Patterns of Inheritance
Autosomal Dominant
There is no skipping of generations.
Males and females have an equally likely chance of
inheriting the mutant allele and being affected.
The recurrence risk of each child of an affected parent
is 1/2.
Normal siblings of affected individuals do not transmit
the trait to their offspring.
The defective product of the gene is usually a
structural protein, not an enzyme
Autosomal Recessive
Males and females are equally likely to be
affected.
On average, the recurrence risk to the
unborn sibling of an affected individual is
1/4.
The trait is characteristically found in
siblings, not parents of affected or the
offspring of affected.
Parents of affected children may be related.
The rarer the trait in the general population,
the more likely a consanguineous mating is
involved.
GIVE AN EXAMPLE OF SPECIFIC X LINKED
DOMINANT DISORDERS
X-Linked Dominant
The trait is never passed from father to son
All daughters of an affected male and a
normal female are affected. All sons of an
affected male and a normal female are normal.
Matings of affected females and normal males
produce 1/2 the sons affected and 1/2 the
daughters affected.
Males are usually more severely affected than
females. The trait may be lethal in males.
In the general population, females are more
likely to be affected than males, even if the
disease is not lethal in males.
•Pseudohyperparathyroidism
•Vitamin D resistant rickets
X-Linked
•Aicardi
syndromeRecessive
•Missing corpus callosum
•Alport
syndrome
As
with any
X-linked trait, the disease is never
passed•Renal
from father
to son.
disease
•SN hearing loss
Males are much more likely to be affected than
•Cataracts
females.
If affected males cannot reproduce,
only males will be affected.
All affected males in a family are related
through their mothers.
Trait or disease is typically passed from an
affected grandfather, through his carrier
daughters, to half of his grandsons.
Remember Punnett Squares?
• Here’s the scenario:
– A teenage girl who’s brother has CF wants to
know her risk for being a CF carrier
Mom 
Dad
↓
A
a
A
AA
Aa
a
Aa
aa
So her risk of being a carrier is 2/3!
Question Time
• Advanced maternal age suggests what kind of
genetic abnormality?
– Chromosomal
• Advance paternal age suggests what kind of
genetic abnormality?
– Autosomal dominant (mutation)
Is it a…
•
•
•
•
•
•
Disruption
Deformation
Malformation
Dysplasia
Sequence
Association
• Club foot
• Clefting, constriction
bands and limb
reduction defects
• Potters facies
• Achondroplasia
• Requires surgical
intervention
• CHARGE
• Pierre Robin
Images
Name the Dysmorphic Feature
Brachydactyly
Clinodactyly
Low-set ears & flat occiput
Simian crease
Brushfield spots
Down Syndrome
Sequence vs. Association
Sequence
Single localized anomaly
In early morphogenesis
Secondary anomalies
Pattern of multiple anomalies
In later morphogenesis
Association
Cluster of anomalies not
explained by chance
Sequence
Association
Pierre Robin Sequence
Primary anomaly in
Mandibular development
Prior to 9 weeks
Coloboma
Heart defect
Atresia (choanal)
Retarded growth and development
Genital anomalies
Ear anomalies
Posterior displacement
of the tongue
Posterior cleft palate
Vertebral anomalies,
Anal atresia
Cardiac defects
T-E fistula with
Esophageal atresia
Radial dysplasia
Renal anomaly
Limb abnormalities
Clefting
• Cleft lip +/- palate
• Isolated cleft palate
– 1/700
– 1/1000
– M > F (2:1)
– M=F
– Asian > white > AA
(3:2:1)
– No difference
Anomalies
• Diagnosis?
• Usually an
isolated anomaly
• Associated
anomalies?
– Undescended
testes
– Inguinal hernias
– Ambiguous
genitalia
Hypospadias
• Is hypospadias a major or minor anomaly?
– MAJOR!
• Major anomalies are of functional significance
– Polydactyly
– Meningomyelocele
– Cleft lift
• Minor anomalies are of cosmetic significance only
– Epicanthal folds
– Single transverse palmar creases
– Super numerary nipples
Morphology
• Causes?
– Folic acid deficiency
– Maternal AED use
• Associated findings
– Neuro
• Flaccid paralysis
• Type II Chiari
– Urologic – incontinence
– Ortho
• Hip / sacral dysplasia
• Clubbed feet
Achondroplasia
Inheritance
Autosomal dominant
About 75% of patients with
achondroplasia represent new mutations
in the fibroblast growth factor receptor-3
(FGFR-3) gene
Clinical Features
Macrocephalic/frontal bossing/small
foramen magna
Rhizomelia
Prominent abdomen and buttocks
rhizomelia: short femur, humerus
mesomelia: short radius, ulna, tibia, fibula
acromelia: hands and feet affected
micromelia: entire limb affected
This patient come to the office, with a history
mild mental retardation, maternal uncles with
similar behavior. You notice the long face,
prominent ears, jaw, and forehead, unusual
speech pattern (fast, fluctuating rate and
repetition of sounds), and if you follow him into
Adolescence he will develop enlarged testicles
Diagnosis : Fragile X Syndrome (most common form of inherited
Mental retardation.
Etiology: Expansion of a trinucleotide repeat CGG in the promoter
Region of FMR1 gene in Chr Xq27.3
Normal
6-54
Premutation carriers
54-200 repeats
Affected individuals
repeats
>200 repeats
Fragile X
• Your best friend tells you her cousin’s little girl
has Fragile X. Is this possible?
– Yes
– Why?
• Females can carry the repeat but there is no clinical
effect in 70?
• Why?
– Lyonization (X inactivation)
Marfan Syndrome
• What’s the pattern of
inheritance?
– Autosomal dominant
• What’s the defect?
– Abnormal fibrillin gene
• What is the major
associated morbidity?
– Aortic dilatation
Associated anomalies?
• Cardiac
– Aortic aneurysms
– Aortic & mitral regurge
• Orthopedic
– Ligament laxity
– Pectus excavatum or
carinatum
• Ophthalmologic
– Lens dislocation
– myopia
• Her disorder is due to
what metabolic defect?
– Cholesterol metabolism
– This is Smith-Lemli-Opitz
(in case you didn’t
know!)
• This child has poor growth
and developmental delay.
• She also has webbed toes!
Name the syndrome
Cornelia de lange!
Her features:
•Heavy eyebrows
•Synophrys
•Long eyelashes
•Small upturned nose
•Long, smooth philtrum
•Cupid’s bow mouth
•Small hands and feet
•Phocomelia
Diagnosis?
Chvostek’s sign
Tetany
Mental Retardation
Diagnosis?
Albright’s
Hereditary
Osteodystrophy
Albright’s Hereditary Osteodystrophy
Genetics
Pathogenesis
20q13.2 – Auto Dom
Defect of G proteins
Characteristics
Unresponsive to PTH
Short stature
Obesity
Hypocalcemia
Shortened 3rd thru 5th
metacarpals
What anomalies?
PRUNE BELLY
• Urologic?
– Cryptorchidism
– Dilated ureters, GU
reflux
• Renal?
– Hydronephrosis
– Cystic dysplasia
• Abdomen?
– Absent abd wall
musculature
• Pulmonary?
– hypoplasia
Diagnosis?
Neurofibromatosis (Von Recklinghausen Disease)
Neurofibromatosis
•
•
•
Mode of inheritance?
– Autosomal Dominant
Pathogenesis?
– Neurofibromin – abnormal neural crest migration
Diagnostic Criteria?
*Café-au-lait macules
*Two or more Neurofibromas or one Plexiform
neurofibroma
*Optic Glioma
*Axillary or inguinal freckling
*Two or more Lisch Nodules
*Bone lesions – sphenoid dysplasia, thinning or long bones
*Family History in a 1st degree relative
A word on diabetes…
• Things to know
– 8 times increased risk for major congenital
anomalies including:
•
•
•
•
•
•
CV
Anencephaly
Spina bifida
Small left colon
Caudal regression/sacral dysgenesis *
Macrosomia
Whew that was a lot of stuff!!!!
Thank you to Regina Zambrano (and Jay Gardner) for their help with this
Next Board Review
Topic:
Hearts and Lungs!!!
(so read cardiology & pulmonary chapters)
Date: To Be announced!