneration of elastic elements in the
aortic root leads to dilation, which can result in acute dissection or rupture. Marfan syndrome is inherited as an autosomal dominant disorder. Tall individuals with suggestive features (thin habitus, hypermobile joints, long digits, pectus excavatum or carinatum, kyphoscoliosis) require consultation with a geneticist.
74. List the syndromes and malformations associated with congenital limb hemihypertrophy
• Beckwith-Wiedemann syndrome
• Conradi-H€unermann syndrome
• Klippel-Trenaunay-Weber syndrome
• Proteus syndrome
• Neurofibromatosis
• Hypomelanosis of Ito
• CHILD syndrome (congenital hemidysplasia, ichthyosiform erythroderma, limb defects)
75. What are the most common chromosome deletion syndromes?
• DiGeorge/velocardiofacial syndrome (DGS/VCF)
• Prader-Willi syndrome (PWS)
• Angelman syndrome (AS)
• William syndrome (WS)
• Alagille syndrome
• Rubinstein-Taybi syndrome (RTS)
• Wilms tumor/aniridia/ambiguous genitalia/mental retardation syndrome (WAGR)
• Miller-Dieker syndrome
• Smith-Magenis syndrome
Ensenauer RE, Michels VV, Reinke SS: Genetic testing: practical, ethical, and counseling considerations, Mayo Clin Proc
80:63–73, 2005.
76. Which of the inborn errors of metabolism are associated with liver disease?
• Neonatal LIVER failure: mitochondrial disorders, hemochromatosis, galactosemia, fatty acid oxidation defects, urea cycle disorders, Niemann-Pick type C (NPC), glycosylation disorders
• SEVERE neonatal jaundice: alpha-1-antitrypsin, NPC, galactosemia, bile acid synthesis disorders, peroxisomal disorders, mevalonic aciduria, tyrosinemia type 1, Crigler-Najjar, Rotor, Dubin-Johnson, Alagille disease, progressive familial intrahepatic cholestasis
• Hepatomegaly+ hypoglycemia: glycogen storage disease type 1 (GSD1), GSD type 3, Fanconi-Bickel disease, disorders of gluconeogenesis, glycosylation disorders
• Hepatosplenomegaly in infancy: lysosomal storage disorders, Tangier disease, hepatic cirrhosis (alpha-1-antitrypsin, GSD type 4, tyrosinemia type 1)
• Infantile cholestatic jaundice: hereditary fructose intolerance, bile acid synthesis defects, mitochondrial depletion syndromes, familial intrahepatic cholestasis, Alagille syndrome
• Infantile acute or chronic hepatic dysfunction: mitochondrial depletion syndrome, glycosylation disorders, tyrosinemia type 1, galactosemia, fatty acid oxidation defects
• Chronic hepatitis or cirrhosis in older children: Wilson disease, hemochromatosis, alpha- 1-antitrypsin, tyrosinemia type 1, hereditary fructose intolerance, transaldolase deficiency