A 5-year-old boy is brought to the physician because of behavioral problems. His mother says that he has frequent angry outbursts and gets into fights with his classmates. He constantly complains of feeling hungry, even after eating a full meal. He has no siblings, and both of his parents are healthy. He is at the 25th percentile for height and is above the 95th percentile for weight. Physical examination shows central obesity, undescended testes, almond-shaped eyes, and a thin upper lip. Which of the following genetic changes is most likely associated with this patient's condition?

Loss of paternal gene expression on chromosome 15

Mitotic nondisjunction of chromosome 21

Mutation of FBN-1 gene on chromosome 15

Microdeletion of long arm of chromosome 7

Deletion of Phe508 on chromosome 7

An 8-year-old boy is brought to the physician for evaluation of developmental delay and recurrent tonic-clonic seizures. There is no family history of seizures or other serious illness. Current medications include risperidone for hyperactivity. He is at the 17th percentile for head circumference. Examination shows protrusion of the mandible, strabismus, and a laughing facial expression. His gait is unsteady. He has a vocabulary of about 200 words and cannot speak in full sentences. Karyotype analysis shows a 46, XY karyotype without chromosomal deletions. Which of the following genetic mechanisms best explains this patient's findings?

Uniparental disomy of chromosome 15

Trinucleotide repeat in FMR1 gene

De novo mutation of MECP2 on the X chromosome

Nondisjunction of chromosome 21 during meiosis I

A 12-year-old boy is brought by his mother to a neurologist for continuing evaluation of seizures. His seizures were previously well-controlled on medication but over the last month he has been having seizures several times per week. The boy is non-verbal and has had severe developmental delays and cognitive disability since birth. On exam, the boy is found to be enthusiastically playing with the toys in the office and laughing at almost any stimulus. Furthermore, his movements are found to be uncoordinated with a wide based gait. Previous genetic testing has revealed an abnormality in an E3 ubiquitin ligase gene. Compared to unaffected individuals, which of the following patterns of gene expression is most likely seen in this patient?

Abnormally decreased expression of the gene from the maternal chromosome

Abnormally increased expression of the gene from the maternal chromosome

Abnormally decreased expression of the gene from both chromosomes

Abnormally decreased expression of the gene from the paternal chromosome

Abnormally increased expression of the gene from the paternal chromosome

A 4-year-old girl is brought to the physician by her parents because she is severely underweight. She is easily fatigued and has difficulty keeping up with other children at her daycare. She has a good appetite and eats 3 full meals a day. She has 4 to 5 bowel movements daily with bulky, foul-smelling stools that float. She has had recurrent episodes of sinusitis since infancy. Her parents report that she recently started to snore during her sleep. She is at the 15th percentile for height and 3rd percentile for weight. Her vital signs are within normal limits. Examination shows pale conjunctivae. A few scattered expiratory crackles are heard in the thorax. There is abdominal distention. Which of the following is the most likely underlying cause of this patient's failure to thrive?

Exocrine pancreatic insufficiency

T. whippelii infiltration of intestinal villi

Impaired intestinal amino acid transport

Small intestine bacterial overgrowth

Intestinal inflammatory reaction to gluten

A 3-month-old male presents to the pediatrician with his mother for a well child visit. The patient drinks 4 ounces of conventional cow’s milk formula every three hours. He usually stools once per day, and urinates up to six times per day. His mother reports that he regurgitates a moderate amount of formula through his nose and mouth after most feeds. He does not seem interested in additional feeding after these episodes of regurgitation, and he has become progressively more irritable around meal times. The patient is starting to refuse some feeds. His mother denies ever seeing blood or streaks of red in his stool, and she denies any family history of food allergies or dermatological problems. The patient’s weight was in the 75th percentile for weight throughout the first month of life. Four weeks ago, he was in the 62nd percentile, and he is now in the 48th percentile. His height and head circumference have followed similar trends. On physical exam, the patient smiles reciprocally and can lift his head and chest when in the prone position. His abdomen is soft, non-tender, and non-distended. Which of the following is the best next step in management?

Counsel on positioning and thickening feeds

A 4-week-old male infant is brought to the physician due to a 1-week history of refusing to finish bottle feeds and becoming irritable shortly after feeding. He spits up sour-smelling milk after most feeds. Pregnancy and delivery were uncomplicated. The baby is at the 70th percentile for length and 50th percentile for weight. His temperature is 36.6°C (98°F), pulse is 180/min, respirations are 30/min, and blood pressure is 85/55 mm Hg. He appears lethargic. Examination shows sunken fontanelles and a strong rooting reflex. The abdomen is soft with a 1.5-cm nontender epigastric mass. Which of the following is the most appropriate next step in the management of this patient?

Initiate IV fluid resuscitation

Surgical consultation for pyloromyotomy

Prader-Willi and Angelman syndromes — USMLE Lesson

Core Genetics - A Tale of One Chromosome

Genomic imprinting silences one parental copy of a gene, allowing only the other to be expressed. Both Prader-Willi (PWS) and Angelman (AS) syndromes map to the 15q11-q13 region, but depend on which parental copy is lost.

Paternal copy lost/inactive → Prader-Willi Syndrome
Maternal copy lost/inactive → Angelman Syndrome

Genomic Imprinting on Chromosome 15q11-q13

⭐ Deletion of the 15q11-q13 region is the most common genetic mechanism for both Prader-Willi and Angelman syndromes.

Prader-Willi Syndrome - The Insatiable Child

Cause: Paternal gene deletion/imprinting defect on chromosome 15q11-q13.
Clinical Phases:
- Infancy: Severe hypotonia (floppy infant), poor suck, feeding difficulties, & initial failure to thrive.
- Childhood: Develops an insatiable appetite (hyperphagia) leading to central obesity. Also presents with short stature, small hands/feet, & hypogonadism.
Behavioral: Temper tantrums, skin picking, obsessive-compulsive features.
Diagnosis: FISH or DNA methylation analysis confirms.

⭐ Classic presentation: The switch from failure to thrive in infancy to morbid obesity in early childhood is a hallmark feature.

Symptoms of Prader-Willi Syndrome

Angelman Syndrome - The Happy Puppet

Angelman syndrome: facial features and hands

Genetics: Caused by loss of function of the maternally inherited UBE3A gene on chromosome 15q11-q13.
Clinical Features (The "Happy Puppet")
- Clinical Triad:
  - Severe developmental delay & intellectual disability.
  - Ataxic gait, jerky arm movements (puppet-like).
  - Inappropriate laughter, excitable/happy demeanor.
- Other Signs:
  - Microcephaly (postnatal onset).
  - Seizures (present in >80% of cases).
  - Facies: Wide mouth, protruding tongue, prognathism.
Diagnosis
- First-line test: DNA methylation analysis.
- Confirmatory: UBE3A gene sequencing.

⭐ The paternal copy of UBE3A is normally imprinted (silenced) in specific brain regions, so only the maternal copy is active. A maternal deletion or mutation causes the syndrome.

Syndrome Showdown - PWS vs. AS

Feature	Prader-Willi Syndrome (PWS)	Angelman Syndrome (AS)
Genetic Defect	Paternal 15q11-13 deletion	Maternal 15q11-13 deletion (UBE3A)
Infantile Tone	Severe hypotonia	Often normal
Intellect	Mild-moderate ID	Severe ID, absent speech
Behavior	Hyperphagia, obsessive	Inappropriately happy, excitable
Seizures	Infrequent	Frequent (>80%)
Key Feature	Almond-shaped eyes, obesity	"Happy Puppet", ataxia, prognathism

Prader-Willi results from the loss of paternal genes on chromosome 15q11-q13, while Angelman is from the loss of maternal genes.

Key features of PWS include neonatal hypotonia, hyperphagia leading to obesity, and hypogonadism.

Angelman syndrome is characterized by inappropriate laughter (“happy puppet”), severe intellectual disability, seizures, and ataxia.

Both are classic examples of genomic imprinting.

FISH is the primary diagnostic test to detect the microdeletion.

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