Globally, only 80 cases of children born without a nose were reported in the past century, according to NIEHS clinical researcher and pediatric endocrinologist Natalie Shaw, M.D.
Although she and others suspected a genetic root to this condition, known as arhinia, the true cause remained unknown. That is, until Shaw and a large, international team of scientists found that mutations in the gene SMCHD1 led to this severe congenital disorder. Shaw is a co-first author of the work, which appeared Jan. 9 in the journal Nature Genetics.
Curiosity leads to surprise discovery
Shaw was a clinical research fellow in the Reproductive Endocrine Unit at Massachusetts General Hospital in Boston when she encountered a patient with arhinia. The person came to the hospital to be treated for amenorrhea, or having no menstrual periods. Shaw was intrigued by the patient’s unusual facial features and wondered whether there was a connection between the amenorrhea and craniofacial defects.
Over the next five years, Shaw and her colleagues looked for similarly affected individuals, and assembled a group of 40 patients with arhinia from around the world. Through next generation sequencing, they were able to pinpoint SMCHD1 as the main genetic driver of arhinia.
She said the finding was a complete surprise to everyone, because SMCHD1 had no known connection to embryonic development. SMCHD1 is an epigenetic repressor, which means it may shut down genes that are critical to the development of a normal face and reproductive system.
"Mutations in SMCHD1, and in some cases, the exact mutations that we see in our patients with arhinia, cause a rare form of muscular dystrophy [MD]" Shaw said. "And those patients have normal noses."
Links between three seemingly unrelated disorders
Shaw thinks there is either an environmental factor or a second genetic defect that is needed to develop arhinia. Nevertheless, this genetic overlap has serious implications for both groups. Some arhinia patients are at risk for developing MD, and some MD patients may be at risk for having a child with arhinia.
In her studies, Shaw discovered that approximately 95 percent of arhinia patients have hypogonadism, a condition in which their reproductive organs produce little or no sex hormones. As a result, they do not go through puberty, usually need sex hormone replacement, and are infertile.
She still has a long way to go to understand the link between SMCHD1 and hypogonadism, but she is studying more patients at the National Institutes of Health Clinical Center, in collaboration with Angela Delaney, M.D., from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. They hope to understand the biological consequences of these mutations.
"This is a truly remarkable achievement," said NIEHS Clinical Director Janet Hall, M.D. "Natalie’s initial idea for the study, and her ability to connect with patients and families worldwide with this rare disorder, is at its heart."
Citation: Shaw ND, Brand H, Kupchinsky ZA, Bengani H, Plummer L, Jones TI, Erdin S, Williamson KA, Rainger J, Stortchevoi A, Samocha K, Currall BB, Dunican DS, Collins RL, Willer JR, Lek A, Lek M, Nassan M, Pereira S, Kammin T, Lucente D, Silva A, Seabra CM, Chiang C, An Y, Ansari M, Rainger JK, Joss S, Smith JC, Lippincott MF, Singh SS, Patel N, Jing JW, Law JR, Ferraro N, Verloes A, Rauch A, Steindl K, Zweier M, Scheer I, Sato D, Okamoto N, Jacobsen C, Tryggestad J, Chernausek S, Schimmenti LA, Brasseur B, Cesaretti C, Garcia-Ortiz JE, Beitrago TP, Silva OP, Hoffman JD, Muhlbauer W, Ruprecht KW, Loeys BL, Shino M, Kaindl AM, Cho CH, Morton CC, Meehan RR, van Heyningen V, Liao EC, Balasubramanian R, Hall JE, Seminara SB, Macarthur D, Moore SA, Yoshiura KI, Gusella JF, Marsh JA, Graham JM Jr, Lin AE, Katsanis N, Jones PL, Crowley WF Jr, Davis EE, Fitzpatrick DR, Talkowski ME. 2017. SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome. Nat Genet 49:238–248.