Arthrogryposis and Other New Zika Virus Birth Defects

Zika virus is now linked to serious damage to babies’ joints and microcephaly developing later in infants.

After research earlier this year showed infection with Zika was definitely linked to the devastating birth defect microcephaly, medical experts at the World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC) warned other Zika-caused health consequences in babies might be discovered in coming weeks and months. And they were right.

First, evidence mounted that serious eye problems, seizures, spasticity, and brainstem problems — in addition to the abnormal brain development and small heads that mark microcephaly — were part of a new congenital syndrome caused by Zika. Now two more serious consequences of infection with the virus before birth can be added to this list. Researchers have linked Zika to severe joint deformities (arthrogryposis), and they’ve identified cases of babies born with normal-sized heads who have the brain abnormalities of microcephaly.

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Arthrogryposis, also called arthrogryposis multiplex congenita is a rare condition that develops before birth and disrupts the ability to move normally. It causes multiple contracted joints (usually in the arms and legs) that are permanently bent or straightened, according to the National Institutes of Health’s Genetic and Rare Diseases Information Center (GARD). Arthrogryposis may cause only a few joints to be contracted or, in the worst case scenario, every single joint in the body, including the back and jaw, can be “locked.” Muscles around the affected areas can atrophy, stiffen, never develop properly, or be totally missing.

Arthrogryposis begins when there’s decreased fetal movement as a baby develops in the womb, and the condition probably has a variety of causes, according to GARD. But until the outbreak of microcephaly in Brazil, no association between arthrogryposis and Zika was suspected. 

After doctors began noticing a few cases of the rare condition in babies born to women infected with Zika, researchers in Recife, Brazil, the center of the Zika epidemic, began looking for a possible connection to the virus. The research team, headed by Recife pediatric neurologist Vanessa van der Linden, MD, one of the first doctors to sound an alarm about Zika’s link to microcephaly, studied seven babies, all born full term with congenital Zika infections. 

The infants were treated at a rehabilitation center in Pernambuco, Brazil, for arthrogryposis. One had contracted joints only in the legs while the others had affected joints in both their arms and legs. Six of the seven infants had smaller than normal heads, too.

High-definition imaging scans found no abnormalities in the babies’ joints and surrounding tissues, so the researchers reasoned damage to the infants’ nervous system and brains before birth likely caused abnormal fetal muscle contraction in the womb, resulting in arthrogryposis. And more high-tech testing backed up their theory.

Electromyography, which records electrical activity produced by skeletal muscles, revealed abnormalities, and MRIs showed thinning of the spinal cords. Imagining tests also discovered calcifications in the babies’ brains.

In their study, published in British Medical Journal (BMJ),  the researchers concluded more research is needed to draw firm conclusions about the effect of Zika on arthrogryposis. However, they suspect the virus destroys brain cells, creating scar-like lesions in the brain that disrupt motor neurons (cells that control the contraction or relaxation of muscles), leading to fixed postures and joint deformities as babies develop inside the womb. Arthrogryposis "did not result from abnormalities of the joints themselves, but was likely to be of neurogenic origin," Van der Liden and her colleagues wrote. 

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Based on their findings, the Brazilian researchers recommend babies born to Zika-infected mothers receive follow-up examinations with orthopedists because the children “could develop musculoskeletal deformities secondary to neurological impairment." 

Babies born with normal sized heads aren’t necessarily free of Zika brain abnormalities 

While most of the focus and worry over Zika-caused birth defects has centered on microcephaly, which is primarily diagnosed by a smaller than normal head and brain, another study from Brazil came up with surprising conclusions about head size.

Using data from the Brazilian Ministry of Health, Federal University of Pelotas epidemiologist Cesar G. Victora, MD, PhD, and colleagues investigated 1,501 suspected cases of microcephaly and found many of the babies studied simply had somewhat smaller than average head size at birth but no brain abnormalities. However, some infants with normal sized heads had evidence of brain defects associated with Zika.

"Our study, which included all suspected cases of microcephaly in newborns in Brazil up to February, discarded three out of five cases after a full investigation as most suspected cases ended up being normal newborn babies with small heads,“ Victora said. “However, one in five definite or probable Zika cases had head circumference values in the normal range. Therefore, the current focus on microcephaly screening alone is too narrow.”

The babies with small head circumference at birth who were born to Zika-infected mothers were four times more likely to die during the first week of life than babies with heads in the normal range — and their mothers were far more likely to have had rashes during their pregnancy. 

The cranium, the part of the skull that holds the brain, typically develops by the 30th week of pregnancy, so the research suggests children can be born with normal sized heads but still develop brain damage due to Zika infection during later weeks of pregnancy. In fact, Zika-linked rashes during late pregnancy were associated with brain abnormalities in babies with normal-sized heads.

The study also raises the worrisome possibility babies infected with Zika as newborns might end up with brain damage, according to the researchers. 

"Our findings suggest that among pregnancies affected by Zika virus, some fetuses will have brain abnormalities and microcephaly, others will have abnormalities with normal head sizes, and others will not be affected,” Victora said. “A surveillance system aimed at detecting all affected newborns should not just focus on microcephaly and rash during pregnancy and should be revised, and examination of all newborns during epidemic waves should be considered." 

Additional Zika research offers a warning — and hope 

To avoid the birth defects associated with Zika, the best protection is, of course, not getting the virus in the first place. In addition to being a mosquito-borne disease, Zika is spread through sexual contact. While avoiding mosquitos is important, the CDC has previously recommended men who have traveled to a location where Zika is active should wait a minimum of eight weeks before having unprotected sex, whether they have any symptoms or of the virus not. But now it’s a good idea to wait far longer. 

Scientists have documented a case of an Italian man who contracted Zika six months previously and still had virus in his semen that could infect his sexual partners. So to be safe, women who are or may become pregnant should abstain from sex or practice safer safe by always using condoms if their partners have any Zika risk factors, even if they could have contracted the virus six months ago. 

While scientists are unraveling the often frightening consequences of Zika infections in babies, researchers are also making remarkable headway in figuring out how the virus does its damage — and how it can potentially be stopped.

The Zika virus contains 10 proteins, and University of Southern California (USC) investigators have pinpointed two, dubbed NS4A and NS4B, that damage fetal brain formation and likely are responsible for microcephaly. The research, published in the journal Cell Stem Cell, could eventually lead to a treatment that prevents Zika-infected mothers from having babies with this birth defect

“We now know the molecular pathway, so we made the first big step toward target therapy for Zika-induced microcephaly,” said study leader Jae Jung, PhD, professor and chair of the Department of Molecular Microbiology and Immunology at the Keck School of Medicine of USC. “Years from now, one shot or a series of shots could target the proteins NS4A and NS4B or their collaborators.” 

The CDC provides comprehensive information on Zika outbreaks, symptoms, and prevention of the virus. The WHO also offers regular updates on Zika. 

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