After 20 years, the patient's family received a response to a decade-long genetic secret. Their daughter had two rare disorders, Angelman's Syndrome, and a P450scc deficiency, which were found after researchers found it to have a uniparental disomy, two copies of chromosome 15 from one parent, and no more.
A research study entitled "Adrenal insufficiency, sexual reversal and angelic syndrome due to uniparental disoma revealing a mutation in CYP11A1" was published on March 22, 2018 and recognized as the best novelty in Hormone Research in Paediatrics in 2018, announced at the Annual Meeting of Pediatric Endocrine in Baltimore on Saturday, April 27, 2019.
Using a variety of genetic tools, including whole-genome sequencing, microchip analysis, and in vitro gene splicing modeling, scientists have confirmed that this patient has an uniparental disomy, a recessive genetic state. They learned that after receiving two damaged copies of chromosome 15 from her father, this woman had a hormonal problem that led to adrenal insufficiency and sex reversal. This explains why she physically presented herself as a woman, although she had testes and Y chromosome. He also explained other symptoms, including developmental delays and seizures.
"It is a unique symptom conglomeration that combines these two very rare disorders," says Andrew Dauber, M.D., MMSc., Head of Endocrinology Division at the Children's National Health System and lead researcher. "The advent of various technologies and techniques has made it possible for her diagnosis to be made over the years – and then a 20-year diagnostic odyssey has begun."
For example, each of these conditions is known and rare: Angelman's syndrome affects approximately one in 10 to 20,000 people in the US. Typical symptoms include those observed in this patient: delayed development, mental disability, speech disorder, and seizures. Very rare is also a side chain cleavage disorder that leads to adrenal disorders and gender reversal. In 2005, the chances of survival with a P450scc defect were slim, but since then, more than 28 children have been diagnosed with this gene deficiency, which is necessary to convert cholesterol to pregnenolone, the hormone in the adrenal glands.
Dr. Dauber notes that the chances of this happening are very unlikely. The course here is one gazillion. In this case, one disorder has revealed another, leaving researchers new insights into the methodology for detecting very rare genetic disorders or for more common rare conditions.
"Knowing the gene that caused the adrenal insufficiency and understanding this etiology will not change the patient's medical care, but it will change the way researchers think about genetic detective work and the combination of different technologies," says Dr. Schmidt. Dauber. "We know that genetic disorders can be complex combinations of different disorders. This patient didn't have one disorder but three."
When Dauber asked about the importance of this award, he notes that: "It's not that other people have not known this concept before, but this case is a striking example. Different technologies will reveal different types of genetic changes that you need to use the right technology or the right technology in the right combination to combine the entire image. "