CYSTIC FIBROSIS
DEFINITION:
An inherited disorder characterized primarily by progressive lung disease, pancreatic insufficiency, gastrointestinal obstruction, and an excess of sodium and chloride in the sweat.
EPIDEMIOLOGY:
incidence:
most common fatal autosomal recessive disease affecting Caucasian populations (carrier rate is 1/20)
incidence varies between different population:
Northern Ireland - 1 in 1700 - 1900
USA: Caucasians - 1 in 1900 - 3700
England: Asian - 1 in 10,000
USA: Black - 1 in 17,000
age of onset:
infancy -> adolescence
risk factors:
familial - autosomal recessive
chrom.#: 7q31.2
gene: cystic fibrosis transmembrane conductance regulator (CFTR) gene
PATHOGENESIS:
1. Background
function of the CFTR gene is unknown and controversial:
1. defective Cl channel per se
2. defective Cl channel regulator - leukotriene LTC4, prostaglandin D2
defective transport of anions (Cl) across epithelial cells in the airways, pancreas, intestine, and sweat glands leads to chronic lung disease, pancreatic insufficiency, gastrointestinal obstruction, and increased sodium and chloride in the sweat
2. Genetic Defect
over 400 mutations of the CFTR gene have been identified
70% of the mutations in the CFTR gene are deltaF508
those homozygous for this mutation tend to be pancreatic insufficient
genotype -> phenotype correlation studies are in progress
CLINICAL FEATURES:
1. Respiratory Manifestations
1. Early Changes
1. Upper Airway
chronic rhinitis/rhinorrhea
nasal polyps (15-20%)
acute/chronic sinusitis
middle ear effusions
culture + for P. aeruginosa
2. Lower Airway
chronic cough (earliest manifestation)
coarse crackles (RUL)
obstructive lung disease (hyperinflation, wheezing)
2. Late Changes
exacerbation of respiratory distress (dyspnea, cough) associated with acute respiratory infections
3. End Stage
hypoxemia, pulmonary hypertension, cor pulmonale, respiratory failure
4. Complications
1. Atelectasis
in 5%, lobar and segmental
2. Pneumothorax
(+/- tension) with high recurrence rate
3. Hemoptysis
seen with bronchiectasis, massive in 5%
4. Clubbing
in 100%, extent correlates with lung severity
5. Allergic Aspergillosis
a. fumigatus with rusty brown plugs of sputum
6. Hypertrophic Pulmonary Osteoarthropathy
in 8-15%, distal tibia, fibula, ulna
7. Bacterial Infections
S. aureus
H. influenzae
Pseudomonas aeruginosa
40% of patients are colonized by 5 years of age
Burkholderia cepacia (formally P. cepacia)
different strains
2. Gastrointestinal Tract Manifestations
1. Intestinal Tract
1. Newborn
1. Meconium Ileus
5-10%, diagnostic for CF
small intestine obstruction
2. Meconium Plug Syndrome
less specific for CF
large intestine obstruction
2. Infant/Children
1. Meconium Ileus Equivalent
distal intestinal obstruction syndrome
a partial or complete obstruction of the terminal ileum
occurs in 20% of patients with CF
2. Rectal Prolapse
20% of CF children
3. Others
intussusception
adhesions (from previous surgury)
appendix (appendicitis, periappendiceal abscess diverticulosis)
duodenal ulcers
2. Pancreatic Disease
1. Exocrine
1. Malabsorption
pancreatic enzyme deficiency (blocked ducts)
of fats, protein, nitrogen
of vitamins D,E,A,K
fecal loss of bile acids
2. Pancreatitis
in <1% of adolescents or adults
2. Endocrine
1. Diabetes Mellitus
in 8% of CF's older than 11
abnormal glucose tolerance test
decreased number of beta cells
may present with symptomatic hyperglycemia but not ketoacidosis
will induce microvascular changes in the retina and kidneys
3. Hepatobiliary Disease
1. Biliary Cirrhosis
focal
may increase alkaline phosphatase
may present with conjugated hyperbilirubinemia due to intrahepatic cholestasis
2-5% of CF patients present with jaundice, ascites, edema, massive hematemesis, splenomegaly
2. Cholelithiasis
12% of older patients
may be associated with biliary colic
may be intra- or extrahepatic
bile becomes lithogenic because of a high cholesterol content
3. Genitourinary Tract Manifestations
1. Males
1. Altered Wolfian Duct Structures
vas deferens, epididymis, seminal vesicles are atrophic, fibrotic, obstructed, or absent
pathogenesis: intrauterine obstruction of the genital tract
2. Infertility
only 2-3% are fertile
volume of ejaculate is 1/3 -> = of normal
complete absence of spermatozoa
a number of chemical abnormalities of the semen (due to absence of secretions from the seminal ves.)
3. Others
inguinal hernia, hydrocele, undescended testes
delay in the onset of puberty and sexual maturation
2. Females
1. Infertility
10% are fertile
may be related to menstrual irregularities (oligomenorhea, anovulation), thick tenacious mucous plugs at the cervial os (abnormal cervial mucous), endocervicitis, polyp formation
2. Others
delay in the onset of puberty and sexual maturation
4. Sweat Gland Manifestations
failure to reabsorb Cl
increased Na, Cl, K in sweat (i.e., loose NaCl through sweat)
salty taste with salt crystals on skin
salt depletion can lead to:
profound hypochloremia, hyponatremia, alkalosis, and/or hypotension
INVESTIGATIONS
1. Pulmonary Function
1. Obstructive Lung Disease
seen within weeks -> months after birth
progresses from peripheral -> general involvement
characterized by:
decreased maximal flow rates
decreased FEV/FVC
increase a-A gradient (V/Q mismatch)
reactive airway disease
2. Restrictive Lung Disease
late stage disease
characterized by decreased VC and TLV
3. End Stage Disease
FEV1 <30% predicted
(PaO2 <55>50 mmHg)
2. For Malabsorption
see file on "Malabsorption"
3. Neonatal Screening
elevated level of trypsinogen in the blood of newborns
MANAGEMENT:
I. APPROACH
1. Diagnosis
2. Education
3. Treatment Options
4. Goals of Therapy
5. Management Stategies
1. Supportive
2. Nonpharmalogical
1. Chest Physiotherapy
2. Diet
1. Newborns
2. Children
3. Pharmalogical
1. Antibiotics
2. Ventolin
4. Surgical
1. For Complications
2. Lung Transplantation
5. Experimental
1. Amiloride
2. DNase (Pulmozyme)
3. Gene Therapy
1. Diagnosis
1. Laboratory
1. Sweat Chloride
Sweat Gain >100 mg
[NaCl] >60 mmol/L
2. Molecular Characterization
as yet there is no correlation between genotype and phenotype
2. Education
diagnosis, definition, epidemiology, prognosis, treatment options
3. Treatment Options
1. No Treatment
for the pancreatic-sufficient type there may be no need for pancreatic enzymes
2. Treatment
management with pancreatic enzymes in the pancreatic-insufficient type
management of respiratory manifestations in all patients
4. Goals of Therapy
no cure for cystic fibrosis and thus management goals revolve around the amelioration of the respiratory and gastrointestinal manifestations
5. Management Strategies
1. Supportive
CF is a chronic and progessive illness that needs close monitering and thus regular follow-up is important
the patient and family should be linked to a CF support group within the community
Psychological support - living with CF, dying with CF
funding for medical therapy is provided through the government and the distribution of medications is through regional centres throughout Canada
the Canadian CF Foundation works with 33 CF Clinics across Canada and 53 Chapters
the Paediatrician coordinates a team approach involving pharmacists, dieticians, psychologists, & physiotherapists
1. Follow-up
clinical assessment every 3-6 months with sputum samples and pulmonary function tests with each visit
chest x-ray every 6-9 months
SMA11 and CBC with differential every 12 months
2. Non-Pharmacologic
1. Chest Physiotherapy
performed at least 3 times per day to relieve mucous obstruction in the lungs
postural drainage of the 17 segments may take up to 20-30 minutes per session
autogenic drainage - breathing at different lung volumes to increase release of mucous from the lower airways
2. Diet
1. Newborn
Goals
to provide 150% of normal caloric requirements
follow clinically - stooling pattern, abdominal distension, weight gain
Breast Feeding
encourage but may not be tolerated
supplement with formula (see below)
Formula
supplement formula to 27 kcals/oz. with Polycose and MTC Oil
if taking elemental formulas by mouth, may switch over to milk-based formula when infant gaining weight (i.e., by 6 weeks of age)
Elemental feeds - Alumentum or Nutramigen
Supplementations
Pancreatic Enzymes
Cotazym supplements needed for all breast and formula-fed infants
may add cotazym powder to apple sauce prior to feed
always wash mouth after enzymes given to prevent autodigestion
Vitamins
Poly-Vi-Sol 0.6 cc po od
Vitamin E 100 mg po tid for 1st year then 400 mg po od
2. Children -> Adulthood
Meals
high calorie meals high in salt
Supplementations
Ensure drinks or puddings
Pancrelipase Preparations
Cotazym and Cotazym ECS
take as much is needed to control diarrhea and malabsorption
must take with each meal and snack
Multiple Vitamins
poly-vi-sol (tablets or drops)
vitamin E (capsules or drops)
NaCl
snacks high in salt (chips, cheezies, salt pills) particularly in hot weather
3. Birth Control
liver function tests should be monitered carefully for hepatits in women on the birth control pill
lung function declines after pregnancy
3. Pharmacologic
1. Antibiotics
1. Prophylaxis (Continuous)
Staph. aureus
Keflex (Cephalexin) 50-70 mg/kg/d po tid-qid
Cloxacillin 100 mg/kg/day po qid
Pseudo. aeruginosa
Tobramycin (Nebulized)- 2cc (80mg) tid after physiotherapy
2. Acute Exacerbations - positive sputum
H. flu
Amoxicillin 25-50 mg/kg/day po tid x 2 weeks
P. aeruginosa
add Ciprofloxacin 40 mg/kg/day po bid x 2 weeks to Tobramycin therapy
B. cepacia
add Ciproflaxacin 40 mg/kg/day po bid or Septra po bid x 2 weeks to Tobramycin therapy
3. Hospitalization
Tobramycin
80 mg nebulized tid and
3-3.5 mg/kg/dose IV q8h
Ceftazidime
150 mg/kg/day IV tid (max. 2g/dose)
Keflex or Cloxacillin po
2. Ventolin
by mask bid
4. Surgery
1. For Complications
pneumothorax, hemoptysis
meconium ileus + equivalent, meconium plug syndrome, rectal prolapse, partial or complete obstruction, appendicitis, cholethiasis, etc.
2. For Lung Transplantation
for end stage lung disease (when FEV1 is <25% normal)
about 10% of patients reach transplantation with a 50% mortality within two years of transplant
5. Experimental Therapies
1. Amiloride
1. Mechanism of Action
decreases NaCl and water absorption (diuretic)
inhibits bacterial growth (gram +)
enhances the activity of tobramycin
given by mask
2. Trials
NEJM 322: 189 (1990)
Am. Rev. Resp. Dis. 141:605 (1990)
preliminary results show less of a decline in pulmonary function with amiloride
2. DNase
1. Mechanism of Action
decreases the viscosity of sputum and thins out lung secretions
increases mucociliary transport
digests the DNA released by inflammatory cells found in the lung secretions
given by mask bid
2. Trials
2.5 mg Pulmozyme od has a minimal effect (2-4%) on pulmonary function tests and is reported to show clinical improvement (decreases dyspnea, CF-related symptoms, and hospitalized days)
side effects: anaphylaxis, hemoptysis
disadvantages: $26,000/yr/patient
3. Gene Transfer Therapy
adenovirus vectors with normal CFTR gene inserted into the genome administered to patients via an aerosol mist
also using liposomes
HUNTINGTON'S DISEASE (WESTPHAL VARIANT)
DEFINITION:
A progressive neurodegenerative disorder characterized initially by bradykinesia and rigidity then choreiform movements.
EPIDEMIOLOGY:
incidence: 5-10/100,000 (prevalance)
age of onset:
of patients with Huntingon's Disease
10% have onset of symptoms prior to 20 years of age
5% have onset of symptoms prior to 14 years of age
1% have onset of symptoms prior to 10 years of age
risk factors:
familial - autosomal dominant
father is affected in 83% of cases
chrom.#: 4p16.3
gene: Huntington Disease (HD) gene
PATHOGENESIS:
1. Background
Huntington's Disease belongs to an expanding family of disorders where the genetic mutation involves unstable trinucleotide repeats (C_G):
Disorder-Trinucleotide Repeat
Fragile X Syndrome - CGG
Myotonic Dystrophy - CTG
Huntington Disease - CAG
Kennedy's Disease - CAG
Spinocerebellar Ataxia-I - CAG
Machado-Joseph Disease - CAG
in this family of disorders, the number of repeats tends to increase with succeeding generations ("genetic anticipation")
in Huntington's Disease:
the HD gene was isolated by James Gusella's group in winter of 1993 and an unstable part of the gene was identified in the coding region characterized by numerous repeats of single trinucleotide sequences containing the bases cytosine, adenine, and guanine (CAG)
in normal individuals, there are between 9-34 CAG repeats but in those with HD, there may be between 30-100 CAG repeats
the function the the HD gene product is unknown
2. Genetic Defect
genetic defect -> amplification of the sequence of unstable trinucleotide repeats (CAG) to greater than 30 -> encodes a long tract of glutamine residues -> altered protein -> pheno-typic expression of the disease
there is a strong inverse correlation between the length of the CAG repeat and the age of onset of the disease
CLINICAL FEATURES:
1. Neurologic Manifestations
1. Initial
initially presents with bradykinesia and rigidity
may also initially present with behavioural or cognitive deterioration and poor school performance
2. Late
chorea tends to involve proximal muscle groups
associated features
50% - generalized tonic-clonic seizures
50% - cerebellar signs
20% - oculomotor apraxia
gait disturbances
more rapid course in children than in adults
average of 8 years till death (14 years in adults)
INVESTIGATIONS:
1. Diagnostic
identification of amplified CAG sequences in the HD gene of affected individuals
2. Imaging Studies
1. CT/MRI
atrophy of the caudate nucleus and frontal cortex
dilatation of the lateral ventricles
MANAGEMENT:
1. Medical
movement disorders
bradykinesia/rigidity - antiparkinsonian drugs
chorea - dopamine antagonists
behavioural problems
neuroleptics and/or antidepressants
seizure disorder
very resistant to anticonvulsant therapy
2. Supportive
genetic counselling
XXX SYNDROME
DEFINITION:
A disorder where affected females have three X chromosomes.
EPIDEMIOLOGY:
incidence: 0.3-1/1000 newborn females
age of onset:
any (with karyotyping)
risk factors:
females only
? advanced maternal age
PATHOGENESIS:
1. Background
XXX Syndrome is the most frequent X chromosomal anomaly in females
first described by P.A. Jacobs, Lancet 2:423 (1959).
also called Chromosome X, Triplo-X and Chromsome 47, XXX karyotype
2. Pathogenesis
due to parental meiotic nondisjunction (usually maternal)
the XXX Syndrome phenotype is quite variable
CLINICAL FEATURES:
1. Dysmorphisms
hypertelorism
tall stature (average height 172 cm)
widely-spaced nipples
webbed neck
2. Neurological Manifestations
variable IQ from superior to moderate-to-severe mental retardation
transient gross motor delays
speech and language delays
fine motor delays
coordination problems with awkwardness
behavioural problems
mild depression, conduct disorder, immature behaviour, socializing problems
occasionally seizures
3. Endocrine Manifestations
normal sexual development and menarche
may be some fertility problems
Mullerian anomalies
INVESTIGATIONS:
1. Karyotype
47, XXX karyotype
2. CT (Head)
occasionally mild ventricular enlargement
MANAGEMENT:
1. Supportive
Paediatrics, Endocrinology, Neurology, Psychology
genetic counselling - no XXX daughter of an XXX mother has been reported
2. Prognosis
normal life span
may need supplemental teaching for poor academic performance
DOWN SYNDROME
DEFINITION:
A chromosomal disorder resulting in a syndrome characterized by specific dysmorphic features (facies) and organ malformations.
EPIDEMIOLOGY:
incidence: 1/800 live births
75% of fetuses with Trisomy 21 abort spontaneously
most common autosomal chromosomal disorder causing mental retardation
age of onset:
newborn
risk factors:
increased maternal age (although 80% are born to mothers <35 years)
HISTORY:
1865 - John Langdon Down
first detailed description
1930 - Brewster and Cannon
first to report an association between Down's & acute leukemia
1954 - Schunk and Lehman
first to report an association between Down's & transient leukemia
1959 - Lejeune
first to associate Down's with Trisomy 21
GENETICS/PATHOGENESIS:
1. Genetics
1. Trisomy 21 (95%)
due to non-disjunction during meiosis
80-90% due to maternal non-disjunction
10-20% " paternal "
1% recurrence risk
2. Unbalanced Translocation (3-4%)
50% are sporadic (de novo)
50% are due to a balanced translocation in one parent
recurrence risk:
100% in parent with a 21:21 translocation
16% in mother with a 21:acrocentric chrom. transloca.
5% in father "
3. Mosaicism (1-2%)
due to nondisjunction after meiosis
? recurrence risk
2. Pathogenesis
trisomy of only the bottom 1/3 of chromosome 21 is sufficient to account for Down's phenotype
chrom. 21: the 800 genes in the 21q22 band appear to be those responsible for the pathogenesis
trisomy results in a 50% increased "dose" of certain proteins:
1. SOD-1
superoxide dismutase
protects cells from oxygen-containing free radicals
? role in MR and accelerated rate of aging
2. Gart
phosphoribosylglycinamide synthetase
involved in purine synthesis
? elevated purines -> mental retardation
3. Ets-2
an oncogene
? role in acute myelogenous leukemia M2
4. Amyloid Beta Protein
major component of neurofibrillary plaques
? pathogenesis in Alzheimers
5. Alpha-A-crystallin Protein
structural component of lens of eye
? role in formation of cataracts, Brushfield spots
3. Pathogenesis (of Transient Leukemia)
proposed mechanisms:
1. spontaneously remitting leukemic clone
2. stress (infections, CHD, etc.) -> over reaction of myeloid elements
3. delay in WBC differentiation which resolves spontaneously as maturation progresses post-natally
4. ineffective regulation of myeloporesis due to delayed maturation of the myeloid and other bone marrow elements
CLINICAL FEATURES:
1. Principle Clinical Features in the Newborn (Clin Peds 5:4 (1966))
100% contain at least 4 of these
89% contain at least 6 of these:
flat facial profile (90%)
poor Moro reflex (85%)
infantile hypotonia (80%)
hyperflexibility of joints (80%)
excess skin on neck (80%)
slanted palpebral fissures (80%)
dysplasia of pelvis (70%)
anomalous auricles (60%)
dysplastic 5th midphalanx (60%)
45 simian crease (45%)
2. Diagnostic Index (J. Peds. 100(6): 903 (1982))
1. Dermatoglyphic Traits
hallucal pattern
forefinger pattern
palmar triradius
2. Physical Traits
ear length
internipple distance ratio
3. Clinical Findings
wide-spaced first toe
excess skin on back of neck
brushfield spots
3. Neurologic Manifestations
1. Hypotonia (100%)
at birth, in infancy, and as a toddler
may delay motor milestones but improves with age
2. Seizures (5-10%)
generalized, myoclonic most common type
3. Learning Disabled
borderline to moderate IQ range (from 80 -> 40)
processing problems:
better at visual than auditory processing
better at simultaneous than sequential processing
4. Global Developmental Delays
gross motor due to hypotonia
fine motor "
speech and language delay
75% have an expressive language disability
behavioural problems
aggression, depression, inappropriate
5. Alzheimers
may affect 15-20% of adults with Down's
mean age of onset is 51 years (range 46-57 years)
4. Respiratory Manifestations
increased incidence of pulmonary hypoplasia and elevated pulmonary vascular resistence (+/- congenital heart defects) may lead to an increased risk of:
respiratory tract infections
acute and chronic airway obstruction
sleep apnea (small airways, large tonsils/adenoid, obesity)
cor pulmonale
5. Cardiovascular Manifestations (40%)
1. Structural Anomalies
1. Endocardial Cushion Defects
complete AV canal (49%)
VSD (22%)
ASD(secundum)- 14%
ASD(primum) - 8%
2. Others
3 PDA (3%)
ToF (3%)
AV valve malformation (prolapse)
aberrant subclavian artery
2. Complications
elevated pulmonary blood flow -> irreversible pulmonary hypertension -> cor pulmonale
structural anomalies and complications are usually detected in the newborn period or in the first 6 weeks of life
6. Gastrointestinal Manifestations (12%)
1. Structural anomalies
duodenal atresia most common problem (+/- polyhydramnios, double bubble)
others: TEF, annular pancreas, Meckel's diverticulum, Hirschsprung's disease, imperforate anus
2. Complications
vomiting (bilious), constipation, failure to thrive, feeding difficulties and intolerance
structural anomalies and complications are usually detected in the newborn period or in the first 6 weeks
7. Genitourinary Manifestations
1. Structural Anomalies
1. Kidney Malformation
uteropelvic junction (UPJ) obstruction with hydro-nephrosis
alterations in structure or maturation of parenchymal structures
2. External Genitalia Malformation
25-50% of males have hypospadias
5% of males have undescended testes
small penis and scrotum
8. Hematologic Manifestations
1. Leukemia
risk is 10-30x that of general population
in newborns AML > ALL (2-4:1)
in children ALL > AML (2:1)
2. Transient (Congenital) Leukemia
presence of a large number of blasts (megakaryoblasts) in the peripheral blood
may be variable leukocytosis +/- thrombocytopenia +/- anemia
clinically may be associated with lymphadenopathy and/or hepatomegaly/hepatosplenomegaly
100% spontaneous remission rate within 1st weeks of life
occurs exclusively in Down's (82% in newborn period)
some cases may give rise to acute megakaryoblastic leukemia (AMKL) or other forms of leukemia during the first 3 years
- diagnosis is retrospective
3. Autoimmune Disorders
higher than average likelihood of developing:
thyroiditis
alopecia areata (in 10-15%)
diabetes mellitus
rheumatoid-type arthropathy
autoimmune hemolytic anemia
9. Endocrine Manifestations
1. Thyroid Dysfunction (15%)
1. Hypothyroidism
often due to lymphocytic thyroiditis
most present after the 1st decade
may appear in conjunction with diabetes mellitus, pre-cocious sexual maturation or hypoparathyroidism - may have congenital hypothyroidism
hyperthryoidism & euthyroid thyroiditis can also occur
2. Growth Disorders
1. Short Stature
both M & F at or near the 3rd % of general population
diminished growth velocity can occur at a variety of times (i.e., decreased adolescent growth spurt)
there are specific growth charts for Trisomy 21
2. Obesity
especially at 2-3 years, 12-13 years, and in adult life
a common problem
3. Sexual Maturation and Development
1. Males
normal but fertility very rare
25-50% have undescended testes
5% have hypospadias
testes may be histologically abnormal
2. Females
normal sexual maturation and development
menstruation
normal age of onset (no delay in onset of puberty)
normal menses
fertility
definite ovulation in 40%, probable in 15%, possible in 15%
abnormal follicular development is common
pregnancy is possible with a 50% chance of Trisomy
21 occurring in the infant
10. Dermatologic Manifestations
1. Dry Skin (90%)
with secondary itching, eczema, and infections (i.e., recur-rent follicular skin infections)
2. Syringomas
benign sweat gland tumors
F > M; onset at beginning of puberty
yellow or skin-coloured, soft 2-3 mm raised papules occur-ring singly or in groups
most commonly found around eyes but also on neck and thor-acic, axillary, umbilical, and pubic areas
3. Others
alopecia areata (in 10%)
rapid aging of skin
increased risk of sunburn
11. Musculoskeletal Manifestations
1. Cervical Spine Problems
1. Atlantoaxial Instability (14%)
incidence: 1/3000
2. Spinal Cord Compression (1-2%)
with persistent neck pain, loss of bladder or bowel control, changes in sensation, long tract signs
2. Others
bony anomalies of the cervical spine
subluxation or dislocation of hips and/or knees
pronation of feet at ankles, pes pannus, short broad hands, short sternum, decreased acetabular and iliac angle (CDH, dysplastic hips), see "Clinical features in Newborn"
hypotonia & ligamentous laxity predisposes to these problems
12. Ocular Manifestations
1. Major
congenital nystagmus or alternating esotropia
congenital cataracts and glaucoma
60% with strabismus
50% with refractive errors
2. Minor
epicanthal folds, oblique palpebral fissures
blepharitis, keratoconus, Brushfield spots
13. Oral and Dental Manifestations
delays and alterations in the sequence of tooth eruption
100% with malocclusions (mandibular overjet, post. cross bite)
60% with relative macroglossia
50% with missing teeth
37-60% with fissuring tongue, enlargement of vallate papillae
14. Otorhinolaryngologic Manifestations
1. Recurrent Otitis Media
75% with sensorineuronal conductive hearing loss due to an accumulation of fluid in the middle ear space
2. Midface Hypoplasia
nasolacrimal duct obstruction (in 20%)
obstructive sleep apnea
sinusitis and purulent rhinitis
INVESTIGATIONS:
1. Prenatal Screening/Diagnosis
chorionic villus sampling at 9-12 weeks
amniocentesis at 16-18 weeks
indications for:
advanced maternal age (>35 years)
previous child with Trisomy 21
balanced translocation in parent
prenatal U/S findings suggestive of Trisomy 21
altered maternal serum markers
decreased alpha fetoprotein
" human chorionic gonadotropin
" unconjugated estriol (uE3)
2. Imaging Studies
1. Cardiac
2D-Echo, chest x-ray, EKG
2. Gastrointestinal
abdominal x-ray, barium swallow/enema
3. Renal
renal ultrasound
4. Skeletal X-Rays
bone age for short stature
C-spine - an atlanto-dens space >5 mm is suggestive of atlantoaxial instability
sinusitis
3. Serum
compensated respiratory acidosis (due to COPD)
elevated urea, creatinine, uric acid, decreased creatinine and uric acid clearance
CBC with blasts
TSH, T3, T4, thyroid antibodies
? GH stimulation tests
4. Others
EEG (hypsarrhythmias)
MANAGEMENT:
1. Neurologic Manifestations
1. Seizures
Neurology consult, EEG, anticonvulsant medications
2. Learning Disabilities
teaching methods which emphasize visual over auditory information
3. Developmental Delays
early intervention
gross/fine motor - physiotherapy
speech/language - total communication techniques (signing or computers), speech therapy, special education
behaviour - mental health assistance, family counsel
2. Respiratory Manifestations
1. Sleep Apnea
decrease weight, repositioning during sleep, nasal CPAP, remove tonsils and adenoids
2. Cor Pulmonale
early surgical correction of congenital heart disease (CHD)
3. COPD
bronchodilators/steroids
3. CVS Manifestations
all Down's patients should have a Cardiology consult and an echo done within the first few weeks of life
surgical correction of CHD
4. Gastrointestinal Manifestations
surgical correction of malformations
treat functional problems, i.e., constipation
feeding team for problems
5. Genitourinary Manifestations
follow serum urea, creatinine, uric acid
follow uric acid and creatinine clearance rates
? role of imaging studies for screening for anomalies
surgical correction of hypospadia, undescended testes
6. Hematologic Manifestations
1. Leukemia
state of the art therapy noting increased risk of infec-tion and sensitivity to anti-folate chemotherapy
lower remission rate and a higher mortality with ALL in
Down's than general population
similar remission rate and mortality with AML in Down's and general population
2. Transient Leukemia
moniter blasts in peripheral blood
spontaneous remission but risk of leukemia (ie. AMKL)
3. Autoimmune Disorders
screen for manifestations i.e., TSH, blood sugar
? role of pneumococcal and influenzae vaccines
7. Endocrine Manifestations
1. Thyroid
screen for clinical s/s of hypothyroidism (dry hair/skin, lethargy, cold intolerance, constipation, hoarse voice)
screen TFT (TSH, T3, T4) annually +/- thyroid antibodies
2. Growth
moniter growth on charts for Down's
true GH deficiency is rare but may respond to GH supplements
obesity - caloric restriction, increase activity/exercise
3. Reproduction
birth control and reproductive health issues need to be addressed (i.e., sterilization)
8. Dermatology Manifestations
moisturizers, hypoallergenic creams for dry skin
steroid creams for eczema
topical or systemic antibiotics for infection
preventive measures to avoid sunburn
topical steroids, minoxidil for alopecia areata
9. Musculoskeletal Manifestations
1. C-Spine
see the Canadian Down's Society Guidlines
initially assessed at 2-4 years and repeated between 8-10 years
earlier assessment if indicated - neurologic findings:
loss of motor skills
asymmetric hypertonicity in lower limbs
increased clumsiness or tripping
widely-spaced stiff-legged gait
any upper motor neuron signs
loss of fine motor skills
torticollis, neck pain, headaches
if abnormal then must restrict activities - tumbling, div-ing, butterfly, collision sports
2. Spinal Cord Compression
may require surgical stabilization (skeletal fixation) of cervical spine
ortho, neuro, neurosurg consults
10. Ocular Manifestations
initial screen should occur in early infancy with follow-up at
18 months and 5 and 15 years
11. Oral and Dental Manifestations
routine preventive dental care
relative macroglossia may be corrected by oral or plastic sur-gery if indicated
12. Otorhinolaryngologic Manifestations
audiologic evaluation by sound field testing or auditory brain-stem responses (ABR) should begin at 6 months and be repeated q6-12m during the preschool years
antibiotics for recurrent OM, sinusitis, or purulent rhinitis
myringotomy tubes for recurrent otitis media (OM)
13. Genetics
genetic counselling if plans for another child
80% survive to age 30 or beyond
HEMOPHILIA
DEFINITION:
A coagulation disorder characterized by a deficiency in Factor VIIIc resulting in a bleeding diathesis.
EPIDEMIOLOGY:
incidence: 1/10,000 (80-85% of Hemophilias)
age of onset:
newborn (severe) -> childhood (mild)
risk factors:
familial - x-linked recessive
chrom.#: Xq28
gene: coagulation factor VIIIc
PATHOGENESIS:
1. Background
Factor VIII is a complex of two components each with different genetic control and biochemical functions:
1. Factor VIIIc - coagulation protein
2. Factor VIIIvW - platelet adhesion protein
Factor VIIIc is the final component of the Intrinsic Pathway and in the presence of activated Factor IX, activates Factor
X within the Common Pathway
Factor VIIIc is complexed with Factor VIIIvW, the latter acting as a carrier protein
in Hemophilia A, the plasma levels of Factor VIIIvW are normal
female carriers and male fetuses in utero have a Factor VIIIc/Factor VIIIvW ratio less than 1 (normally this ratio is equal to 1)
2. Genetic Defect
genetic defect -> deficiency of Factor VIIIc -> clinical severity related to the level of Factor VIIIc:
1. Severe
Factor VIIIc activity is < 1% of normal
onset of bleeding in the newborn period
Factor VIIIc does not cross the placenta
hematomas after injections or circumcision
hemarthroses and deep tissue hemorrhages
bleeding may be spontaneous
clinical evidence of increased bleeding in 90% of these patients by 1 yr of age
2. Moderate
Factor VIIIc activity is 1-5% of normal
onset of bleeding during infancy
excessive bruising with ambulation
some arthrosis
bleeding may be spontaneous but usually following mild to moderate trauma
3. Mild
Factor VIIIc activity is > 6% of normal
onset of bleeding during childhood
bleeding is not spontaneous and follows moderate to severe trauma, dental work, or surgery
CLINICAL FEATURES:
1. Common Sites of Hemorrhage
1. Hemarthrosis
hallmark of Hemophilia
elbows, knees, and ankles
pain, swelling, limited range of motion of affected joint
2. Muscle Hematomas
pain, swelling, may produce muscle atrophy
3. Mucous Membranes
mouth, teeth, nose (epistaxis), gastrointestinal
4. Hemorrhage Causing Peripheral Nerve Lesions
femoral - iliopsoas
sciatic - buttock
tibial - calf
perineal - anterior leg compartment
median and ulner - forearm flexors
5. High Risk Hemorrhages
intracranial, intraspinal
retropharyngeal
retroperitoneal
6. Hematuria
INVESTIGATIONS:
1. Serum
prolonged PTT
decreased Factor VIIIc
normal PT, bleeding time, thrombin time, platelet count, Factor
VIIIvW
MANAGEMENT:
1. Supportive
avoid trauma and anticoagulants (i.e., ASA)
pad crib and playpen
pressure and cold compresses to bleeding sites
initially immobilize affected area then passive exercises within 48 hrs to prevent stiffness and fibrosis
immunize against hepatitis B
2. Replacement Therapy
1. Principles
to increase Factor VIIIc activity in order to secure hemostasis
ordinary hemostasis
raise Factor VIIIc activity to 50% of normal and maintain activity above 5% for 48-72 hrs
may use e-aminocaproic acid (Amicar) and desmopressin (DDAVP) to raise Factor VIIIc activity
high risk hemorrhages
raise Factor VIIIc activity to 50% of normal for 2 wks
2. Cryoprecipitate
inexpensive
prepared from fresh plasma - risk of HIV and Hepatitis C
1 bag/5 kg body weight increases the recipients Factor VIIIc level to 50% of normal
3. Factor VIIIc Concentrate
expensive
dispensed as a lyophilized powder in bottles of 250-500 units
1 unit/kg IV raises the Factor VIIIc activity by 2%
contain anti-A and anti-B isohemagglutinins so recipients with blood groups A or B may respond with massive hemolysis
4. Hemophilia with Factor VIIIc Inhibitors
massive doses of Factor VIIIc concentrate
plasmapheresis with replacement of Factor VIIIc
Factor IX concentrates
porcine Factor VIII
ZELLWEGER'S SYNDROME
DEFINITION:
A disorder of peroxisomes characterized by the congenital absence of functioning peroxisomes resulting in a cerebrohepatorenal syndrome.
EPIDEMIOLOGY:
incidence: rare
age of onset:
newborn
risk factors:
familial - autosomal recessive
chrom. #: 7q11.23
gene: ?
M = F
PATHOGENESIS:
1. Group 1 Peroxisomal Disorders
thought to be a group of disorders of peroxisome biogenesis where the primary defect involves the import mechanisms of matrix enzymes
the peroxisomes in these disorders are not entirely absent but consist of empty membrane "ghosts" (these membranes contain the 3 integral membrane proteins specific to peroxisomes)
this results in abnormalities of peroxisomal function secondary to the failure of multiple peroxisomal enzymes:
1. Anabolic Dysfunction
decreased plasmalogen
increased bile acid intermediates
2. Catabolic Dysfunction
increased catalase (in the cytosol)
increased VLCFA
increased phytanic acid
increased L-pipecolic acid
2. History
Bowen et al., (1964)
first to describe Zellweger's Syndrome
Goldfischer et al., (1973)
first to establish a connection between the absence of peroxisomes and Zellwegner's Syndrome
CLINICAL FEATURES:
1. Typical Facies
epicanthal folds
high forehead
hypoplastic supraorital ridges
upslanting palpebral fissures
2. Neurologic Manifestations
severe infantile hypotonia
neonatal seizures
limited psychomotor development
3. Ophthalmologic Manifestations
corneal clouding
Brushfield spots
cataracts
glaucoma
optic nerve dysplasia
pigmentary retinopathy
4. Cardiovascular Manifestations
VSD (32%)
aortic anomalies (22%)
5. Gastrointestional Manifestations
cholestasis +/- fat malabsorption due to paucity of the intrahepatic bile ducts
hepatomegaly
INVESTIGATIONS:
1. Diagnostic (Biopsy)
the presence of peroxisomal "ghosts" in the liver, kidney, and cultured skin fibroblasts
2. Pathology
1. Central Nervous System
striking & characteristic disorder of neuronal cell migration involving the cerebral hemispheres, cerebellum, and inferior olivary nucleus
2. Liver
enlarged (78%), fibrotic (76%), micronodular cirrhosis (37%)
excessive iron deposits early
3. Renal
cysts (78%) - vary from glomerular microcysts to large cortical cysts of glomerular and tubular origin
4. Adrenal Gland
cytoplasmic lamellar inclusions
3. Imaging Studies
1. Skeletal X-Rays
calcific stippling of the patella and acetabular synchrondosis (50%)
2. CT/MRI
agenesis of the corpus callosum
MANAGEMENT:
1. Classic Zellweger syndrome
1. Supportive
no treatment for underlying disorder
multidisciplinary approach
Paediatrics, Neurology, Ophthalmology, Cardiology, etc
genetic counselling
2. Prognosis
rarely live more than a few months (mean = 12.5 weeks)
2. Milder Forms
1. Supportive
multidisciplinary early intervention
oral administration of plasmalogens
restricted phytanic acid intake
OT, PT, hearing aids, nutrition
NOONAN SYNDROME
DEFINITION:
A disorder of unknown etiology with phenotypic features similar to those of Turner Syndrome.
EPIDEMIOLOGY:
incidence: 1/1,000-1/2,500 live births
age of onset:
newborn
risk factors:
familial - autosomal dominant with variable expression (sporadic cases thought to represent de novo mutations)
chrom.#: ?
gene: ?
M = F
PATHOGENESIS:
1. Etiology
unknown, but may be similar to that hypothesized for Turner Syndrome
genetic defect -> lymphangiectasia during a critical period in perinatal development -> disruption of normal tissue migration and organ placement by lymphedema -> Noonan phenotypes
in support of this hypothesis, cystic hygromas and edema have been detected prenatally in suspected cases
CLINICAL FEATURES:
1. Craniofacial Dysmorphisms
1. Newborn
hypertelorism with down-slanting palpebral fissures (95%)
deeply-grooved philtrum (95%)
low-set posteriorly-rotated ears with thick helix (90%)
low posterior hairline (55%)
high-arched palate (45%)
micrognathia (25%)
2. Infancy
large head with turricephaly
hypertelorism with prominent eyes and level palpebral fissures
thick-hooded eyelids or ptosis
nose with depressed root, wide base, and bulbous tip
3. Childhood
face appears coarse or myopathic then triangular
neck lengthens accentuating the webbing
4. Adolescence
eyes less prominent
nose with pinched root, wide base, and thinner higher bridge
5. Adult
prominent nasolabial folds
high anterior hairline
transparent wrinkled skin
2. Organ Malformations
1. Central Nervous System Manifestations
articulation abnormalities (72%)
mild-moderate mental retardation (33%)
gross motor developmental delay (25%)
speech and language developmental delay (20%)
mild hearing loss (12%)
2. Cardiovascular Manifestations
1. Congenital Heart Malformations (66%)
pulmonary valve stenosis (50%)
ASD (10%)
asymmetric septal hypertrophy (10%)
3. Endocrine Manifestations
1. Short Stature
birth: 40% have a normal birth weight
infancy: 40% failure to thrive
infancy -> puberty: 60% grow along the 3rd% with a normal growth velocity
adolescence : growth spurt reduced or absent
adult (untreated) : short stature (lower limit of normal)
2. Fertility
1. Males
60% have cryptorchidism (usually bilateral) -> deficient spermatogenesis
small testes
delayed and/or inadequate development of secondary sexual characteristics
2. Females
normal or delayed development of secondary sexual characteristics
normal fertility
the 3x greater maternal transmission of the gene over male transmission is thought to be due to male infertility due to crytorchidism
4. Musculoskeletal Manifestations
pectus carinatum superiorly with pectus excavatum inferiorly (70%)
cubitus valgus (50%)
dental malocclusion (35%)
clinobrachydactyly with blunt finger-tips (30%)
vertebral/sternal anomalies (25%)
5. Other Manifestations
1. Ocular
keratoconus, myopia
strabismus, nystagmus
2. Hematology (20%)
various bleeding anomalies - platelet dysfunction, Factor XI Deficiency, von Willebrand Disease
3. King Syndrome
Noonan phenotype + malignant hyperthermia
INVESTIGATIONS:
1. Karyotype
normal: male (XY), female (XX)
2. Imaging Studies
2D Echo, ECG
Skeletal X-rays
3. Serum
CBC, Factors XI, VIIIwW
MANAGEMENT:
1. Supportive
multidisciplinary approach
Paediatrics, Cardiology, Endocrinology, Orthopedics,
Ophthalmology, Hematology
2. Surgery
for cryptorchidism
