Genetics Flashcards
A newborn presents with the following:
- Microcephaly
- Atretic ear canals
- “Frog-like” position with legs flexed, externally rotated, and in hyperabduction
- Depressed midface
- Protruding mandible
- Deep-set eyes
- Everted lower lip (“carp-like” mouth)
What is the most likely diagnosis?
18q Deletion (de Grouchy Syndrome)
18q deletion, or de Grouchy syndrome, is due to deletion of the long arm of chromosome 18. Remember this one when you see a patient with depressed midface, deep-set eyes, protruding mandible, everted lower lip, and “frog-like” legs.
You diagnose a child with trisomy 18.
What is the most likely cardiac abnormality?
VSD
90% of children with trisomy 18 have a structural heart defect. Most often this is a VSD with multiple dysplastic valves.
What are the complications associated with achondroplasia?
- Serous Otitis Media, Motor Milestone Delay, Bowing of Legs, Orthodontic Problems
- Serious Complications of Spinal Cord Compression: Apnea, Quadriparesis, Growth Delay, Hydrocephalus
Foramen magnum stenosis and/or craniocervical junction abnormalities can occur in infancy and cause compression of the upper cord, resulting in the serious complications listed above. Most males have final heights of 46–57 inches and females of 44–54 inches. Adults are at risk for obesity and spinal stenosis.
A 4-year-old presents with the following:
- History of severe hypotonia at birth
- Short stature
- Small hands and feet
- Hypogonadism
- Mild intellectual disability
- Obesity
What is the most likely diagnosis?
Prader-Willi Syndrome
(Paternally Derived 15q11–13 Deletion)
Prader-Willi syndrome is due to paternally derived microdeletion of 15q11–13 (in contrast to maternally derived deletion of the same area, which causes Angelman syndrome).
You are evaluating a 4-year-old boy with the following findings:
- Intellectual disability
- Large head
- Long face with large ears
- Large hands and feet
- Hyperextensible joints
What is the most likely diagnosis?
Fragile X Syndrome
This disease is caused by an unstable cytosine-guanine-guanine (CGG) repeat in the FMR1 gene on the X chromosome. It is the most common inherited intellectual disability syndrome and occurs in 1/1,650 males. This syndrome exhibits features not normally seen in X-linked disorders: 30% of carrier females have a similar clinical phenotype to affected males; and a normal phenotypic male could transmit the gene to his daughters, who subsequently have a 50% risk of having an affected male.
A young child presents with:
- Generalized overgrowth
- Macroglossia
- Ear lobe creases
- Posterior auricular pits
- History of omphalocele
- Cryptorchidism
- Hemihypertrophy
- Large for gestational age
What is the most likely diagnosis?
Beckwith-Wiedemann Syndrome
Beckwith-Wiedemann syndrome is an autosomal dominant disorder with the features listed. Remember that Wilms tumor is likely in these children.
A newborn presents with:
- Macrocephaly
- Prominent forehead
- Hypertelorism
- Intellectual disability
- Large hands/feet
- Large for gestational age
What is the most likely diagnosis?
Sotos Syndrome
Sotos syndrome is an extremely rare autosomal dominant growth abnormality disorder that presents as a very large-appearing child with these findings. 80–90% of cases are caused by mutation of the NSD1 gene.
What is VATER/VACTERL association?
- Vertebral Defects
- Anal Atresia
- Cardiac Defects
- Tracheoesophageal Fistula
- Renal Anomalies
- Limb Abnormalities (Radial Ray)
VATER/VACTERL association is a common exam question, so be sure you know what the acronym stands for. Also know that it is an association of findings and not a syndrome.
You are given a pedigree on the test with the following characteristics:
- Both sexes are equally affected.
- Both sexes can transmit to offspring.
- Disorders may be seen in one or more siblings but not in all generations.
- Consanguinity increases the risk of having an affected offspring.
What is the most likely classic Mendelian inheritance pattern?
Autosomal Recessive (AR)
AR disorders require 2 copies of an altered allele to produce a disease phenotype. AR disorders are less common than autosomal dominant disorders, but heterozygote carriers are much more common in the general population. Cystic fibrosis is a classic example.
If a 10-year-old presented with one of the following:
- ≥ 2 hemangioblastomas in the cerebellum or retina
or
- 1 single hemangioblastoma plus 1 of the following:
- Pheochromocytoma
- Endolymphatic sac tumors
- Kidney/pancreatic cysts
- Renal cell carcinoma
- Pancreas involvement, neuroendocrine tumors
What would be the most likely diagnosis?
von Hippel-Lindau (VHL) Syndrome
VHL syndrome is a highly penetrant autosomal dominant multisystem cancer disorder that presents with benign and malignant tumors of the eyes, CNS, kidneys, pancreas, adrenal, and reproductive glands. The most classic presentation is a cerebellar hemangioblastoma or retinal angioma by 10 years of age.
Which type of craniosynostosis is the most common?
Sagittal Synostosis
Craniosynostosis is the early, pathologic fusion of calvarial sutures. Sagittal synostosis is the most common single-suture fusion, followed by coronal, metopic, and the very rare isolated lambdoid. Sagittal synostosis is more common in males by a ratio of 5:1.
WAGR syndrome is characterized by which 4 abnormalities?
- Wilms Tumor
- Aniridia
- Genitourinary Malformation
- Mental Retardation (Intellectual Disability)
WAGR syndrome results from a deletion of the short arm of chromosome 11 (11p13 deletion). Wilms tumor occurs in up to 50% of cases, most often by 3 years of age. The GU abnormalities are generally male genital hypoplasia (hypospadias, cryptorchidism, etc.). These kids are at increased risk of gonadoblastoma as well.
A newborn presents with the following:
- Craniosynostosis
- Brachycephaly
- Hypertelorism
- Strabismus
- Maxillary hypoplasia
- Narrow palate (“cathedral ceiling”)
- Syndactyly
- “Single nails”
- Broad thumbs
What is the most likely diagnosis?
Apert Syndrome
Apert syndrome is an autosomal dominant disorder with these features. “Single nails” refers to the mitten-hand deformity, common with this disorder, in which 2, 3, or 4 fingers are completely fused with a common nail bed.
Absence of which 2 genes may result in WAGR syndrome?
PAX6 and Wilms tumor 1 (WT1)
Remember that WAGR syndrome is associated with:
- Wilms tumor
- Aniridia
- Genitourinary malformation
- Mental Retardation (intellectual disability)
Phenotypically, these children have a long face with poorly formed ears, upward-slanting palpebral fissures, ptosis, and a beaked nose.
- Cleft palate
- Thymus agenesis or hypoplasia
- Parathyroid gland hypoplasia/agenesis
- Hypoplasia of the auricle and external auditory canal
- Tetralogy of Fallot, interrupted aortic arch, VSD, or truncus arteriosus
- Short stature
- Behavioral problems
What syndrome is characterized by these findings?
22q11.2 Deletion (Velocardiofacial/DiGeorge Syndrome)
22q11.2 deletion includes phenotypes referred to as DiGeorge syndrome or velocardiofacial syndrome. CATCH 22 (cleft palate, absent thymus, and congenital heart disease) is a mnemonic that is not used clinically, but that is very helpful for exam situations! 22q11.2 deletion is the most prevalent microdeletion syndrome, with ~ 1/6,000 live births affected.
A newborn presents with the following:
- Mandibular and maxillary hypoplasia
- Zygomatic arch clefts
- Ear malformations that may include microtia, anotia, atresia
- Downward-slanting palpebral fissures
- Colobomata of the lower eyelids
- Conductive hearing loss
What is the most likely diagnosis?
Treacher-Collins Syndrome
(Mandibulofacial Dysostosis)
Treacher-Collins syndrome (mandibulofacial dysostosis) is a rare autosomal dominant congenital disorder that affects the development of bones and other tissues of the face. The signs and symptoms of this disorder vary greatly, ranging from almost unnoticeable to severe. It is a common exam question and a common choice as a distractor.
A 1-month-old presents with the following:
- Hypotonia
- Small ears
- Brachydactyly
- High-arched palate
- Microcephaly
- Up-slanted palpebral fissures
- Epicanthal folds
- Single transverse palmar crease
- Speckled irises
- Hypoplasia of the middle phalanx of 5th finger
What is the most likely diagnosis?
Trisomy 21 (Down Syndrome)
Trisomy 21 is the most common autosomal chromosome trisomy and occurs in 1/800 live births. Approximately 95% have 3 copies of the whole chromosome 21, with the remainder having an extra part of the long arm or mosaicism. Increasing maternal age is the only known risk factor.
What are the most common heart defects seen in Down syndrome?
Of Those with Heart Defects:
- 1/3 Have AV Canal Defects
- 1/3 Have VSDs
- 1/3 Have ASDs of the Secundum Variety and Tetralogy of Fallot
50% of children with Down syndrome have a cardiac defect; therefore, echo is mandatory. Remember that AV canal defects commonly do not have an associated murmur!
You are given a pedigree on the test with the following characteristics:
- Only females can transmit the disease to their sons; there is never male-to-male transmission.
- If a generation has only females, the disease will appear to “skip” that generation.
- An affected father transmits the disease to all of his daughters (the daughters are obligate carriers but are typically unaffected).
What is the most likely classic Mendelian inheritance pattern?
X-Linked Recessive
X-linked recessive disorders generally affect males only, with some rare exceptions. Hemophilia A and Duchenne and Becker muscular dystrophy are classic examples.
You diagnose a child with Williams syndrome.
What is the most likely cardiac defect?
Supravalvular Aortic Stenosis
This is the classic cardiac defect in Williams syndrome, occurring in 45–75% of patients. Know it!
A 12-year-old presents with the following:
- Hyperextensible skin
- Hypermobile joints
- Easy bruising
- Dystrophic scarring
- Skin texture is like “wet chamois.”
- Wrinkled palms and soles
- Mitral valve prolapse
- Proximal aortic dilatation
- Coagulation tests (PT, PTT, bleeding time) are normal except for capillary fragility testing, which is abnormal.
What is the most likely diagnosis?
Ehlers-Danlos Syndromes
Ehlers-Danlos syndromes are a group of autosomal dominant connective tissue disorders that include 6 major variants. The joint hypermobility is common but may not appear in all types. Wrinkled palms and soles are common. The skin findings are classic!
You are given a pedigree on the test with the following characteristics:
- Both sexes are equally affected.
- Both sexes can transmit to offspring.
- No generation is skipped.
- You see father-to-son transmission.
What is the most likely classic Mendelian inheritance pattern?
Autosomal Dominant (AD)
Remember that AD disorders are expressed with only 1 copy of an altered allele. A heterozygous parent has a 50% chance of passing the disorder to his/her children. Father-to-son transmission excludes all X-linked and mitochondrial transmissions! Neurofibromatosis 1 is a classic example. Note that spontaneous new mutations are common, so it is possible that prior generations were unaffected.
