Genetics Flashcards
A pedigree has 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
Explanation
X-linked recessive disorders generally affect males only; hemophilia A, Duchenne muscular dystrophy, and Becker muscular dystrophy are classic examples. Some female carriers of X-linked diseases may be affected depending on X-inactivation.
Which endocrine disorder should be screened for at 6 and 12 months of age in a child with Down syndrome?
Hypothyroidism
Explanation
After the 1st year of life, annual screening should occur for hypothyroidism. Other problems of Down syndrome in childhood are atlantoaxial instability and leukemia. Later in life, patients need to also be monitored for Type 2 diabetes, hyperthyroidism, cataracts, seizures, cognitive dysfunction, and dementia or early-onset Alzheimer disease.
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
Explanation
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 in 4,000 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 newborn presents with the following:
Mandibular and maxillary hypoplasia Zygomatic arch clefts Ear malformations that include microtia on one side and atresia on the other side Downward-slanting palpebral fissures Colobomata of the lower eyelids Conductive hearing loss What is the most likely diagnosis?
Treacher-Collins syndrome (mandibulofacial dysostosis)
Explanation
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.
What cancer is most likely to occur in a child with Down syndrome?
Leukemia
Explanation
Leukemia (particularly acute lymphocytic leukemia) has a markedly increased incidence in children with Down syndrome and should be monitored throughout childhood and into adulthood.
A newborn presents with the following:
Brachycephaly Frontal bossing Wormian bones (abnormal intrasutural bones) Hypoplastic/absent clavicles Joint laxity What is the most likely diagnosis?
Cleidocranial dysostosis
Explanation
In addition to these findings, there is delayed eruption of deciduous and permanent teeth. It is common to have supernumerary and fused teeth as well.
What are the clinical findings of achondroplasia?
Disproportionately short stature with rhizomelic shortening
Lumbar lordosis
“Trident” hands
Macrocephaly
Flat nasal bridge, prominent forehead, and midfacial hypoplasia
Explanation
Note the hands have a “trident” appearance—hands are short and fingers are quite broad, with digits 3 and 4 splayed more distally than proximally. Growth curve at birth is on track, but by 2–3 months of age the length of these children has fallen to < 5th percentile. They do not have other malformations and are of normal intellect.
Autosomal dominant inheritance Bile duct paucity with cholestasis Pulmonary valve stenosis and peripheral artery stenosis Posterior embryotoxon Butterfly vertebrae Triangular face with pointed chin Long nose with broad midnose What disorder is associated with these findings?
20p12 deletion (Alagille syndrome)
Explanation
Alagille syndrome is caused by absence or mutation of the JAG1 gene. Hepatic involvement presents in the first 3 months of life with jaundice, pruritus, and cholestasis. The posterior embryotoxon is a developmental anomaly marked by a prominent white ring of Schwalbe and iris strands that partially obscure the chamber angle. The most common cardiac manifestations are peripheral and branch pulmonic stenoses (67% of patients) and tetralogy of Fallot (7–16% of patients).
An infant presents with infantile spasms.
The infant has a 50% risk of having what genetic condition?
Tuberous sclerosis
Explanation
It is helpful to look at an infant who is experiencing infantile spasms with a Wood lamp. This enhances the ash-leaf spots (hypopigmented macules) that occur in ~ 90% of cases of tuberous sclerosis, helping to make an earlier diagnosis.
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)
Explanation
Prader-Willi syndrome is most often due to paternally derived microdeletion of 15q11–13 (in contrast to maternally derived deletion of the same area, which causes Angelman syndrome). Other mechanisms include uniparental disomy and methylation abnormalities.
You diagnose a child with trisomy 18.
What is the most likely cardiac abnormality?
Ventricular septal defect
Explanation
90% of children with trisomy 18 have a structural heart defect. Most often this is a ventricular septal defect with multiple dysplastic valves.
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
Explanation
Beckwith-Wiedemann syndrome is an autosomal dominant disorder with the features listed. Remember that Wilms tumor is likely in these children.
A 10-year-old presents with the following:
Multiple café-au-lait spots Freckling of the axilla and inguinal areas Optic glioma 3 iris hamartomas (Lisch nodules) Sphenoid dysplasia History of learning disorder What is the most likely diagnosis?
Neurofibromatosis Type 1 (NF1)
Explanation
NF1 is an autosomal dominant disorder that affects about 1/3,000 (the most common neurocutaneous disease). Clinical diagnosis is based on presence of 2 of the following:
Six or more café-au-lait macules over 5 mm in diameter in prepubertal individuals and over 15 mm in greatest diameter in postpubertal individual
Two or more neurofibromas of any type or one plexiform neurofibroma
Freckling in the axillary or inguinal regions
Two or more Lisch nodules (iris hamartomas)
Optic glioma
A distinctive osseous lesion, such as sphenoid dysplasia or thinning of long bone cortex, with or without pseudoarthrosi
First-degree relative (parent, sibling, or offspring) with NF1
WAGR syndrome is characterized by which 4 abnormalities?
Wilms tumor Aniridia Genitourinary malformation Reduced intellectual abilities Explanation 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 (e.g., hypospadias, cryptorchidism). These kids are at increased risk of gonadoblastoma as well.
What is VATER/VACTERL association?
Vertebral, Anal atresia, Cardiac, Tracheal, Esophageal, Renal, and Limb defects Explanation 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.
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.
Explanation
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!
A newborn presents with a disruptive cleft of her face and palate, as well as apparent amputation of her 4th and 5th digits on her left hand.
What is the likely etiology?
Amniotic band sequence
Explanation
Amniotic band sequence presents with disruptive clefts of the face and palate resulting from amniotic bands adhering to this area. Bands can also form in other parts of the fetal body. Other defects can include constriction rings of the limbs and/or digits; amputations are common. Most cases are sporadic without a known genetic cause.
A newborn presents with the following:
Intrauterine growth restriction Hirsutism Downturned mouth Micrognathia Low hairline Long eyelashes Thin upper lip Cardiac defects Micromelia (hands/feet) 2,3 syndactyly of toes What is the most likely diagnosis?
Cornelia de Lange syndrome
Explanation
Cornelia de Lange syndrome is a very rare autosomal dominant disorder with > 50% resulting from a new mutation of the NIPBL gene. This is one of the classic short stature syndromes. Hirsutism and micromelia can help differentiate this from other disorders.
A 1-month-old presents with the following:
Hypotonia Small ears Brachydactyly High-arched palate Speckled irises Upslanted palpebral fissures Epicanthal folds Single transverse palmar crease Hypoplasia of the middle phalanx of 5th finger What is the most likely diagnosis?
Trisomy 21 (Down syndrome) Explanation 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.
A child presents with the following:
Partial albinism White forelock Premature graying Iris heterochromia History of cleft lip Cochlear deafness What is the most likely diagnosis?
Waardenburg syndrome I
Explanation
Waardenburg syndrome I is an autosomal dominant disorder. It is occasionally associated with Hirschsprung disease. Affected girls can be born without a vagina.
