Jeremy Hobbs, age 7, weighed only 4 lbs, 3 oz at birth. No one knew why he was so small. He had very bad reflux and wasn't gaining weight. At three months, his parents noticed nystagmus, or wobbling of his eyes. By 4 months he had gone completely blind.
The MRI showed delayed white matter development in his brain. His parents were told he probably had a leukodystrophy, but this was later ruled out and his white matter became more normal on subsequent MRIs.
Jeremy's main symptoms are severe low muscle tone (hypotonia) and weakness, as well as craniosynostosis, in which the plates that form the skull fuse too soon, putting pressure on the brain which has no space to expand. Jeremy has endured multiple operations to separate the skull bones and relieve the pressure. These have relieved his symptoms for a time and enabled his vision to come back, but his skull bones have repeatedly re-fused, causing the pressure in his head to return, so much that surgeons described his brain as "exploding" out of his skull.
The high pressure made Jeremy throw up, lose his vision and suffer terrible headaches. He became terrified of pain and has been diagnosed with post-traumatic stress disorder. "Every time he has a headache, he freaks out, thinking he will have to have surgery," says Angela Hobbs, Jeremy's mother.
Jeremy has had 38 surgeries to date, including urologic surgery and two heart operations to correct a blocked pulmonary valve. For unknown reasons, he has discrepancies in muscle strength on the two sides of his body, leading one leg to be shorter than the other.
Jeremy cannot speak, but does well in academics (he is in first grade) and can communicate with writing and with sign language. The family has visited multiple cities in search of answers. All genetic tests have come up negative. The doctors suspect some kind of metabolic disorder. Jeremy's two siblings are unaffected.
"We just want our son not to be in so much pain," says Angela. "We would love an answer and a treatment, if not a cure."
What CLARITY Undiagnosed found
For many of the other Challenge families, several teams reported the same variant. But for Jeremy, nearly every team had a different guess.
Since Jeremy has craniosynostosis, the teams tested for known craniofacial syndromes but, consistent with previous testing, he had no positive findings. However, one of the teams reported that Jeremy has a small genetic deletion in the gene EFNB1 that occurred in a "mosaic" pattern, affecting only some of his cells. Despite many prior genetic evaluations, including exome sequencing, this mutation was a new finding, likely because mosaic mutations are difficult to detect.
EFNB1 is known to cause craniofrontonasal dysplasia, a condition that includes craniosynostosis, asymmetry of the lower legs and hypotonia — all features Jeremy has. Interestingly, the condition is only reported in males with mosaicism of this gene. The diagnosis does not explain all of Jeremy's features, so it could represent an "expansion of phenotype," further describing a spectrum of a disorder.
The Hobbs have enrolled Jeremy in the Manton Center, which will seek to confirm the mutation in his blood, saliva and possibly a skin sample, and then to determine the degree of mosaicism, whether the mutation was inherited or de novo and its role in Jeremy's health problems.
Though many of Jeremy's physicians had suspected a metabolic disorder, none was identified in the Challenge.
"The Manton Center will try to figure out the implications of what the teams found and go from there," says Angie. "We were surprised to see that they found something and I'm curious to see where this goes. We're really glad for this opportunity. It would make a difference to be able to tell the doctors that there's a diagnosis, so they'll be less scared about treating him."