A 2-year-old boy is brought to the family doctor by his concerned mother. She is worried he is not growing normally despite always being hungry and eating much more than his older sister did. His mother also mentions that he becomes very upset with changes to routine and struggles to interact with others. He had trouble sitting upright earlier in infancy and only recently learned to walk. Despite being heavier now, his mother mentions he had trouble feeding and growing in the first year of life. On physical examination, the boy is clinically obese but short for his age and cries throughout the examination. A narrowed nasal bridge and a down-turned mouth are noted, as well as hypotonia. A genetic cause is suspected given the presentation.
Which of the following is the most likely underlying pathophysiology present in this child?
- A) Balanced translocation between chromosomes 8 and 14 (t8; 14)
- B) De novo mutation in paternal chromosome 15
- C) Hypermethylation of paternal UBE3A gene
- D) Terminal deletion on chromosome 5
- E) Trinucleotide CGG repeat expansion in FMR1 gene
B) De novo mutation in paternal chromosome 15
The likely diagnosis is Prader-Willi Syndrome (PWS). PWS is characterized by hypotonia, behavioral difficulties (often obsessive-compulsive behaviors), short stature, hyperphagia, and obesity. It is the most common genetic cause of obesity and can be life-threatening. Most often, the cause is a de novo mutation on 15q11-13.
Imprinting of the maternal copy of 15q11-13 occurs in most individuals due to hypermethylation. The silencing of the maternal copy means the paternal copy must function to express the necessary genes at that locus. However, most commonly a de novo mutation in 15q11-13 results in disease when no functioning copies of those genes remain. Other causes of paternal 15q11-13 loss of function include a microdeletion, chromosomal translocation, and uniparental disomy (both copies of a chromosome, or part of a chromosome, from one parent).
Hypermethylation is an epigenetic change mediated by methyltransferase enzymes that work to silence genes by increasing the number of positively charged methyl (CH3) groups. The positive charge wraps the sections of DNA closer to positively charged histone proteins and prevents attachment by RNA polymerases, thus reducing gene transcription.
Answer choice A: Balanced translocation between chromosomes 8 and 14 (t8; 14), is incorrect. This answer corresponds to the translocation of c-myc oncogene on chromosome 8 and the heavy-chain locus on chromosome 14, often seen in Burkitt lymphoma and acute lymphoblastic leukemia (ALL).
Answer choice C: Hypermethylation of paternal UBE3A gene, is incorrect. This answer relates to imprinting of the paternal UBE3A gene copy, located at the same 15q11-13 locus as PWS-related genes. In this case, paternal gene silencing creates a dependency on maternal UBE3A transcription, but a microdeletion (present in 75% of cases of Angelman syndrome) causes maternal loss of function and thus disease. Angelman syndrome is characterized by microcephaly, intellectual disability, developmental delay, seizures, ataxia, and speech impairment. Typically, patients are happy infants with characteristic hand-flapping movements.
Answer choice D: Terminal deletion on chromosome 5, is incorrect. This option corresponds to Cri-du-Chat syndrome. Patients often have a high-pitched cat-like cry, microcephaly, feeding and breathing problems, and characteristic facies.
Answer choice E: Trinucleotide CGG repeat expansion in FMR1 gene, is incorrect. This option represents Fragile X syndrome, an X-linked inherited disorder. Patients often have macro-orchidism, speech impediments, chronic otitis media, moderate intellectual disability, joint laxity, and pes planus.
Key Learning Point
Prader-Willi Syndrome is often caused by a loss-of-function de novo mutation on chromosome 15q11-13 leading to obesity, short stature, and behavioral difficulties.