Diseases of Infancy and Childhood

M. Kent Froberg, MD

2009

Objectives

• Learn basic epidemiology of childhood causes of death

• Learn factors contributing to intra-uterine growth retardation (IUGR)

• Understand the pathophysiology of Respiratory Distress Syndrome (RDS)

• Know the major factors related to metabolic inherited diseases of childhood, SIDS, and benign & malignant neoplasms of childhood

Causes of Death & Age

• Under 1 yr IUGR, RDS, congenital anomalies, SIDS, pneumonia

• 1-4 yrs injuries, congenital anomalies, malignant neoplasms, homicide

• 5-9 yrs injuries, malignant neoplasms, congenital anomalies, homicide

• 10-14 yrs injuries, malignant neoplasms, suicide, homicide

• 15-24 yrs injuries, suicide, homicide

Birth Weight and Gestational Age

• AGA=appropriate for gestational age, SGA=small,

LGA=large• 10-90th percentile = AGA • Before 37th week = preterm, >42 = post-term

– 1500gm infant at 32 weeks has mortality risk of ~20%

– 700gm infant at 32 weeks has mortality risk of 65%

Mortality is related to gestational age, but birth weight is more important for infants of the same gestational age. So for a 32 week infant of 700 g the expected mortality is 63%, while for a 1750 g infant of the same gestational age the expected mortality is ~6%. Neonatal intensive care has improved the survival of preterm infants.

IUGR

• Underlies SGA, detect by US• Factors relating to IUGR:

– Fetal - trisomies, congenital anomalies & infections (symmetric growth retardation-Type I)

– Placental - uteroplacental insufficiency, thrombosis, infarction, abruption, placenta previa, confined placental mosaicism (disproportionate growth retardation-Type II)

– Maternal - most common: includes toxemia, HTN, malnutrition, ETOH, smoking, narcotics, teratogens (often cause learning disabilities, cerebral dysfunction)

Organ Immaturity

• Problem of preterm regardless of weight– Lungs - alveoli mature late in gestation (7th month),

alveoli lined by cuboidal epith prior to 26-32 weeks, septa thick, reach full compliment of alveoli by 8 yrs

– Brain - smooth surface, soft, nerve fibers poorly myelinated

– Liver - large but physiologically immature, jaundice esp in low birth wt infants (def bilirubin glucuronyl transferase, etc)

Infant Mortality

• 20.0 per 1000 population in 1970 7.5 per 1000 in 1995

• Rate for blacks >twice whites: 14.9/1000 compared to 6.3/1000

• US infant mortality ranks 21st among industrialized nations

Socioeconomic factors underlie the frequency of low birth weight babies

Congenital Anomalies

• In 3% of newborns, major cause of M&M in 1st yr • Definitions:

– Malformations - intrinsic abnl occurring during development, ex. Anencephaly

– Deformations - arise later in fetal life, alteration in structure from mechanical factors (small uterus, leiomyomata) or fetal-placental (abnl presentation, multiple births, oligohydramnios, ex. Clubfeet)

More Definitions

• Disruptions - 2 interference with previously nl organ or region, ex amniotic bands

• Sequence - pattern of cascade anomalies, ex. Potter’s sequence: renal agenesis oligohydramnios pulmonary hypoplasia

• Other terms: agenesis - organ & primordium absent; aplasia - failure of organ development; atresia - absent opening; hypoplasia - # of cells; hyperplasia - # of cells; dysplasia - abnl organization

Causes of Malformations

1. Genetic - include karyotypic aberrations, single gene mutations, multifactorial – Abnl karyotype in 10-15% of live-born infants with

congenital malformations; frequency - Down, Klinefelter, Turner, Patau syndromes

– Usually arise during gametogenesis, so not familial

– Single gene mutations - Mendelian, uncommon (2-10%) - Marfan syndrome

– Multifactorial - interaction with environment (20-25%)

More Causes2. Environmental - infections (TORCH), maternal disease

states (diabetes), drugs (thalidomide)Infections -

rubella in 1st trimester can cause cataracts, heart defects, deafness (50% in 1st month of gestation)

CMV - most common cause of fetal viral infection, can cause MR, deafness, hepatosplenomegalythalidomide - limb malformations (50-80%), amelia & phocomelia ETOH - growth retardation, microcephaly, ASD

Malformations

Timing - critical to type & severity of malformation

early embryogenesis - 1st three weeks death more likely

organogenesis - weeks 3-9 most susceptible to teratogens

Teratogens & genetic defects may act on cell proliferation, migration, differentiation or damage formed organs - affect growth factors (WT-1, TGF-)

Hox (homeobox) genes interact with multiple downstream genes, hence is a regulator of morphogenesis, can be affected by retinoids - temporal & spatial expression of retionic acid-binding proteins may affect morphogenesis

Forms of vitamin A are necessary for normal development but in excess can cause malformations

Perinatal Infections

Ascending - transcervical leading to – funisitis (cord) &– chorioamnionitis (membranes), – fetus may inhale amniotic fluid or contact

microbe in birth canal during delivery; most bacterial, few viral

• Hematological - most viral or parasitic; Treponema, Listeria, HIV, Hep B

Perinatal Infections• Perinatal sepsis - group B Strep and E. coli lead to

pneumonia and sepsis in 4-5 days, late sepsis - Listeria and Candida

• TORCH syndrome: toxoplasma, rubella, cytomegalovirus, herpesvirus and others (syphilis, etc.).– Cause similar clinical & pathological picture in newborn. – Clinical: fever, encephalitis, chorioretinitis,

hepatosplenomegaly, pneumonitis, myocarditis, hemolytic anemia, and vesicular or hemorrhagic skin lesions.

– Chronic sequelae: growth & learning delays, cataracts, cardiac anomalies and bone defects

Respiratory Distress SyndromeHyaline Membrane Disease

• Still common in newborn period, affects 60-70,000 infants/yr– Risk Factors:

• excess sedation of mother respiratory depression & brain injury

• Prematurity muscle & resp immaturity (1 atelectasis)

• Aspiration of blood, mucus, squames, amniotic fluid

• Umbilical cord coils hypoxia

RDS

• Mortality previously 25,000 infants/yr, now 5,000

• CSx: usually preterm, or associated with maternal diabetes or cesarean section – May see resuscitation at birth improve– Soon develop resp distress grunting,

retraction, cyanosis, rales on auscultation, ground-glass picture by CXR, may progress despite ventilator assistance

RDS

• Pathogenesis: incidence ~ 1/gestational age,60% <28 wks, 15-20% if 32-36 wks, <5% if over 37 wks– Main defect is lack of surfactant - 75% is

phosphatidylcholine (lecithin) made by type II pneumocytes esp after 35th week, sphingomyelin is universal cell membrane component (use for relative baseline)

– L/S ratio 2.0 or > in amniotic fluid = 95% chance of no RDS, matures rapidly (1-2 days)

RDS Pathology

• Gross - lungs stiff, solid, reddish purple • Micro - atelectasis & dilation, hyaline membranes,

cell debris• Rx: oxygen, ventilatory assistance, surfactant• Complications: bronchopulmonary dysplasia

(emphysematous changes 2 to ventilatory injury), PDA, IVH, necrotizing enterocolitis

• Mortality ~1/body wt

Atelectasis & hyaline membranes in RDS

Atelectasis

Hyaline membranes (arrows)

Dilation

Phenylketonuria (PKU)

• Autosomal recessive disorder caused by lack of phenylalanine hydroxylase PKU, incidence 1/20,000 births, pathogenesis unknown

• NL at birth, rapid serum phenylalanine severe MR by six months,

Only 4% of untreated PKU pts have IQ>50 or 60, also see

SZ, eczema, hypopigmentation, 2/3 unable to talk, 1/3 unable to walk

• Can prevent MR by restricting phenylalanine in diet

PKU

• Other forms of PKU: – Maternal PKU: profound MR in child of non-compliant

mother with PKU (although child is heterozygote)

– Benign PKU: perinatal screen (Guthrie test) positive but only partial def of phenylalanine, serum levels NL (so ), don’t develop stigmata

– Other variant forms: may affect other enzymes in cascade, some transient, some due to lack of tetrahydrobiopterin cofactor, can see neurological impairment with NL serum phenylalanine levels

Guthrie Card for PKU Testing

PKU

• Newborn screening tests: – Urine + FeCl3 black color in presence of

phenylpyruvate – Guthrie test - heel stick -bacterial inhibition

assay, repeat if + and follow serum phenylalanine (1% of newborns +, but 90% FP rate)

– Molecular tests

Galactosemia

• Autosomal recessive: classic form - lack of galactose-1-phosphate uridyl transferase & accumulate substrate (some galactokinase def.), incidence 1 per 80,000 whites– Targets liver, brain & eyes steatosis,

cirrhosis, cataracts, neuronal loss & gliosis– Eye: galactose converted by aldose reductase to

galactilol absorbs water cataracts

The most common variant of galactosemia occurs from a lack of galactose-1-phosphate uridyl transferase. A rare variant is due to galactokinase deficiency

Galactosemia

• Mechanism of liver & CNS damage unknown• CSx: reluctant to nurse, FTT, V & D,

hepatomegaly, MR by 6-12 months, jaundice, neonatal sepsis (E. coli)

• Dx: enzyme def in RBCs, heel stick for enzyme immunoassay, can do on amniotic fluid

• Rx: restrict dietary galactose (milk)

Fibrosis & fatty liver from galactosemia

Cystic Fibrosis

• See Robbins 7th edition, pp. 489-495. CF genetics module. (no test questions)

Sudden Infant Death Syndrome

• “Crib Death,” sudden, unexplained death of infant <1 yr of age after thorough investigation

1. ~ 6000/yr in US, worldwide 1-5/1000 live births

2. 90% in first 6 months of life (peak 2-4 months)

3. Cyanosis and cessation of respirations, most have minor manifestations of URI

SIDS

4. Risk factors: mother <20 yrs, unmarried, smoking, low socioeconomic status, drug abuse, black race, infant prematurity, LBW, male sex, SIDS in prior sibling 5. 1-10% have inborn error of metabolism like

acyl-CoA-dehydrogenase def, may be heterogeneous group of disorders with same outcome, some homicides

6. Apnea & abnl temperature control thought to be involved, delayed autonomic development?7. Supine SIDS

Tumors & Tumor-Like Lesions

• Only 2% of all malignant neoplasms occur in infancy & childhood, but 2nd leading cause of death 4-14 yrs of age

1. Heterotopia (choristoma) - NL cells in abnl location, ex. adrenal rests

2. Hamartoma - excessive growth of cells/tissues native to organ, ex. Cardiac myomas & subependymal hamartomas of tuberous sclerosis

Tumors & Tumor-Like Lesions

3. Benign - may be difficult to distinguish from hamartomas, are most common neoplasms of childhood

• Hemangiomas - most common tumor of infancy, skin of face & scalp, flat to elevated, irregular, red-blue masses. Very large = port-wine stains. May regress spontaneously. May be part of von Hippel-Lindau Syndrome

4. Teratomas - tumor composed of more than one germ cell layer, may be benign (mature) cystic or malignant (imature) solid masses. May be congenital.Sacrococcygeal > head & neck, gonads, mediastinum, incidence 1/20,000, F:M is 4:1, 75% benign, may cause non-immune hydrops fetalis; Rx: surgery

Spontaneous regression of large capillary hemangioma

As seen at birth As seen at 2 years of age

Sacrococcygeal teratoma

Fetal ultrasound showing heart chambers of 18 week of gestation fetus

Ultrasound seven weeks later showing a large mediastinal mass

Macerated, stillborn 27 week female fetus

The heart (red arrow) is displaced by a large mediastinal mass (black arrow)

An island of cartilage is surrounded by glands showing dissolution in mature teratoma

Neuroepithelial rosette (arrow) in benign teratoma

Histology?

Tumors:MalignantConcepts

• May be related to abnl development• May regress or cytodifferentiate • Rx may lead to 2 malignancies• Small , round, blue cell tumors• Sites: hematopoetic, nervous system, soft tissue,

bone• Include neuroblastoma, lymphoma,

rhabdomyosarcoma, PNET/Ewing’s sarcoma

Neuroblastoma

• Most commnon malignant tumor of children <1yr, 15% of childhood cancer deaths, 35% in 1st yr of life, 85-90% prior to age 5

• 25-35% arise in adrenal medulla, rest along sympathetic chain (paravertebral mediastinum or abdomen, pelvis, neck, even brain)

• Gross: soft, gray, hemorrhagic, areas of necrosis, calcifications

Neuroblastoma

• Histopath: small, round, blue-cell tumor (neuroblasts), Homer-Wright pseudorosettes (no lumen-fibrillar extensions), may show some level of diffentiation (~ganglioneuroma)

• Clinical: present as abdominal mass, fever & wt loss. Later may be signs of mets (GI or resp complaints)

• Produce catecholamines (90%) elevated urine VMA and HVA (unlike pheochromocytomas do not typically produce hypertension)

Neuroblastoma

• Clinical:– Prognosis: age & stage dependent

• <1yr good regardless of stage, if <1yr and stage I or II 95-98% 5-year survival,

• >1yr and stage III or IV 10%

– Stage IV-S (1 plus skin, liver or bone mets) 80% 5-yr survival (4S limited to infants <1yr)

– Disseminated neuroblastoma to skin may present as “blueberry muffin baby”

Neuroblastoma

• Genetics: Commonly have – 17q gain (50% of tumors) in unbalanced

translocation usually with 1q adverse outcome

– 1p deletion in region of band p36 (25-35% of tumors), site of likely tumor suppressor gene have worse prognosis

• 25-50% of neuroblastomas have 14q del & aggressive course

Neuroblastoma

• 25% have amplification of N-myc oncogene, see double minutes by karyotype have poorer prognosis

• Hyperdiploid or near triploid tumors have a better prognosis, while diploid tumors have unfavorable outcome

Neuroblastoma

• Neuroblastomas may spontaneously regress or differentiate

• IF nerve growth factor receptor Trk A favorable outcome

• If Trk A poorer prognosis • Trk A may play a role in maturation of tumor to

ganglioneuroma (mature neural elements) • Cytodifferentiation may be spontaneous or

following Rx

Large, necrotic mass centered in area of right adrenal gland

Neuroblastoma

Neuroblastoma: primitive cells forming Homer-Wright pseudorosettes

Ganglioneuroma: neurons, neurites, fibroblasts & Schwann cells

Retinoblastoma

• Most common malignant eye tumor of childhood

• 1% of all cancer deaths to 15 yrs

• Seen in 1 of 17,000 live births

• 90% diagnosed prior to age 7

Retinoblastoma

• Gross: nodular mass within globe (arising from retina), do fundoscopic exam on all neonates

• Histopath: small, round, blue-cell tumor with Flexner-Wintersteiner rosettes (central lumen), histogenesis ~ retinoblasts

• Clinical: often present at birth or by 2 yrs with poor vision, strabismus, whitish hue to pupil (cat’s eye) or eye pain, usually fatal once spread beyond orbit

Retinoblastoma• Rx: radiation, laser photocoagulation, cryotherapy,

enucleation• Genetics: loss of Fx of retinoblastoma gene at 13q14, a tumor

suppressor gene• Hypophosphorylated Rb binds E2F & prevents G1 S

transition of cell cycle• Tumors sporadic or hereditary: Knudson “two-hit” hypothesis • Sporadic 60-70% of cases, require two somatic mutations

in same retinoblast• Familial (autosomal dominant) have one germline and one

somatic mutation• Rb alterations also seen in osteosarcomas, etc. Bone tumors

may follow Rx for retinoblastoma

Knudson two-hit hypothesis: requires one germline and somatic mutation of the Rb gene. Sporadic forms have two mutations within retinal cells after birth

Loss of Rb function leads to loss of tumor suppression & cell cycle regulation.

Genetic alterations in retinoblastoma include large deletions seen by karyotyping or Southern blot or by point mutations leading to a stop codon.

Retinoblastoma: primitive neuroepithelial cells forming Flexner-Wintersteiner rosettes

Wilms Tumor

• Most common 1 renal malignancy of childhood• Gross: solitary, gray-tan, well-circumscribed

mass, 10% bilateral • Micro: recapitulate stages of nephrogenesis,

usually triphasic with blastemal (nephroblasts), stromal and epithelial elements

• Clinical: 2-5 yrs, abdominal mass (hematuria, obstruction)

• Rx: 5-yr survival now >90% with triple therapy

Wilms tumor at lower pole of kidney

Wilms Tumor: triphasic histology with blastema (blue), tubular epithlium (red) and stroma (black)

Wilms Tumor

• Genetics: sporadic vs inherited, genetic alterations of 11p13 (WT-1) or 11p15.5 (WT-2). WT-1 necessary for NL nephrogenesis

• Associated congenital malformations risk of developing Wilms tumor:

– WAGR syndrome: aniridia, genital anomalies, MR, & 33% chance of Wilms tumor

– Denys-Drash syndrome: gonadal dysgenesis & nephropathy leading to renal failure

– Beckwith-Wiedemann syndrome: organomegaly, hemihypertrophy, renal medullary cysts, adrenal cytomegaly (WT-2 altered), some have genomic imprinting

• Premalignant condition: nephroblastomatosis-persistent immature nephrogenic elements