Mode of inheritance in achondroplasia?
Autosomal dominant IRL 75% of patients are de novo mutations
Mode of inheritance in Marfans?
What is the classical x-ray finding in achondroplasia?
Rhizomelic shortening of the limbs Trident hands Normal length trunk ie: proximal bone shortening of femur and humerus with normal distal limbs
What gene is involved in achondroplasia?
How do you diagnose achondroplasia?
Clinically! Only sequence the gene if in doubt or atypical case
Name the most common and most serious complications in achondroplasia
lumbosacral spinal stenosis is the most common other common: delayed motor milestones, otitis media, bowing of the lower legs, GERD, sweating, snoring, lumbar lordosis serious: hydrocephalus, craniocervical junction compression, restrictive pulmonary disease, upper airway obstruction, thoracolumbar kyphosis
Can achondroplasia be diagnosed antenatally?
Yes, there can be limb foreshortening on ultrasound but before counselling a parent confirm with molecular testing of the FGFR3 gene as the bone findings are non-specific
What should every infant with achondroplasia be evaluated for?
Unexpected infant death secondary to central apnea from compression of the arteries at the level of the foramen magnum: CT or MRI, polysomnography, careful neurologic histories and physical exams always put infant in a seat or carrier that supports their neck and back, minising uncontrolled head movement
What is the most common fatty acid oxygenation disorder?
MCAD Medium Chain AcylCoA Dehydrogenase Deficiency (autosomal recessive)
What is the typical presentation of MCAD?
Episodes of acute illness triggered by prolonged fasting: hypoketotic hypoglycemia with no or minimal metabolic acidosis -hepatomegaly with fat deposition, transaminitis and synthetic defects, including build-up of ammonia
What is the prognosis of MCAD?
Excellent if they avoid prolonged fasting and hypoglycemia; no cognitive impairment or cardiomyopathy. Fasting tolerance increases with age, some have muscle pain and reduced exercise tolerance. SCREEN SIBLINGS since as many as 35% of affected patients never have an episode
What are common organic acidemias and how do they present?
Maple syrup urine disease Methylmalonic acidemia Propionic acidemia Isovaleric acidemia (sweaty feet) They present with metabolic acidosis + ketosis, neutropenia, hyperammonemia with CEREBRAL EDEMA Stop catabolism, don't give leucine/isoleucine/valine, patient may require dialysis. TEST urine organic acids (aka organic acidURIAs = urine)
How does MSUD present?
within first few days of life with hypoglycemia, ketones, metabolic acidosis and hyperammonemia correction of blood glucose does not correct the condition!
How do urea cycle defects present? Which is the most common?
Hyperammonemia and respiratory alkalosis after a high protein diet or catabolic state. Ornithine Transcarbamylase Deficiency is the most common
What tests to perform on T21 at birth?
confirmatory karyotype CBC, TSH Echo cataract & hearing screens
What tests to perform on T21 at 6 months, 12 months and then annually?
CBC, TSH ophtho hearing
When do you do cervical spine x-rays in a T21 patient?
At 3-5 years or when participating in contact sports OR if symptomatic
When do you do a celiac screen in a T21 patient?
At 2 years or if they are symptomatic!
When do you do a sleep study in a T21 patient?
By 4 years old
What are the classic findings of galactosemia?
Eyes (cataracts) Liver (substrate buildup and direct bili *jaundice) Kidneys (RTA) Brain (mental retardation) **increased risk of E. coli sepsis screen for with urine reducing substances confirm with GALT
How to diagnose galactosemia?
The demonstration of nearly complete absence of galactose-1-phosphate uridyl transferase (GALT) activity red blood cells (RBCs) is the gold standard for diagnosis
What is the treatment for galactosemia?
How to diagnose Klinefelters?
What's particular about puberty in Klinefelters?
Puberty occurs at the normal age, but the testes remain small. Patients develop secondary sex characters late; 50% develop gynecomastia. Tall stature.
What to do with a positive PKU screen?
diagnosis should be confirmed by quantitative measurement of plasma phenylalanine concentration
Findings of a patient with PKU?
mousy odor normal at birth, vomiting develops profound mental retardation/seizures/spasticity/hyperreflexia/tremors
What is the breakdown of T21 etiologies and why do we care?
95% classic SPORADIC T21 (1% recurrence) 4% Robertsonian (translocation 21-21 100% recurrence, otherwise variable 5-7%) 1% Mosaicism
What two features characterize Schwachman-Diamond?
exocrine pancreatic insufficiency cytopenias also short & small(<3rd% x2), skeletal & dental abnormalities
What are characteristics of fetal hydantoin syndrome?
Limb: small, absent nails, hypoplastic distal phalanges, altered palmar creases, digital thumb, dislocated hip Craniofacial: hypertelorism, wide fontanelle, broad nasal bridge, low hair line, coarse scalp hair, broad alveolar ridge, short neck, metopic ridging, microcephaly, cleft lip & palate, abnormal ears, epicanthal folds, ptosis, coloboma About 10% of infants will have a major malformation, 30% have minor abnormalities.
What is the mode of inheritance in PKU?
What is osteopetrosis?
RARE autosomal recessive disorder in the acidification required for osteoclast function presents with macrocephaly, HSM, deafness, blindness, severe anemia, FTT, delay. Commonly have fractures, osteomyelitis, dental problems x-rays with bone-within-bone appearance
What are clinical features of Fragile X?
macrocephaly macroorchidism long and narrow face with prominent forehead and chin (prognathism), large ears joint hyperlaxity MVP
What is Waardenburg Syndrome?
Syndrome with depigmented areas of skin and hair deafness occurs in 9-37% of heterochromia irides +/- Hirschsprung in type IV
What's the metabolic cocktail?
In suspected inborn errors of metabolism, mega doses of cofactors can be started and have been found to be effective for a number of disorders: Cobalamin (B12) Thiamine (B1) Biotin Riboflavin Folic Acid Carnitine
What is the classic cardiac finding in Turner's?
Left ventricular outflow tract abnormalities: Bicuspid aortic valve Aortic stenosis Coarctation of the aorta MVP
What are the classic findings in William's syndrome?
Elfin face Cocktail personality Developmental delay Heart disease Idiopathic hypercalcemia hypotonic, small, poor feeders at birth
What is the classic heart finding in Williams?
Supravalvular aortic stenosis
What is the classic heart finding in Di George?
Tetralogy of Fallot Also truncus arteriosus, interrupted aortic arch, double outlet RV
What are the classic findings in Di George?
CATCH-22 Congenital heart disease Abnormal face Thymic aplasia or hypoplasia Cleft palate Hypocalcemia 22q11 microdeletion
What a psychiatric comorbidities associated with Fragile X?
Anxiety 70-100% ADHD 80% Autism 20-30%
What are the features of homocystinuria?
Mental retardation Marfanoid habitus Downwards lens dislocation Strokes diagnosed by elevated levels of methionine and homocystine
What are features of cystinosis?
accumulation of the amino acid cystine within cells: the kidneys (**renal Fanconi syndrome) and eyes are especially vulnerable to damage; the muscles, thyroid, pancreas, and testes may also be affected.
How does alpha-1 antitrypsin usually present in pediatrics?
liver disease: jaundice, acholic stools, hepatomegaly little or no pulmonary findings to be detected in childhood
What are adrenoleukodystrophies and how do they present?
X-linked recessive - boys present between 5 and 15 with academic difficulties, behavioural disturbances, gait abnormalities - accumulation of VLCFA in neural tissue and adrenals resulting in hypoadrenalism
What is MELAS and how does it present?
Mitochondrial myopathy, encephalopathy, lactic acidosis, stroke-like episodes normal development and then stepwise deterioration with stroke like episodes and exacerbations in almost all by 15 years old
Give an example of a gangliosidoses and features of the disease
Neurodegenerative disorder of childhood Autosomal recessive example: Tay Sachs
What is Hurler syndrome? What is the mode of inheritance?
Mucopolysaccharidoses type 1; a lysosomal storage disease. They're born looking okay but as GAGs accumulate they get sicker: frequent URTI, failing growth, coarse facial features, CVS, CORNEAL CLOUDING, hepatosplenomegaly, hernias and bone disease +/- CNS involvement autosomal recessive
What is Hunter syndrome? What is the mode of inheritance?
Mucopolysaccharidoses type 2; very similar to Hurler but x-linked and later onset (one to two years of age), slower clinical course, and absence of corneal clouding. Distinctive pearly papular skin lesions over the scapulae and on the lateral upper arms and thighs develop in some Hunter patients
What is San Filippo syndrome and its mode of inheritance?
Autosomal recessive Usually present at two to seven years of age with developmental delay and behaviour problems, including hyperactivity and aggression; physical findings similar but more subtle than other MPS with coarse facial features, HSM, hernias
What is Morquio syndrome?
MPS IV; Loic skeletal dysplasia and smart
Lactic acidosis is a feature of what?
defects in glycogenolysis or gluconeogenesis as in glycogen storage disease type 1 or Von Gierke
How does Von Gierke present?
hypoglycemia, lactic acidosis, hyperuricemia and hyperlipidemia commonly at 3-4 months of age with hepatomegaly and hypoglycemic seizures *type 1b has recurrent bacterial infections
Name features of Trisomy 13
cutis aplasia, cleft lip and palate, holoprosencephaly, CHD, microophthalmia, abdominal wall defects
Name features of Trisomy 18
micrognathia and microcephaly, narrow features, dysplastic/malformed ears, rocker bottom feet, clenched hands, CHD
What is the phenotype of Noonan syndrome? Other findings?
Webbing of neck with low posterior hairline, pectus, edematous hands and feet, cryptorchidism *lower IQ *ptosis CVS: *PV stenosis, *HOCM, ASD, ToF, Coarct, MV anomalies bleeding diathesis short stature- postnatal in 50% *RARE renal abN (*=differences with Turners)
Associated conditions with Turner's?
Renal malformations in (>50%) and hypertension, Autoimmune: Celiac disease, DM, hypothyroid (30-50%), Streak ovaries, Eyes and ears, Heart disease (LVOT), **do genetic testing to verify if mosaicism including Y chromosomal material --> gonadoblastoma (therefore to be removed)
What is type 2 glycogen storage disease?
Pompe disease: lysosomal glycogen accumulation in multiple tissues and cell types, with cardiac, skeletal, and smooth muscle cells being the most seriously affected hypotonia, macroglossia, hepatomegaly, HCM
What is the triad of Sturge Weber?
1) port wine stain (aka leptomeningeal angioma) 2) abnormal blood vessels of the brain 3) abnormal blood vessels of the eye leading to glaucoma
How do patients with Sturge Weber present?
V1 port-wine stain (8-33% with stain have S-W) seizures hemiparesis stroke-like episodes headaches developmental delay
List features of Pierre-Robin sequence
micrognathia glossoptosis (displacement of tongue to pharynx) cleft palate
Name 4 hematological disorders associated with T21
Myeloproliferative disorders Acute megakaryoblastic leukemia Acute lymphoblastic leukemia Iron deficiency anemia
What is the genetic issue with Prader Willi?
Maternal UniParental Disomy (missing the paternal chromosome 15) or maternal imprinting (MOTHER'S AMPLIFIED)
What is the genetic issue with Angelman syndromes?
Paternal UniParental Disomy of chromosome 15 or paternal imprinting (DAD'S AMPLIFIED)
Name clinical findings with Prader Willi
Hypotonia, Hyperphagia, Hypogonadism, Obesity, Short stature (responsive to growth hormone) Small hands and feet, Almond eyes, Mental retardation IQ 60-70, Behavioural problems
Name clinical findings with Angelman
ataxia, "happy puppet”, inappropriate laughter, poor or absent speech, severe mental retardation, hypotonia, feeding difficulties, GE reflux, fair hair and skin, midface hypoplasia, prognathism, seizures, tremors, sleep disturbances
Any special implications for family members of Fragile X?
Yes! Screen them, according to AAP, if an early diagnosis might favour early intervention or treatment.
Name 7 features of NF1 How many are required for diagnosis?
1) >/= 6 cafe au lait macules >5mm big or >15mm in postpubertal 2) axillary or inguinal freckling 3) Lisch nodules 4) neurofibroma or plexiform neurofibroma 5) osseous lesion ie: spenoid dysplasia, cortical thinning long bones 6) optic glioma 7) 1st degree relative with NF1 need at least two for diagnosis
Pigmented hamartomas of the iris
Rocker bottom feet with T18
note: cubitus valgus, lack of secondary sexual characteristics, widely spaced nipples, webbed neck, short stature
V1 angiofibroma think Sturge Weber
Elfin face in William's syndrome
Cornelia De Lange Syndrome
Synophrys (unibrow), Thin Downturning Upper Lip, Micromelia (abnormally shortened limbs)
lots of GE reflux, malrotation
-proximal femoral lucency, rhizomelic shortening, trident hands, thoracolumbar kyphosis
Coast of Maine cafe au lait
Polyostotic fibrous dysplasia
Brushfield spots T21
cleft lip / palate
rocker bottom feet
clenched hand and fingers
small head and jaw
Hypohydrotic ectodermal dysplasia
X-linked dominant genodermatosis that is usually lethal in males in utero
gene disorder: IKBKG/NEMO
four stages of variable duration: vesicular, verrucous, hyperpigmented, and atrophic/hypopigmented. Lesions are typically distributed along the lines of Blaschko on the trunk and extremities.
Cornelia de Lange
Name three amplification syndromes
Name clinical findings in Williams
(microdeletion chr7) friendly cocktail personality, supravalvular aortic stenosis, Intellectual Disability, hypercalcemia
Describe Alagille syndrome
Autosomal dominant, triangular face, bile duct paucity with cholestasis, pulmonary valve stenosis, butterfly vertebrae, posterior embrotoxin on the eye
Features of Di George syndrome?
22q11.2, Cleft palate, Absent thymus=immune deficiency, Congenital heart disease (ToF, interrupted Ao Arch), Hypoparathyroidism=hypocalcemia, short stature