Study on abnormal shortness opens window on a ‘new’ disease

Research into the genetic causes of why some people fail to grow to a normal height has led to the discovery of a previously unknown disease. In “Soft Syndrome,” extremely short individuals, who never grow beyond the height of an average eight-year-old, also have abnormal nails, peculiar facial traits and sparse hair.

A team consisting of researchers from Ha’emek Medical Center in Afula and Sourasky Medical Center (Ichilov Hospital) in Tel Aviv found that these and other conditions have a common molecular basis — an absence of, or a major defect, in a specific protein, called POC1A.

After seven years of research, the team published its findings on the cause of the newly-discovered disease in the American Journal of Human Genetics, said Prof. Eli Sprecher, chair of the Department of Dermatology at Sourasky and a leader of the study, along with Prof. Stavit Shalev, director of the Institute of Human Genetics at Ha’emek.

“Soft Syndrome” is named, said a spokesperson for the research team, as an acronym for its chief features: short stature, abnormal nails (onychodystrophy), peculiar facial traits, and sparse hair (hypotrichosis).

The study analyzed the DNA of members of two Arab Muslim families, members of whom have suffered from abnormal skeletal development over several generations. Alongside retarded skeletal development – extremely short bones in legs, arms, and other areas where they are generally long – the Soft Syndrome sufferers had badly bent pinkies, disproportionately short fingers and toes, small head circumferences, underdeveloped fingernails (associated with Cooks syndrome), and sparse and short hair.

Researchers suspected that there was a connection between the shortness and the other symptoms, but the cause and reason were unidentified until new DNA analysis techniques established the relationship between the conditions and POC1A. According to Dr. Ofer Sarig, who led the final and successful phase of the research program, “we discovered that in the absence of POC1A, the patient cells replicate very slowly, which of course very nicely fits the clinical phenotype displayed by affected individuals, who suffer from arrested growth of bone, nails and hair.”

The results of the study are definitive, Sprecher told The Times of Israel. “In fact, there is another study published in the same issue of American Journal of Human Genetics by a Saudi team investigating other aspects of inherited short stature that confirms our research,” he said.

The protein defect is observable via ultrasound as early as during the second trimester of pregnancy, Sprecher said. “Now that we know what to look for, we can provide parents with genetic counseling on what to expect and how to deal with the issue when their child is born.”

Further research, he said, would aim to figure out ways to prevent genetic transmission of the disease to future generations.

But the most important aspect of the study, said Sprecher, is what it means to the field of research in general, and its implications for future research. “One of the objectives of the next stage of research would be to see the connection between POC1A and other diseases and syndromes, the causes of which are still being studied. We are finding more and more that the genetic issues that research shows affects a specific aspect of the body is often implicated, if not directly involved, in more common disorders.

“For example, researchers found that MC1R, a gene connected to hair pigmentation problems, is also closely connected to more common conditions, like melanoma.”

The body is far more interconnected than many people realize, Sprecher added. “By discovering one gene connected to a rare condition, you very often get a clue on the cause, and perhaps even the cure, for far more common problems.”