Tuesday, February 9, 2016

4H syndrome

Sitting in a college library on Labor Day 2009, Deanna Rennon tried to ignore the guilt she felt about spending the holiday at Mary Washington University instead of boating with her family as her husband, Doug, had planned.

Before she plunged into research for a psychology paper, Rennon, who was working 20 hours a week and carrying a full load of undergraduate courses, decided to spend a few minutes online searching for the subject that had become a preoccupation: the neurological disorder affecting the youngest of her four children, Erica, who was nearly 3.
“At that point I was just grasping at straws,” recalled Rennon, now 39.

She clicked on a 2007 article in a pediatric journal, and the accompanying photos of the patients’ missing and distinctively misaligned teeth stopped her cold.

“The teeth looked just like Erica’s,” she recalled, as she pored over the article by an international team of researchers, who suggested they had uncovered a new disorder based in large part on dental anomalies. The similarities did not stop there: Descriptions of other characteristics of the four children in the article — including their speech and motor problems — seemed to match Erica’s.

Rennon immediately emailed the article to the pediatric neurologist newly assigned to Erica’s case: Adeline Vanderver at Children’s National Medical Center in Washington.

“Do you think Erica has the same disorder?” she inquired.

Several hours later, Rennon was startled when Vanderver, who hadn’t seen Erica and wasn’t scheduled to do so for months, called from Europe, where she was attending scientific meetings. Intrigued by Rennon’s question, she asked her to schedule an appointment for Erica when she returned.

Rennon’s chance perusal of an article in a specialized medical journal and her connection to Vanderver, who also works with the National Human Genome Research Institute at the National Institutes of Health, proved to be pivotal.

“It was a lot of serendipitous events,” Vanderver said, adding that such coincidences “happen more often than you think.” In this case, “so many little puzzle pieces came together. For years, these children walked around with no front teeth, but nobody noticed that, because they were seen by neurologists” who were focused on their brains. “In fact,” she said, “it was a crucial clue.”...

For her 18-month checkup, she took Erica to a new pediatrician. “She noticed things immediately,” Rennon recalled. Erica’s muscle tone was abnormal, she was unusually small and she barely spoke. The toddler still could not stand unassisted, and the teeth that had erupted were in the back of her mouth, not the front, as is typical...

The MRI performed in November 2008 marked the end of Rennon’s hope that Erica would catch up...

Two days later, McClintock called with the results: Erica’s brain was severely deficient in white matter, which controls how nerve cells conduct signals. Also, her cerebellum, the part of the brain that controls speech and motor movements, was shrunken, about half the size of normal. The cause, the neurologist explained, was probably a leukodystrophy, a constellation of rare, progressive and incurable genetic disorders affecting the central nervous ­system...

Vanderver first met Erica in October 2009, several weeks after her mother’s email. A month shy of her third birthday, Erica was attending a special-ed preschool, which she loved, and had recently been fitted for eyeglasses to compensate for her poor vision. She used a walker because she could not stand unsupported, and her speech was difficult to understand for those who did not know her well. But she appeared to be a very sociable and happy child.

Vanderver told the Rennons that Erica might have the disorder described in the article Rennon had emailed, a leukodystrophy called 4H syndrome; its features include hypomyelination (too little myelin) and hypodontia (too few teeth). Those affected do not go through puberty because the central nervous system can’t initiate it. Abnormally stiff muscles, speech difficulties and vision problems are common...

The payoff was swift. Erica’s participation was instrumental in the identification in 2011 of POLR3B, one of the genes known to cause 4H. The disorder is passed down in an autosomal dominant fashion: Affected children receive an errant gene from one parent, who may not show signs of the disorder...

“At least I could say this is what she has,” Rennon said. She battles the guilt she feels from wanting to replicate the large family she grew up in. “Had we stopped with three children, Erica wouldn’t have to go through any of this,” she said.

Erica’s condition, she knows, has profoundly affected her other children, and she worries that it might make them leery about forming relationships as adults or having children of their own.

“They are all extremely helpful, and although it’s caused difficult feelings at times — upset, jealousy or whatever — they are much more aware of disabilities and differences.”

Erica is now 9. “My biggest concern for her is that she has friends and fun and is part of the family and giving her everything we possibly can,” her mother said. She enjoys attending her brother’s travel hockey games and an older sister’s gymnastics meets and “knows a lot of people.”

“We are preparing for a future with her and know that our lives will always be a little different than we expected,” Rennon said. “It’s been a roller coaster, but I’m thankful we have some answers.”



  1. Muthusamy K, Sudhakar SV, Yoganathan S, Thomas MM, Alexander M. Hypomyelination, Hypodontia, Hypogonadotropic Hypogonadism (4H) Syndrome With Vertebral Anomalies: A Novel Association. J Child Neurol. 2015 Jun;30(7):937-41.


    Hypomyelination, hypodontia, hypogonadotropic hypogonadism (4H) syndrome is a rare hypomyelination disorder with around 40 cases reported worldwide. Children with hypomyelination, hypodontia, hypogonadotropic hypogonadism syndrome present with varying degrees of developmental delay with a spastic ataxic syndrome with delayed eruption of teeth along with disruption in the eruption sequence, hypogonadotropic hypogonadism, and a fluctuating clinical course with intercurrent infections and varying periods of stability. The disorder is caused by mutations in POL3A and POL3B genes and is collectively termed as pol III-related leukodystrophies. Here we describe 2 children with hypomyelination, hypodontia, hypogonadotropic, hypogonadism syndrome and the association of multiple vertebral fusion anomalies in one of them, which has not been previously described in the literature. We conclude that the spectrum of the disorder is not limited to brain parenchyma alone and involves all the structures arising from neural ectoderm, and this needs further research.

    1. Buonasera mia figlia Vanessa ha 8 anni e al Gaslini le hanno appena diagnosticato la sindrome 4h con 2 mutazioni drl gene Pol3b

  2. Wolf NI, Bernard G. Mutations in RNF216 do not cause 4H syndrome. Parkinsonism Relat Disord. 2015 Nov;21(11):1387-8.


    We comment on the recent publication by Ganos et al. classifying a patient with non-specific white matter abnormalities, cerebellar atrophy, hypogonadotropic hypogonadism and absent lower median incisors as 4H syndrome. He had mutations in RNF216. Mutations in this gene cause Gordon-Holmes syndrome, distinct from 4H syndrome.

    Ganos C, Hersheson J, Adams M, Bhatia KP, Houlden H. Syndromic associations and RNF216 mutations. Parkinsonism Relat Disord. 2015 Nov;21(11):1389-90.

    Ganos C, Hersheson J, Adams M, Bhatia KP, Houlden H. The 4H syndrome due to RNF216 mutation. Parkinsonism Relat Disord. 2015 Sep;21(9):1122-3.