NeoReviews Vol.9 No.1 2008 e29
© 2008 American Academy of Pediatrics
Common Dysmorphic Syndromes in the NICU
Nader Bishara, MD*
Carol L. Clericuzio, MD
* Division of Neonatology, Department of Pediatrics, University of New Mexico Health Sciences Center, Albuquerque, NM
Division of Clinical Genetics/Dysmorphology, Department of Pediatrics, University of New Mexico Health Sciences Center, Albuquerque, NM
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Abstract
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Neonatologists are responsible for the care of newborns who have a wide variety of critical illnesses, including complications of multiple congenital anomalies. This review article provides an overview of state-of-the art information on the diagnosis and management of a number of genetic disorders frequently encountered in the neonatal intensive care unit (NICU). The latest diagnostic tool for children who have unknown syndromes (array comparative genomic hybridization) as well as Internet-based search engine databases that can be accessed from the NICU are examined.
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Objectives
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After completing this article, readers should be able to: - Recognize the phenotypes of selected dysmorphic conditions encountered in the neonatal intensive care unit.
- Describe appropriate medical management, prognosis/recurrence risk information, and prenatal diagnostic options for the disorders.
- Delineate the clinical applications of routine and high-resolution chromosome studies, fluorescence in situ hybridization, and array comparative genomic hybridization.
- Explain how to use three Internet-based databases (PubMed, OMIM, GeneReviews) to help diagnose and treat infants who have dysmorphic conditions.
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Introduction
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The fields of perinatal and neonatal medicine have seen remarkable advances in the past 3 or 4 decades, particularly in regard to the diagnosis and management of genetic disorders. Improvements in amniocentesis, chorionic villous sampling (CVS), and high-resolution three-dimensional ultrasonographic imaging are some of the advances. High-resolution chromosome studies, fluorescence in situ hybridization (FISH), and array comparative genomic hybridization (aCGH) are some of the tools that have increased the ability to diagnose genetic disorders.
Genetic conditions have an impact on physical health, but also have psychological and social implications for the patient and his or her family. It is essential to understand the general aspects of genetic disorders encountered in the perinatal and neonatal periods and the tools available for diagnosis. Those who have an affected child often are faced with difficult family planning decisions because the diagnosis may affect future pregnancies. Depending on the diagnosis, parents may be faced with choices regarding prenatal testing and pregnancy termination.
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Lethal or Semilethal Multiple Malformation Syndromes
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Trisomy 18 –Edwards Syndrome
Trisomy 18 and other trisomy syndromes are associated with increased maternal age. Trisomy 18 is the second most common autosomal trisomy syndrome seen in liveborn children, with an average incidence of 1 per 3,000. Typically, affected infants are small for gestational age and have a history of maternal polyhydramnios. Multiple maternal serum marker screening can detect many cases of trisomy 18 prenatally. Characteristic facial features include microcephaly, prominent occiput, small mouth and jaw, low-set and malformed ears, short palpebral fissures, and mild hypertrichosis of the forehead and back (Fig. 1). The hands are often clenched with overlapping fingers, and the sternum usually is short. Cardiac defects are common but typically nonlethal.
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Figure 1. Small-for-gestational age infant who has trisomy 18, showing short palpebral fissures, hypertrichosis of the forehead, short sternum, clenched hands, hypoplastic genitalia, and malformed foot. The infant also had cardiac and renal anomalies.
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The neonatal course is complicated by poor sucking abilities, necessitating nasogastric tube feedings. However, even with adequate caloric intake, infants usually fail to thrive. They exhibit hypertonia after the initial hypotonic neonatal phase. More than 50% die within the first week after birth, although 10% are still alive by 1 year of age. Trisomy 18 is considered a semilethal syndrome because of this small but definite number of survivors beyond 1 year.
Diagnosis can be confirmed by a 48-hour culture of lymphocytes in the cytogenetics laboratory. Overnight FISH can yield a more rapid result if the infant is medically unstable, but a karyotype always ultimately is required to rule out a translocation. The recurrence risk is 1%, and future pregnancies can be tested by CVS or amniocentesis.
Trisomy 13 –Patau Syndrome
Trisomy 13 is the third most common autosomal trisomy (Fig. 2), with an incidence of 1 per 10,000. Liveborn infants typically have normal birthweights but have microcephaly. Other birth defects include holoprosencephaly, both typical and nontypical clefting, cardiac anomalies (most commonly ventricular septal defect), omphalocele, postaxial polydactyly, cystic dysplastic kidneys, cutis aplasia, and "rocker-bottom" feet with prominent calcanei.
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Figure 2. Interphase amniocyte fluorescence in situ hybridization (FISH) of a female who has trisomy 13 showing three blue hybridization signals for chromosome 13 centromeres and two red hybridization signals for X chromosome centromeres.
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The condition is associated with profound mental retardation, and the median survival for affected infants is 7 days. Most infants die within the neonatal period, although as with trisomy 18, 10% are still alive by 1 year of age. Diagnosis, recurrence risk, and prenatal diagnosis are the same as for trisomy 18.
Triploidy
Triploidy is the presence of 69 chromosomes (Fig. 3). Fetuses that survive exhibit severe growth restriction and typically have syndactyly and clubfeet (Fig. 4). Chromosome studies from either placental or fetal tissue should be obtained for confirmation. The recurrence risk is not increased for future pregnancies.
Osteogenesis Imperfecta Type II
Osteogenesis imperfecta type II is a lethal skeletal dysplasia and is the most severe type of osteogenesis imperfecta subtypes. It is due to a defect in the genes that code for type I procollagen (COL1A1 and COL1A2). Most cases are sporadic mutations and have a recurrence risk of up to 6% due to gonadal mosaicism in one of the parents. The condition is characterized by short limbs, ribbonlike long bones (Fig. 5), and multiple fractures, most commonly seen in utero with callus formation. The ribs are beaded, and the long bones are markedly deformed. Craniofacial features include large fontanelles, deficient calvarial ossification, shallow orbits, blue sclerae, and low nasal bridge. Most infants are either stillborn or die in the neonatal period, primarily from respiratory failure due to pulmonary hypoplasia and fragile ribs or due to central nervous system (CNS) malformations or hemorrhages. Prenatal diagnosis is by fetal ultrasonography or DNA analysis for known procollagen mutations.
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Figure 5. Osteogenesis imperfecta type II. Note the "ribbonlike" fractured long bones and deficient skull ossification.
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Meckel-Gruber Syndrome
Meckel-Gruber syndrome is a rare autosomal recessive disorder characterized by large polycystic kidneys, postaxial polydactyly, and occipital encephalocele (Fig. 6). Patients rarely survive beyond the neonatal period due to the severe CNS and renal defects as well as pulmonary hypoplasia (due to compression of the fetal lungs by the large kidneys). The recurrence risk is 25%, and prenatal diagnosis can be made by fetal ultrasonography or DNA analysis for known mutations.
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Figure 6. An infant who has Meckel-Gruber syndrome exhibits occipital encephalocele and enlarged abdomen due to polycystic kidneys.
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Nonlethal Multiple Malformation Syndromes
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Trisomy 21
Down syndrome is the most common pattern of malformations in humans, with an incidence of 1 per 800. Like other trisomies, it is associated with increased maternal age. Down syndrome is characterized by generalized hypotonia, brachycephaly with mild microcephaly, upslanting palpebral fissures, epicanthal folds, and small ears. The hands are relatively short, with hypoplasia of the mid-phalanx of the fifth finger and clinodactyly, single transverse palmar creases, and wide gap between first and second toes. Cardiac defects occur in 40% of patients and include endocardial cushion defects, ventricular septal defect, patent ductus arteriosus, and atrial septal defect.
In all cases of suspected trisomies, routine chromosome analysis should be ordered. Ninety-five percent of patients have nondisjunction trisomy 21. The recurrence risk is 1% until exceeded by the maternal age-related risk (maternal age 40 y). Parents do not need to undergo karyotyping unless there is a translocation chromosome, in which case the recurrence risk depends on whether one of the parents carries the translocation chromosome. Approximately 1% of infants who have Down syndrome have mosaic trisomy 21, a mixture of normal and trisomic cells, and the recurrence risk for this defect is the same as for typical nondisjunction trisomy 21. Prenatal diagnosis is performed by CVS or amniocentesis. Although first and second trimester maternal screening is offered to all pregnant women, this does not replace diagnostic studies for couples at high risk.
Turner Syndrome
Turner syndrome (TS) should be suspected in female infants who have evidence of fetal edema (Fig. 7), such as excess posterior nuchal skin folds (Fig. 8) or dorsal edema of the feet with small nails. Females who have critical aortic stenosis due to bicuspid aortic valve or coarctation of the aorta also should undergo karyotyping. Affected infants often are small at birth. TS is caused by the partial or complete absence of one of the X chromosomes. Half are mosaic, eg, 45,X/46,XX. Routine chromosome studies should be obtained for diagnosis, and if TS is diagnosed, an additional 200 cells should be screened with X and Y chromosome FISH probes to rule out the presence of a Y chromosome. Medical management involves cardiology evaluation for bicuspid aortic valve, coarctation of the aorta, valvular aortic stenosis, and mitral valve prolapse. Renal ultrasonography is indicated because 40% of affected infants have renal anomalies such as horseshoe kidney. There is no increased risk for future pregnancies. TS is suspected prenatally when fetal nuchal cystic hygroma or edema/hydrops is identified.
5p- Syndrome (Cri du chat)
5p- syndrome should be suspected in infants who are small for gestational age, exhibit microcephaly with a round face and hypertelorism with downward slant of the palpebral fissures, and have single palmar transverse creases. Affected infants often have a characteristic catlike cry in infancy due to hypotonia and laryngeal abnormalities. Most patients have moderate-to-severe mental retardation. In contrast to cytogenetic evaluation for suspected trisomies, a high-resolution rather than routine chromosome study should be obtained. The high-resolution study is required to look for small genomic duplications or deletions; routine resolution is less expensive and adequate to determine the number of chromosomes. If high-resolution chromosomes appear normal, but clinical suspicion remains high, FISH for 5p should be requested. De novo deletions are responsible for 85% of cases, and 15% are due to parental translocations. Therefore, in all cases, parents should be offered chromosome analysis. Prenatal diagnosis by CVS or amniocentesis is available for pregnancies at risk.
Microdeletion Syndromes
Microdeletion syndromes are recognizable disorders caused by chromosomal deletions that span several genes and frequently are too small to be detected by conventional and high-resolution cytogenetic methods. Molecular cytogenetic techniques, including FISH and aCGH, are used to diagnose these conditions.
VELOCARDIOFACIAL/DIGEORGE (DEL 22Q11.2) SYNDROME.
Originally, this condition had two independent syndrome descriptions. In 1965, DiGeorge described underdevelopment of the thymus and parathyroids that caused neonatal hypocalcemia, conotruncal cardiac defects (eg, interrupted aortic arch, truncus arteriosus and tetralogy of Fallot), broad facies, minor ear anomalies, and feeding problems. In 1981, the cause was found to be deletion of chromosome 22 at q11.2. In 1978, Sphrintzen described a syndrome that encompassed cleft palate, Pierre Robin sequence with a long narrow face, tubular nose with round tip, ventricular septal defect, and growth and learning deficiency. This syndrome is inherited as an autosomal dominant condition and in 1992 also was found to be due to the 22q11.2 deletion. Hence, the syndrome descriptions reflect the phenotypic variability of this very common chromosomal deletion.
Current practice is to evaluate all patients who have congenital heart disease for this deletion. When suspected, high-resolution chromosome studies and FISH for del 22q11.2 should be ordered. The laboratory needs to know the indication for the study, eg, congenital heart defect and cleft palate. Parents of affected infants should be offered the FISH deletion study because 7% have been found to carry the deletion, and recurrence risk is dependent on whether the deletion is de novo (very low risk) or due to parental deletion (50% risk for future pregnancies). Prenatal diagnosis is accomplished by CVS or amniocentesis, and the FISH testing must be specifically requested.
WILLIAMS SYNDROME (DEL 7Q11.23).
Williams syndrome is characterized by growth restriction; characteristic facial features, including broad forehead, periorbital fullness, long philtrum, and wide mouth; supravalvular aortic stenosis; and idiopathic hypercalcemia in 15% of affected patients. Diagnosed patients should undergo renal ultrasonography and evaluation for feeding difficulties. Williams syndrome is caused by a deletion of the elastin (ELN) gene and others at 7q11.23. When suspected, high-resolution chromosome studies and FISH for del 7q11.23 should be ordered. Virtually all deletions are de novo, and parental studies usually are not indicated.
The microdeletion in Williams syndrome also can be detected by aCGH and FISH (Fig. 9). The aCGH study has the power to detect smaller genomic imbalances than high-resolution chromosome studies and allows for screening of the entire genome. In Figure 9, the array results for chromosome 7 only are depicted, but commercially available arrays cover the entire genome.
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Figure 9. The upper left two chromosome 7s have no deletion, as indicated by the presence of the two pink signals indicating hybridization of the ELN probe. The green probes are control probes. In contrast, the lower left chromosome 7 (from a different patient), has no pink hybridization signal, indicating an ELN deletion, which is diagnostic of Williams syndrome. The right two panels represent the results of an array comparative genomic hybridization (aCGH) of both patients. On the upper right, genomic material along the length of chromosome 7 shows no significant deviation from baseline, ie, no loss or gain of genomic material. On the lower right, the red arrow indicates a deficiency of genomic material at the ELN locus, diagnostic of Williams syndrome. Data slide courtesy of Kate Rauen, MD, PhD.
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Imprinting Disorders
Normally, each gene is represented by two copies or alleles inherited from each parent at the time of fertilization, and they function equally well whether maternally or paternally inherited. However, less than 1% of genes are imprinted, meaning that there is a parent-of-origin difference in gene expression. Several recognizable disorders are due to errors in imprinted genes. In the neonatal setting, the two most common imprinting disorders are Prader-Willi and Beckwith-Wiedemann syndromes.
PRADER-WILLI SYNDROME (PWS).
PWS is characterized by severe neonatal hypotonia, undescended testes/hypoplastic scrotum, and severe feeding difficulties that require intervention. Females may show hypoplastic labia minora. Other findings include almond-shaped eyes, narrow bifrontal diameter, and thick saliva. PWS is due to the absence of the paternally contributed genes at 15q11–13, which can arise by three different mechanisms (Fig. 10). Some 70% of cases are due to a paternal deletion at 15q11–13. Maternal uniparental disomy, ie, two chromosomes from the same parent, accounts for 25% of cases. Abnormal persistence of the imprint on the paternal chromosome 15 accounts for the remaining 5%.
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Figure 10. Genetic mechanisms leading to Prader-Willi syndrome (PWS). Note that the 15q11–13 critical PWS region normally is imprinted (turned-off) in the maternal chromosome, indicated by the black bar.
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Diagnosis of PWS is confirmed by a DNA methylation study, which looks for the presence of appropriately imprinted maternal and paternal 15 chromosomes. Absence of a paternally imprinted 15 is diagnostic of PWS, regardless of the mechanism. Because FISH for del 15q11–13 detects only 70% of affected infants, DNA methylation is the preferred diagnostic test. Karyotype also is ordered routinely to rule out translocations. The recurrence risk usually is low, although its determination can be complicated, and genetic consultation is recommended if the family wishes to learn the risk for future pregnancies. (Editor's Note: See also NeoReviews. 2005;6:e559–e566.)
BECKWITH-WIEDEMANN SYNDROME (BWS).
BWS is a congenital overgrowth syndrome characterized by macroglossia, hemihyperplasia, abdominal wall defects (omphalocele or umbilical hernia), hypoglycemia, ear lobe creases, and posterior helical pits (Fig. 11). The diagnosis is based on the presence of three of the clinical findings noted previously. Six known mechanisms lead to BWS, involving a handful of imprinted genes at 11p15.5, including paternal IGF2, which usually is overexpressed. Molecular studies are available in clinical laboratories, and all children should undergo a high-resolution chromosome study to evaluate for a familial translocation. Approximately 20% of individuals who have BWS have a familial mutation that can be detected by molecular analysis. The recurrence risk is low, except for familial translocation and mutations. Prenatal diagnosis includes fetal ultrasonography and molecular/cytogenetic analysis for families who have those abnormalities. BWS occurs with increased frequency in pregnancies achieved by in vitro fertilization.
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Figure 11. Infant who has Beckwith-Wiedeman syndrome, exhibiting macrosomia, macroglossia, and a repaired omphalocele. This infant subsequently developed hepatoblastoma.
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Because 5% to 10% of children who have BWS develop malignant kidney (Wilms), liver, or adrenal tumors, recognition of this syndrome is important to establish the tumor screening protocol. Abdominal ultrasonography and measurement of serum alpha-fetoprotein (AFP) at diagnosis and every 3 months until age 4 years plus subsequent quarterly abdominal ultrasonography until 8 years of age is recommended. Normal AFP values at birth are extremely high, and reference values should be consulted.
CORNELIA DE LANGE SYNDROME.
Cornelia de Lange syndrome is characterized by pre- and postnatal growth restriction and a distinctive facial appearance that includes arched eyebrows and synophrys, long eyelashes, anteverted nares, long philtrum, and thin upper lip with a central peak. Affected individuals may have upper limb deficiencies, including oligodactyly. Virtually all infants have gastroesophageal reflux and feeding difficulties. A number of affected patients have mutations in the NIPBL gene. More than 99% of cases are sporadic with low recurrence risk, although rare autosomal dominant families have been reported.
FGFR-related Craniosynostosis Syndromes: Crouzon, Pfeiffer, and Apert
Most individuals who have these disorders have new autosomal dominant mutations in the FGFR2 gene. Bilateral coronal craniosynostosis or cloverleaf skull is the characteristic cranial feature in all (Fig. 12). The syndromes are distinguished by the limb findings (Table). Cleft palate or choanal atresia may result in upper airway obstruction. Proptosis is common and may lead to exposure keratopathy. Spinal radiographs are needed to evaluate for vertebral anomalies and computed tomography scan or magnetic resonance imaging are required to assess for hydrocephalus. Most patients need treatment at a craniofacial center by the age of 2 to 3 months. Recurrence risk depends on whether one of the parents is affected, in which case the recurrence risk is 50%. Prenatal diagnosis by fetal ultrasonography or molecular analysis for known mutations is available.
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Figure 12. Postmortem picture of Pfeiffer syndrome. Note the cloverleaf skull and broad medially deviated thumb and great toe.
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Table. Distinguishing Clinical Features of FGFR-related Craniosynostosis Syndromes
| Disorder |
Hands |
Thumbs |
Feet |
Great Toe |
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| Crouzon |
Normal |
Normal |
Normal |
Normal |
| Pfeiffer |
Variable syndactyly |
Broad and medially deviated |
Variable syndactyly |
Broad and medially deviated |
| Apert |
Bone syndactyly |
May be fused to fingers |
Bone syndactyly |
May be fused to toes |
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Modified from www.genetests.org—see Suggested Reading.
VATER/VACTERRL Association
VATER/VACTERRL is an acronym for the nonrandom association of vertebral, anal, cardiovascular anomalies, tracheoesophageal fistula, renal or radial anomalies, and other limb anomalies (Fig. 13). Three anomalies generally are required to make the diagnosis. The condition usually is nonhereditary and nongenetic, although it is seen with increased frequency in infants of woman who have insulin-dependent diabetes. Because the same anomalies can be seen in Fanconi anemia syndrome (FA) (Fig. 14), it is very important to consider this diagnosis, particularly if a radial ray defect is present. FA is an autosomal recessive cancer syndrome diagnosed by chromosomal breakage studies. Consultation with clinical genetics is recommended if there are any concerns regarding the diagnosis of FA.
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Figure 13. Typical presentation of VATER association, with left radial ray deficiency, vertebral anomalies, anal atresia, and lower limb defects. The patient also had congenital heart disease and a single kidney.
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Figure 14. Bilateral thumb abnormalities in a patient who has Fanconi anemia syndrome after stem cell transplant for leukemia. She originally was diagnosed with VATER association on the basis of vertebral anomalies, radial ray defects, and renal anomaly.
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Footnotes
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Author Disclosure
Drs Bishara and Clericuzio did not disclose any financial relationships relevant to this article.
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Suggested Reading
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Cassidy SB, Allanson JE, eds.
Management of Genetic Syndromes. 2nd ed. Wilmington, De: Wiley-Liss; 2004de Revel TJ, Devriendt K, Fryns JP, Vermeesch JR. What's new in karyotyping? The move towards array comparative genomic hybridisation (CGH).
Eur J Pediatr. 2007;166
:637
–643[CrossRef][Medline]
Faivre L, Portnoï MF, Pals G, et al. Should chromosome breakage studies be performed in patients with VACTERL association?
Am J Med Genet. 2005;137
:55
–58
Jessica MJ, Laurie AD. Genetic syndromes determined by alterations in genomic imprinting pathways.
NeoReviews. 2007;8
:e120
–e126[Abstract/Free Full Text]
Jones KL, ed.
Smith's Recognizable Patterns of Human Malformation. 6th ed. Philadelphia, Pa: WB Saunders; 2005
Online Mendelian Inheritance in Man, OMIM.TM Available at: http://www.ncbi.nlm.nih.gov/omim/
Robin NH, Falk MJ, Haldeman-Englert CR. FGFR-related craniosynostosis syndromes. In:
GeneReviews at GeneTests: Medical Genetics Information Resource (database online). © University of Washington, Seattle. 1997–2007. Available at http://www.genetests.org. Accessed October 2007
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Abstract
Objectives
