Congenital Abnormalities and Common Neonatal Syndromes

Dr Mohd Hanifah Mohd Jamil Consultant Paediatrician and Neonatologist

Introduction:
2% of newborn infants have a major malformation. 5% if include malformation detected later in life. Malformation more in spontaneous abortuses. About 9% of perinatal deaths due to malformations. The incidence of congenital abnormalities is higher in preterm and SGA infants. Classification into malformations and deformations.

Critical periods in embryogenic development

Brain Eye Heart Limbs Ear 15-25 days 25-40 days 20-40 days 24-36 days 40-60 days

Classification of congenital abnormalities

Malformations:
Result from a disturbance of growth during embryogenesis e.g congenital heart.

Deformations:
Result from late changes in previous normal structures by destructive pathological processes or intrauterine forces.

Malformation Syndromes
Limited number of cranio-facial syndromes can be diagnosed with confidence during the neonatal period Period of follow-up is essential for the growth and development of the child Characteristic cranio-facial features of some syndromes are age-dependent

Deformations - Causes
Primigravidity. Oligohydramnios. Abnormal presentation. Multiple pregnancy. Uterine abnormality Growth retardation.

Malformations - Causes
Estimated incidence (%) Genetic Chromosomal Environmental Infection Drugs and chemicals Radiation Maternal metabolic dis. Unknown Polygenic 20% 10 2-3 2-3 <1 1-2 35-40 25-30

Multifactorial / Polygenic Inheritance

Anecephaly. Spina bifida. Cleft lip / palate. Clubfoot. Congenital dislocation of hip. Cong. Heart. Hirschsprungs disease. Pyloric stenosis.

Multifactorial Inheritance
For isolated affected case Factors increasing risk
Close relationship to proband High heritability of disorder Proband of more rarely affected sex Severe disease in proband Multiple family members affected

Multiple adverse factors are present

Risk may approach autosomal recessive disorders

Spinal Bifida

Anecephaly / Hydrocephalus

Cleft Lip and Palate

Epigenetic Disease

RNA interference
E.g. Asthma

Recognizable Malformation Syndromes in Paediatric Practice

Down syndrome Edwards syndrome Pataus syndrome Turner syndrome Prader Willi syndrome De Lange syndrome Achondroplasia Noonan syndrome Rubinstein-Taybi syndrome

Syndrome Diagnosis
Gestalt recognition
Unusual facial appearance e.g. Down , Patau, Edward, Noonan, William syndromes.

Recognisable combination of malformation

CHARGE association TAR syndrome

Specific malformation (malformation handle)

Malformation Handle
A Malformation handle an accurate dx dysmorphic syndromes:
uncommon in the general population and not common to all dysmorphic syndromes.

Good handles:
Anal atresia; cleft palate ; polydactyly

Bad handles:
Clinodactyly; low-set ear; microcephaly; Simian crease.

Common Neonatal Syndromes

Lethal Multiple Malformation Syndromes

Trisomy 18 Edwards Syndrome Trisomy 13 Patau Syndrome Triploidy Osteogenesis Imperfecta Type II Meckel-Gruber syndrome

Edwards syndrome

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 with an average incidence of 1 per 3,000. Affected infants are small for gestational age and have a history of maternal polyhydramnios. 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. The hands are often clenched with overlapping fingers, and the sternum usually is short. Cardiac defects are common but typically nonlethal.

Trisomy 18

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

Bishara, N. et al. Neoreviews 2008;9:e29-e38

Copyright 2008 American Academy of Pediatrics

Rocker bottom foot

Edward Syndrome - cont

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

Third most common autosomal trisomy , 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. 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.

Trisomy 18

Cleft Lip and Palate

Trisomy 13 ( Patau)

Scalp defect in Pataus

Triploidy facies

Triploidy
Triploidy is the presence of 69 chromosomes Fetuses that survive exhibit severe growth restriction and typically have syndactyly and clubfeet Chromosome studies from either placental or fetal tissue should be obtained for confirmation. The recurrence risk is not increased for future pregnancies.

69,XXX triploidy karyotype

Bishara, N. et al. Neoreviews 2008;9:e29-e38

Copyright 2008 American Academy of Pediatrics

A 23-week triploid fetus who exhibits severe growth restriction and syndactaly

Bishara, N. et al. Neoreviews 2008;9:e29-e38

Copyright 2008 American Academy of Pediatrics

Osteogenesis Imperfecta Type II

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% . The condition is characterized by short limbs, ribbonlike long bones , 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.

Osteogenesis imperfecta type II

Bishara, N. et al. Neoreviews 2008;9:e29-e38

Copyright 2008 American Academy of Pediatrics

Meckel-Gruber Syndrome
A rare autosomal recessive disorder characterized by large polycystic kidneys, postaxial polydactyly, and occipital encephalocele 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.

Non-Lethal Multiple Malformations Syndrome

Non-Lethal Multiple Malformation Syndromes

Trisomy 21 Downs Syndrome Turner syndrome 5p- deletion Cri du Chat Microdeletions syndrome Imprinting Disoders e.g. Prader Willi Syndrome, Beckwick Wiederman syndrome Cornelia de Lange VATER syndrome CHARGE associations

Trisomy 21

Low set ears

Clinodactyly

Trisomy 21

Trisomy 21 Down Syndrome

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.

Trisomy 21 Down Syndrome

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. 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.

Down Syndrome
Incidence 1-1.4 /1000 live births Associated problem:
Heart diseases 40-50% Doudenal obstruction 2.6% Leukemia 1%

Growth
Puberty delayed Final height: Men 5 ft, women 4 ft 10 in

Down Syndrome
Genetic risk Maternal age:
30 yr 35 yr 40 yr 45 yr 1:1000 1:380 1:110 1:30

Risk of recur
Mum < 35 yr 1 in 200 Mum > 35 yr 2 x normal risk

Down Syndrome
IQ
Final IQ between 35-55 Early dementia start from teen 50% sit by 1 yr Walk by 2 yr Speak few words by 3 yr

Turner Syndrome
Turner syndrome (TS) should be suspected in female infants who have evidence of fetal edema , such as excess posterior nuchal skin folds 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.

Webbed neck

Excess posterior nuchal skinfolds in Turner syndrome

Bishara, N. et al. Neoreviews 2008;9:e29-e38

Copyright 2008 American Academy of Pediatrics

Wide spaced nipples

XO Syndrome

Hand edema in Turners

Pedal edema in Turner syndrome

Bishara, N. et al. Neoreviews 2008;9:e29-e38

Copyright 2008 American Academy of Pediatrics

Turners Syndrome

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. 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 15q1113, which can arise by three different mechanisms 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%.

Beckwith-Wiedemann Syndrome
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 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.

Infant who has Beckwith-Wiedeman syndrome, exhibiting macrosomia, macroglossia, and a repaired omphalocele

Bishara, N. et al. Neoreviews 2008;9:e29-e38

Copyright 2008 American Academy of Pediatrics

Cranisynostosis 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 The syndromes are distinguished by the limb findings 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.

Postmortem picture of Pfeiffer syndrome

Bishara, N. et al. Neoreviews 2008;9:e29-e38

Copyright 2008 American Academy of Pediatrics

VATER/VACTERL Association
No known molecular cause. Described by Quan and Smith in 1973 Acronym describes the components: Vertebral defects, Anal atresia, Tracheo-Esophageal fistula with esophageal atresia, and Radial and Renal dysplasia. Kaufman (1973) and Nora and Nora (1975) subsequently added "C" for cardiac defects and "L" for limb defects to broaden the acronym to VACTERL.

Clinical Findings VACTERL association

Vertebral defects that have been described in VACTERL association include hemivertebrae, congenital scoliosis, hypersegmentation defects, and sacral dysgenesis; thoracolumbar hemivertebrae have been reported most frequently. Anal atresia or stenosis requires prompt surgical consultation and intervention. A wide range of cardiac anomalies have been described in the VACTERL association, although septal defects appear to be most common. Tracheoesophageal fistula or esophageal atresia occurs in approximately 1 in 3,500 births and is associated with other anomalies in about 50% of cases.

Verterbral Defects VACTERL association

Hemivertebrae Congenital scoliosis Hypersegmentation defects Sacral dysgenesis Thoracolumbar hemivertebrae.

Clinical Findings VACTERL association

Renal anomalies include renal agenesis, ureteropelvic junction obstruction, and severe reflux. Limb defects tend to involve the upper limbs more often than the lower limbs; with upper limb involvement, the radial bones are affected more frequently than the ulnar bones. Radial aplasia, deviation of the hand, absence of the thumb, hypoplastic and rudimentary thumb, and preaxial polydactyly have been described.

Genetic Testing
Evaluations in the neonatal period should include echocardiography, renal ultrasonography, radiographs of the spine, radiographs of the extremities if abnormalities are noted on examination, and an ophthalmologic evaluation. In addition, high-resolution chromosome analysis and a genetics consultation should be obtained to exclude other genetic causes. The recurrence risk for parents and for the individual is low, and the cause is unknown, although VACTERL is related to maternal diabetes in the minority of cases.

Retinal coloboma

Kaplan, J. et al. Neoreviews 2008;9:e299-e304

Copyright 2008 American Academy of Pediatrics

CHARGE Syndrome
The acronym CHARGE initially was coined by Pagon and colleagues in 1981 Including Coloboma, Heart defect, Atresia choanae, Retarded growth and development, Genital hypoplasia, and Ear anomalies/deafness. A common pathogenetic basis was discovered in 2004, the association now is referred to as CHARGE syndrome. CHARGE syndrome has a prevalence of 1 per 10,000 15,000 An autosomal dominant disorder, most cases represent simplex cases (the first case discovered in a family).

Clinical Findings
Colobomas are present in 80% to 90% of patients who have CHARGE syndrome, and retinal colobomas are more common than iris colobomas Retinal involvement can affect the optic nerve or macula, leading to impaired visual acuity. Severe chorioretinal colobomas can be associated with microphthalmia. Newborns in whom CHARGE syndrome is suspected should receive an ophthalmologic evaluation for retinal colobomas and be monitored by ophthalmology with an eye examination every 6 months.

CHARGE syndrome and CVS

Heart defects are often complex and found in 75% to 85%. 38-40% of defects are conotruncal anomalies (tetralogy of Fallot, double-outlet right ventricle, truncus arteriosus, and perimembranous ventricular septal defect) and aortic arch anomalies (interrupted aortic arch, vascular ring, and aberrant subclavian artery). Other common defects include atrioventricular canal defects, atrial septal defects, ventricular septal defects, and patent ductus arteriosus.

Choanal Atresia
Affected individuals may have a complete blockage (choanal atresia) or a partial blockage (choanal stenosis), and the blockage may be unilateral or bilateral. Bilateral choanal atresia causes significant respiratory distress in the newborn, unilateral choanal atresia or choanal stenosis may not be detected in the newborn period; the older child who has choanal stenosis or unilateral choanal atresia may present with persistent rhinorrhea or infections. Choanal atresia or stenosis is present in 50% to 60% of patients who have CHARGE syndrome and should focus the clinician's attention on involvement of other organ systems, such as the eye and heart.

Choanal Atresia
Individuals who have bilateral posterior choanal atresia often have a prenatal history of polyhydramnios, believed to be due to an insufficient swallowing mechanism. The inability to pass a nasogastric tube should alert the clinician to the possibility of choanal atresia, but computed tomography (CT) scan of the nasopharynx and nasal cavity is necessary to evaluate the quality of the blockage. Bilateral choanal atresia is a medical emergency that should be corrected surgically as soon as possible. Chronic otitis media and deafness are potential complications of choanal atresia.

Mechanical Blockage of Airway: Choanal Atresia

Mechanical Blockage of Airway: Pharyngeal Airway Malformation

Airway obstruction from Robin syndrome can be helped by inserting a nasopharyngeal tube and placing the baby prone

Neurological in CHARGE Syndrome

Normal growth parameters at birth, but their linear growth tends to decline by late infancy. Some children have been found to have growth hormone deficiency, but growth deceleration frequently is due to cardiac, respiratory, or feeding problems. Early intervention for feeding difficulties is important.

Hypoplastic lobule, prominent antihelix, and trangular concha characteristic of the typical "CHARGE ear

Kaplan, J. et al. Neoreviews 2008;9:e299-e304

Copyright 2008 American Academy of Pediatrics

Ear Anomalies
Occur in approximately 90% of children and can involve the outer, middle, or inner ear. The typical "CHARGE ear" is protuberant, short, and wide, with a hypoplastic lobule, prominent antihelix, and triangular concha Middle ear anomalies include ossicular malformations, an abnormal or absent oval window, and absent stapedius muscle. Among the inner ear anomalies are aplastic or hypoplastic semicircular canals, and the Mondini defect (decreased number of turns to the cochlea) is present in up to 95% of affected individuals and can be detected by CT scan of the temporal bones. Temporal bone abnormalities also may be present. The combination of ossicular malformations and inner ear defects frequently results in a mixed (conductive and sensorineural) hearing loss that can range from mild to profound.

Cranial Nerve Anomalies

Although not described in the original acronym, cranial nerve (CN) anomalies also are common and now are included among the major diagnostic criteria Such anomalies usually are asymmetric and can involve CN I, resulting in hyposmia or anosmia (an absent or hypoplastic olfactory bulb is highly indicative of CHARGE); CN V, resulting in the incoordination of sucking, chewing, and swallowing; CN VII, resulting in facial paralysis that is usually unilateral ; CN VIII, resulting in sensorineural hearing loss; and CN IX/X/XI, resulting in dysfunctional swallowing, gastroesophageal reflux, and velopharyngeal aspiration.

Unilateral facial paralysis caused by an anomaly of cranial nerve VII

Kaplan, J. et al. Neoreviews 2008;9:e299-e304

Copyright 2008 American Academy of Pediatrics

Clinical Diagnosis of CHARGE Syndrome

A clinical diagnosis of CHARGE syndrome can be made based on the major and minor diagnostic criteria defined by Blake and associates in 1998. The presence of all four major criteria
choanal atresia coloboma, characteristic ears cranial nerve anomalies) or three major and three minor characteristics indicates a diagnosis of CHARGE syndrome.

Clinical Diagnosis of CHARGE Syndrome

The diagnosis should be considered strongly in any neonate who exhibits one of the major diagnostic criteria, and evaluation for abnormalities in other organ systems involved in CHARGE should be initiated.

Genetic Testing
In 2004, a molecular cause for CHARGE syndrome was identified. The responsible gene is CHD7 (chromodomain helicase DNA-binding protein 7) Clinical testing is currently available, and the mutation detection frequency is approximately 60% to 65%. CHARGE syndrome remains a clinical diagnosis. In the neonatal period, the presence of iris or retinal coloboma, choanal atresia, characteristic ears, hearing loss, facial nerve palsy, or congenital heart defects should alert the physician to the possible diagnosis. The evaluations initiated in the neonatal intensive care unit should include an ophthalmology examination, echocardiography, ear-nose-throat evaluation, renal ultrasonography, and hearing screen. The most sensitive diagnostic study, which has implications for management, is a CT scan of the temporal bones.

De Large Syndrome

Diagnostic Approach
History
Family history Parental consanguity Maternal drug/alcohol Maternal illness Antenatal scan

Neonatal examination
Cranio-facial

Diagnostic Approach
Clinical examination
Measurement and documentation of abnormalities Clinical photograph

Investigation
Development assessment X-ray/biochemical assay Chromosome study Biopsy/postmortem

Investigations
Chromosome analysis Fluorescent in situ hybridisation (FISH) Molecular genetic tests Metabolic tests Radiology Neuroimaging Echocardiogram Renal ultrasound scan Eye /Hearing /tests of immune function

Indications for chromosomal analysis

Unexplained stillbirths and neonatal deaths. Recurrent abortions, infertility. Fresh stillbirth with physical abnormalities. Neonate with features suggestive of chromosomal abnormality. Neonate with two or more dysmorphic features. Unexplained mental retardation / mental retardation with congenital abnormalities

Chromosome culture techniques

Peripheral blood. Bone marrow urgent diagnosis. Skin (fibroblast culture) useful up to 2 days after death. Desquamated cells in amniotic fluid. Chorion villus cells.

Tissues and Technical Procedures Used in Prenatal Diagnosis

The cells in amniotic fluid. Amniotic fluid Alpha Fetoprotein. Secretor substance. Ultrasound. Amniography. Fetoscopy. Radiography.

Principle of Genetic counseling

First step is to make a correct diagnosis. Both parents should be present. Discuss the medical consequences. Review family history of each parent. Family interpretations of conditions. Describe genetic basis of condition using visual aids. Explain genetic risks in plain language. Outline the options available. Provide summary of issue being discussed. Regular follow-up

Genetic Counseling
Process of communication 3 Functions
Discuss on diagnosis and patient implication Advice on probability of the next child affected. Early diagnosis of condition (prenatal diagnosis)

Genetic Counselling
Risk of a child being born
with some congenital abnormalities A serious physical/mental handicap 1 in 30 1 in 50 1 in 30-100 1 in 150 1 in 8

Risk of perinatal death Risk of child dying after 1 wk to 1 yr Risk of a pregnancy end with spontaneous abortion Risk of a couple to be infertile

1 in 10

Follow-up
In no diagnosis can be made, follow up is important Truth to parents about no diagnosis made

Thank you