First Aid for the Pediatrics Clerkship, 3 Ed.

Congenital Malformations and Chromosomal Anomalies

 

It is important for all pediatricians in all fields to recognize signs and symptoms of congenital disorders, including dysmorphologic features. It is also important to involve genetics in the patient’s care, for appropriate screening and treatment of conditions associated with genetic syndromes, genetic testing, if available and appropriate, and counseling regarding siblings and possible future offspring of the patient. Finally, physicians strive for a unifying diagnosis, and usually one is sufficient, but patients can have more than one thing going on, and children with genetic disorders can also get the diseases children without genetic conditions get!

ENVIRONMENTAL FACTORS

Image

A 3-week-old infant is brought for seizure. On physical examination, the patient has microcephaly. Cerebral calcifications are seen on brain CT scan. What does the infant likely have? Congenital Cytomegalovirus infection

Teratogens:

Image Cause 10% of all birth defects.

Image Include maternal metabolic disorders (diabetes mellitus), maternal/intrauterine infections (TORCHeS [toxoplasmosis, others, rubella, cytomegalovirus, herpes simplex, syphilis]), drugs, radiation, mechanical forces.

Image Common teratogenic drugs include ethanol, warfarin, isoretinoin, lithium, valproic acid, fluoroquinolones, tetracyclines, and phenytoin.

GENETIC FACTORS

Include single gene, parental imprinting, molecular cytogenetics.

Image Single gene:

Image Autosomal (dominant/recessive).

Image X-linked (dominant/recessive).

Image Parental imprinting: Genetic defect is dependent on which parent passes the abnormal gene.

Image Molecular cytogenetics:

Image Unstable repeat sequences

Image Uniparental disomy

Image Translocation


Image

Trisomies:

Image Age 13, Puberty: Patau

Image Age 18, can vote—“Elect”: Edwards

Image Age 21, can Drink: Down


TRISOMY SYNDROMES

Trisomy 21 (Down Syndrome)

Image

A female infant has slanted palpebral fissures, epicanthal folds, and some delayed development. Think: Down syndrome.

This is a classic description of an infant with Down syndrome. The diagnostic clinical features include flat facial profile, oblique palpebral fissures and epicanthic folds are usually evident at birth. It is also a leading cause of severe mental retardation in children. It is the most common chromosomal disorders.

Image

A 33-week-gestation male infant born to a 40-year-old mother was noted to have facial dysmorphism with depressed nasal bridge, wide-spaced eyes, low hairline, and low-set ears. He was also noted to have a single palmar crease in both hands. At 2 hours of life he was noted to have bilious emesis, and an abdominal x-ray was obtained, as shown in the figure. What is the diagnosis and management of this infant?

The infant described was born to a mother with advanced maternal age (> 35 years) and features consistent with trisomy 21 (Down syndrome). X-ray is notable for the classic double-bubble sign, which is pathognomonic for duodenal atresia. Management includes surgical repair of the duodenal atresia and also to confirm the diagnosis of trisomy 21 by chromosome analysis.

Image Extra copy of the genetic material on chromosome 21.

Image Most common malformation syndrome.

Image Most common chromosome disorder.

Image Most common genetic cause of moderate mental retardation.


Image

Patients with Down syndrome develop Alzheimer’s dementia early, around age 35.


ETIOLOGY

Image Ninety-five percent complete trisomy (meiotic nondisjunction of homologous chromosomes).

Image Four percent Robertsonian translocation (to chromosome 14).

Image One percent mosaicism.

EPIDEMIOLOGY

One in 600 births.

RISK FACTORS

Advanced maternal age.

SIGNS AND SYMPTOMS

Image More than 100 different physical signs can be present.

Image Varying degrees of mental retardation (most with IQs between 35 and 70).

Image Generalized hypotonia (of central nervous system [CNS] origin; most meet major motor milestones at 2× normal age).

Image Balding scalp hair pattern.

Image Upslanted eyes with epicanthal folds (see Figure 7-1).

Image Flat nasal bridge.

Image Prominent tongue.


Image

Think of duodenal atresia in a newborn with Down syndrome presenting with bilious vomiting.


Image Extra neck skin folds (sometimes visible on prenatal ultrasound).

Image Transverse palmar (simian) creases.

Image Small ears.

Image Short stature.

Image Joint laxity.

Image Hypoplastic nipples.

Image Brushfield spots on irises.

Image Subendocardial cushion defect (atrial/ventricular septal defect [ASD/VSD], atrioventricular [AV] canal).

Image Duodenal atresia, Hirschsprung’s disease, imperforate anus.

Image Hypothyroidsim.

Image Amyloid plaques and neurofibrillary tangles in brain—early onset dementia.

Image Image risk of leukemia (acute lymphocytic leukemia [ALL], acute myelogenous leukemia [AML], acute megakaryocytic leukemia).

Image Image risk of neonatal leukemoid reactions.

Image Atlantoaxial instability becomes an issue later in life.

Image Most males with Down syndrome are sterile but some females have been able to reproduce.


Image

Look for “double-bubble sign” in a plain abdominal radiograph.


DIAGNOSIS

Image Prenatal diagnosis can be made via amniocentesis or chorionic villus sampling.

Image Maternal serum α-fetoprotein (AFP) is Image.

Image

FIGURE 7-1. Location of epicanthus and palpebral fissure.

In Down syndrome, there are epicanthal folds and upwardly slanted palpebral fissures.

Image Low maternal serum unconjugated estriol level.

Image Elevated maternal beta-human chorionic gonadotropin (β-hCG).

TREATMENT

Image Early childhood intervention to maximize social and intellectual capacity.

Image Life skills training.

Image Surgery for correction of cardiac and duodenal defects.

Image At risk for atlantoaxial dislocation and cervical cord compression.

Image Image risk for leukemia and respiratory tract infections.

Image Yearly screening for thyroid disease.

Trisomy 18 (Edwards Syndrome)

ETIOLOGY

Image Most common type is complete trisomy.

Image Small percentage are due to mosaicism.

EPIDEMIOLOGY

One in 6000 live births; second most common trisomy.

SIGNS AND SYMPTOMS

Image Prominent occiput.

Image Low-set ears.

Image Small mouth.

Image Short sternum.

Image Thumb and radius agenesis/hypoplasia.

Image Camptodactyly (little finger fixed in flexion).

Image Redundancy of cardiac valve leaflets.

Image Hypertonia.

Image Seizures.

Image Rocker-bottom feet.

TREATMENT

Image Supportive.

Image Fifty percent die within first week of life. Most common cause of death is apnea.

Image Five to ten percent survive beyond the first year.

Image Those who survive are severely mentally retarded.

Trisomy 13 (Patau Syndrome)

Higher frequencies in stillbirths and spontaneous abortions.

ETIOLOGY

Image Seventy-five percent complete trisomy.

Image Twenty-three percent Robertsonian translocation (to chromosome 14).

Image Four percent mosaicism.

EPIDEMIOLOGY

One in 10,000 live births.

SIGNS AND SYMPTOMS

Image Holoprosencephaly (failure of telencephalon to divide into two hemispheres, resulting in large central ventricle; brain assumes configuration of a fluid-filled ball).

Image Microphthalmia and other eye defects (coloboma, cyclops).

Image Midline facial defects.

Image Polydactyly.

Image Scalp cutis aplasia.

Image Cystic kidneys.

Image VSD.

TREATMENT

Image Supportive.

Image Eighty percent die within first month; 5% survive past 6 months.

SEX CHROMOSOME ANOMALIES


Image

Turner syndrome is the most common cause of primary amenorrhea.


Turner Syndrome

Image

A newborn infant has lymphedema of the hands and feet, extra skin folds at a short neck, widely spaced nipples, and Image femoral pulses. Think: Gonadal dysgenesis (45, X) Turner syndrome, and do a chromosomal analysis to confirm the diagnosis.

Many infants with Turner syndrome are recognized at birth due to the presence of edema of the hands and feet and loose skin folds at the nape of the neck. Coarctation of aorta may be present in up to 20%.

ETIOLOGY

45, XO—missing one X chromosome.

EPIDEMIOLOGY

One in 2000–5000 live female births.

RISK FACTORS

Not related to advanced maternal age.

SIGNS AND SYMPTOMS

Image Short stature.

Image Webbed neck.

Image Lymphedema of hands and feet.

Image Coarctation of the aorta + biscuspid aortic valve.

Image Small mandible.

Image Narrow maxilla and high arched palate.

Image Epicanthal folds.

Image Impaired hearing (sensorineural).

Image Delay in motor skill development with normal intelligence.

Image Ovarian dysgenesis.

Image Phenotypically female.

Image Association with spontaneous abortion.

TREATMENT

Image Replacement for secondary sex characteristic development.

Image Monitor for autoimmune hypothyroidism.

Image Refer to an endocrinologist for induction of puberty at an appropriate age.

Image Resection of any intra-abdominal gonads to prevent malignancy.

Noonan Syndrome

Image Phenotypically similar to Turner syndrome but can affect both sexes.

Image Girls with Noonan syndrome have normal XX chromosomes.

Image Autosomal dominant.

Image Pulmonary stenosis.

Image Mental retardation often present.

Klinefelter Syndrome

ETIOLOGY

Image Presence of an extra X chromosome in males.

Image 47,XXY most common.

Image Most common cause of hypogonadism and infertility in males.

EPIDEMIOLOGY

One in 500 males.

RISK FACTORS

Advanced maternal age.

SIGNS AND SYMPTOMS

Image Hypogonadism.

Image Small testes but puberty occurs at the normal age.

Image Most patients are phenotypically normal until puberty.

Image Azoospermia (absence of sperm).

Image Tall stature (eunuchoid).

Image Female hair distribution, gynecomastia.

Image Learning disabilities.

Image Delay of motor skill development

Image Presence of inactivated X chromosome (Barr body).

TREATMENT

Image Administration of testosterone during puberty to improve secondary sex characteristics.

Image Interventions for developmental delays/learning disabilities.

IMPRINTING DISORDERS

Imprinting—different phenotype, same genotype.

Angelman Syndrome

ETIOLOGY

Image Sixty percent due to maternal deletion 15q11–13 (see Prader-Willi syndrome).

Image Forty percent have two normal paternal copies of chromosome 15.

EPIDEMIOLOGY

One in 20,000.

SIGNS AND SYMPTOMS

Image Happy, laughing disposition—previously known as the “happy puppet” or “marionette joyeuse” syndrome because of this and stereotyped flapping of hands.

Image Often, strikingly attractive children with lighter pigmentation than other family members (often blond-haired, blue-eyed).

Image Mental retardation (severe).

Image Microcephaly.

Image Ataxia.

Image Hypotonia (ataxia and hypotonia create the characteristic “puppet”-like gait).

Image Epilepsy (80%) with characteristic electroencephalographic (EEG) findings.

Image Complete absence of speech.

Image Unusual facies characterized by a large mandible and open-mouthed expression revealing tongue.

Image Inappropriate laughter.


Image

The same chromosomal deletion causes Angelman syndrome and Prader-Willi syndrome. The only difference is that in Angelman the missing genetic material is maternal, and in Prader-Willi, paternal.


TREATMENT

Image Supportive.

Image Seizures are often refractory to anticonvulsant therapy.

Image Normal life span.

Prader-Willi Syndrome

ETIOLOGY

Image Genetic.

Image Seventy-five percent paternal deletion 15q11–13 (see Angelman syndrome).

Image Twenty-five percent maternal disomy.

Image Hyperphagia/lack of satiety, Image caloric requirement secondary to hypotonia/Image movement, and obsessions/compulsions that focus on food all contribute to the vicious cycle Image obesity in these patients.

Image Obesity.

Image Small hands and feet.

Image Hypogonadism.

EPIDEMIOLOGY

One in 15,000–20,000.

SIGNS AND SYMPTOMS

Image Hypotonia and poor feeding (in infancy) progressing to hyperphagia and obesity by childhood.

Image Precocious puberty.

Image Micropenis.

Image Mild mental retardation.

Image Sleep disturbances.

Image Lighter pigmentation than other family members.

Image Significant behavioral problems (stubborn, manipulative, aggressive).

Image Fluent speech.

Image Obsessive/compulsive traits.

TREATMENT

Image Strict diet and behavioral interventions to prevent obesity.

Image Growth hormone to promote stature, and other timely hormone supplementation to promote secondary sex characteristics.

Image Patients develop complications from obesity that limit their life span.

Image Early prevention of obesity is the key to quality and quantity of life in these patients.

MOLECULAR CYTOGENETIC DISORDERS

22q11 Syndrome

Image Caused by deletion of a small piece of chromosome 22.

Image Seen in DiGeorge syndrome, velocardiofacial syndrome.

Image Occurs in 1 in 4000 births.

Image Most common features include congenital heart defects (85%), palatal abnormalities, thymic aplasia, immune deficiency (defective T-cell function), hypocalcemia (parathyroid involvement), characteristic facial features.

Image Cardiac features include tetralogy of Fallot, interrupted aortic arch.

Image Detected by fluorescence in situ hybridization (FISH).

Fragile X Syndrome

ETIOLOGY

Due to Image number of repeated nucleotide sequences (CGG).


Image

Fragile X is the most common form of heritable mental retardation.


EPIDEMIOLOGY

Image One in 2000 births

Image Male-to-female ratio: 2:1.

RISK FACTORS

Family history.

SIGNS AND SYMPTOMS

Image Mental retardation.

Image Macroorchidism in boys.

Image Protruding ears, macrocephaly, triangular, elongated facies, flat malar bones.

Image Shyness, autistic behavior, avoidance of eye contact.

AUTOSOMAL-DOM I NANT CONDITIONS

Image People in every generation are affected.

Image Examples include adult polycystic kidney disease, familial hypercholesterolemia, Marfan syndrome, neurofibromatosis type 1 (von Reckling-hausen’s disease), von Hippel–Lindau, Huntington disease, familial adenomatous polyposis, and hereditary spherocytosis.

Image Marfan syndrome:

Image Connective tissue disorder affecting fibrillin.

Image Chromosome 15.

Image Tall stature, long limbs.

Image Cardiovascular—aortic root dilatation, mitral valve prolapse, aortic regurgitation.

Image Ophthalmologic—lens subluxation.

Image Sudden death usually due to aortic dissection.

AUTOSOMAL-RECESSIVE CONDITIONS


Image

The X chromosome lyonizes randomly early in embryogenesis when there are relatively few cells. Since all daughter cells lyonize the same X, the odds that a significantly disproportionate inactivation of the “good” X will occur in carrier females, while small, are not infinitesimal. When this occurs, the carrier is affected, and the mechanism is termed unfortunate lyonization.


Image Skips generations (often a grandparent has had a similar condition).

Image Examples include cystic fibrosis and many enzyme deficiencies/metabolic disorders.

Image History of early deaths from unknown disorders or multiple miscarriages.

Image Consanguinity really Image the odds—you must ask if the parents are blood relatives.

X-LINKED RECESSIVE CONDITIONS

Image Usually only males are affected; females are unaffected or only partially affected (due to lyonization) carriers of the trait.

Image Examples include Duchenne and Becker muscular dystrophies, hemophilia A and B, Fabry disease, glucose-6-phosphate dehydrogenase (G6PD) deficiency, Hunter syndrome, ocular albinism, red–green color blindness, and Alport syndrome.

CONGENITAL ANOMALIES

Polydactyly

DEFINITION

Image Presence of more than five fingers or toes, which may be rudimentary to fully developed.

Image Incidence: 2 per 1000 live births.

ETIOLOGY

Image May occur as an isolated defect (whether genetic, toxic, or mechanical) or in conjunction with syndromes such as:

Image Ellis–van Creveld syndrome: With congenital heart disease.

Image Bardet-Biedl syndrome: With obesity, pigmentary retinopathy, mental retardation, hypogonadism, and renal failure.

Image Meckel-Gruber syndrome: Triad of occipital encephalocele, large polycystic kidneys, and postaxial polydactyly. Associated abnormalities include oral clefting, genital anomalies, CNS malformations, fibrosis of the liver, and pulmonary hypoplasia.

DIAGNOSIS

Observation, x-ray, fetal sonogram.

TREATMENT

Surgery, usually at 1 year of age.

Syndactyly

Definition

Webbing or fusing of two or more fingers or toes. May be bony and/or cutaneous. Often looked for between the second and third toes.

PATHOPHYSIOLOGY

Failure of cell apoptosis between digits during development.

TREATMENT

Surgery.

Craniosynostosis

DEFINITION

Image Premature closing of one or more cranial sutures due to abnormalities of skull development.

Image Can be primary skull/bone defect or a result of failure of brain growth.

Image Syndromic craniosynostosis in 20%.

Image Most common: Apert syndrome and Crouzon syndrome.

ETIOLOGY

May occur alone or in conjunction with syndromes such as:

Image Apert syndrome

Image Chotzen syndrome

Image Pfeiffer syndrome

Image Carpenter syndrome

Image Crouzon syndrome

SIGNS AND SYMPTOMS

Early closure of fontanels and sutures.

COMPLICATIONS

Image Hydrocephalus.

Image Image intracranial pressure (ICP).

Image Developmental delay.

TREATMENT

Image Craniotomy to prevent intracranial and ophthalmologic complications.

Image Multidisciplinary approach—genetics, psychology, pediatrics, surgery, neurology.

Image Genetic counseling.

Image Long-term follow-up.

Amniotic Bands

DEFINITION

Image Fibrous strands of membrane stretching across chorionic cavity.

Image Form of disruption.

EPIDEMIOLOGY

Not associated with problems in future pregnancies.

ETIOLOGY

Image Spontaneous.

Image Associated with abdominal trauma.

Image May be associated with chorionic villus sampling (CVS).

PATHOPHYSIOLOGY

Caused by early amnion rupture and leakage of chorionic fluid.

SIGNS AND SYMPTOMS

Image May be innocent and not cause any harm to the fetus.

Image Can Image limb or other body part constriction or amputation (amniotic band syndrome).

Image May be associated with oligohydramnios and Image fetal movement.

DIAGNOSIS

Ultrasound.

TREATMENT

Most bands disappear on their own, not appearing on follow-up ultrasound.

Cleft Palate/Lip

DEFINITION

Image Spectrum of defects of the upper lip, philtrum, and hard and soft palates.

Image Cleft lip, cleft palate, or both.

Image Unilateral or bilateral.

EPIDEMIOLOGY

Image Fourth most common birth defect.

Image Incidence of orofacial clefting is 1 in 700 live birth.

Image Occur more often in infants of Asian, Latino, or Native American descent.

Image More common in males.

ETIOLOGY

Image Teratogens—ethanol, anticonvulsants, steroids, chemotherapy, maternal vitamin A excess.

Image Gestational factors—maternal diabetes, amniotic bands.

Image Chromosomal abnormalities.

Image Idiopathic (majority).

PATHOPHYSIOLOGY

Image Clefting of lip and anterior (primary) palate due to defect in fusing of both maxillary processes with the frontonasal process during weeks 5 and 6.

Image Clefting of posterior (secondary) palate due to defect in fusion of palatal shelves during weeks 7 and 8.

SIGNS AND SYMPTOMS

Can affect feeding, speech, illness (colds and ear infections), teething, hearing, and emotional coping.

DIAGNOSIS

Physical exam of lips, palate, and oropharynx.

TREATMENT

Image Infants with cleft palate may require assistance with feeding.

Image Surgical repair of lip within first months of life, palate around 1 year of life; potential for final repairs and scar revisions in adolescence.

Image Cleft team can include plastic and oral surgeons; geneticist; ear, nose, and throat (ENT) specialist; dentist; speech pathologist; audiologist; social worker or psychologist; and nurse coordinator.

Image Genetic counseling.

Omphalocele

DEFINITION

Herniation of abdominal contents (usually only intestine, though can include liver and/or spleen) through umbilical root, which is covered only by peritoneum.

EPIDEMIOLOGY

Image May be associated with other congenital defects, including chromosomal anomalies, heart defects, and diaphragmatic hernia.

Image Association: Beckwith-Wiedemann syndrome (omphalocele, macrosomia, hypoglycemia), trisomies 13 and 18.


Image

In a normal pregnancy, there is approximately 600 mL of amniotic fluid surrounding the baby at 40 weeks’ gestation.


DIAGNOSIS

Some may be detected on prenatal ultrasounds.

TREATMENT

Image Until any other, more serious conditions have been taken care of, the extruded contents are covered.

Image Serial reductions of intestines back into abdomen until skin closure is possible.


Image

Amniotic fluid volume Image as gestational age advances beyond 32 or 34 weeks’ gestation.


Oligohydramnios

DEFINITION

Image Abnormally small amount of amniotic fluid (amniotic fluid index [AFI] < 5.0 cm or single pocket of fluid < 2 cm).

Image Volume < 500 mL = oligohydramnios.

Image Complicates 1–5% of pregnancies.


Image

Isolated third-trimester oligohydramnios is not necessarily associated with poor perinatal outcome.


ETIOLOGY

Image Premature rupture of membranes (PROM).

Image Intrauterine growth retardation (IUGR).

Image Postdates pregnancy.

Image Renal anomalies (eg, bilateral renal agenesis, multicystic dysplastic kidneys, posterior urethral valves).

Image Other congenital anomalies (eg, aneuploidy).

Image Placental abruption.

Image Twin-twin transfusion.

Image Iatrogenic—nonsteroidal prostaglandin synthetase inhibitors, firsttrimester chorionic villus sampling, second-trimester amniocentesis; amniotic fluid level may return to normal.

Image Idiopathic.


Image

Oligohydramnios becomes most evident after 20 weeks of gestation.


PATHOPHYSIOLOGY

Amniotic fluid is regulated by fetal urine, as well as fetal oral secretions and respiratory secretions. Any process disrupting this exchange of fluid can Image pathological amniotic fluid levels.

COMPLICATIONS

Image Fetal demise.

Image Pulmonary hypoplasia.

Image Facial deformities.

Image Skeletal deformities (eg, compressed thorax, twisted feet).


Image

Pulmonary hypoplasia is the most serious complication of oligohydramnios.


Potter Syndrome

Image Potter syndrome specifically refers to bilateral renal agenesis, though other renal anomalies Image oligohydramnios have also used the eponym.

Image Potter syndrome includes pulmonary hypoplasia, skeletal anomalies, and characteristic facies (sloping forehead; flattened nose; recessed chin; and low-set, floppy ears).

Image It is incompatible with neonatal life.

Image Death occurs due to pulmonary hypoplasia.


Image

Patients with second-trimester oligohydramnios have a higher prevalence of congenital anomalies and a lower fetal survival rate than those women with oligohydramnios in the third trimester.


DIAGNOSIS

Image Amniotic fluid index (AFI)—sum of the maximum vertical pocket of amniotic fluid in each quadrant of the uterus.

Image Best to use average of three readings.

TREATMENT

Image Depends on etiology.

Image First goal is to remove the inciting cause or correct the underlying problem (eg, discontinue prostaglandin inhibitor, place a shunt).

Image Measures to prepare fetus for possible premature birth (corticosteroids and antibiotics for PROM).

Image Antepartum testing to determine appropriate time for delivery in IUGR.


Image

Suspect bilateral renal agenesis if maternal ultrasonography shows oligohydramnios, nonvisualization of the bladder, and absent kidney.


Hypospadias

DEFINITION

Improper location of urethral meatus, not at tip of penis, but on underside of penis, even as far back as the scrotum.

ETIOLOGY

Hereditary—if father has, there is a 20% chance that child will.


Image

Infants with hypospadias should not be circumcised at birth, as the foreskin may be useful in the repair.


SIGNS AND SYMPTOMS

Image Curvature of penis downward; foreskin “hooding.”

Image Potentially may have to sit down to urinate.

DIAGNOSIS

Clinical, though radiologic studies may be necessary if other congenital defects possibly present.

TREATMENT

Image Surgical correction to extend urethra to end of penis before 18 months of age and chordae repair if sexual function will be affected by bent erect penis.

Image May require more than one operation.

Image Beware of postoperative bleeding, infections, stenosis, and fistulae.

Image



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