Mariana ZanettiLips, gums, nose, and the roof of the mouth—each of these facial structures can be affected to varying degrees by one of the world’s most common congenital malformations: cleft lip, cleft palate, or cleft lip and palate. Collectively known as orofacial clefts, these three conditions affect a ratio ranging from one in every 500 to one in every 2,000 infants, with approximately 1,500 new cases per year in Brazil. They are more prevalent in Asians than in other ethnicities and are two to three times more frequent in boys than in girls. Treatment for orofacial clefts begins with surgery to close the cleft, ideally within the first year of life. However, there is no consensus on the most appropriate age for the initial operation. Overall treatment extends into adulthood, involving surgeons, dentists, speech therapists, and other specialists.
An international study published in August in The New England Journal of Medicine (NEJM) has made an important contribution to determining the optimal timing for the first operation, particularly when the cleft affects the palate (roof of the mouth) only. The study, which included inputs from experts at the Craniofacial Anomalies Rehabilitation Hospital (HRAC) at the University of São Paulo (USP) in Bauru, suggests that the earlier the intervention, the better. The researchers found that infants who underwent primary surgery for cleft palate at 6 months of age were less likely to have speech disorders at the age of 5 than those who had surgery at 12 months of age. Due to safety concerns related to anesthesia and complications such as infections or airway obstruction, many medical centers opt to delay the surgery.
“These findings are currently under discussion at the hospital. We are now considering conducting surgery at an earlier age whenever feasible,” says Ana Paula Fukushiro, a speech therapist, HRAC researcher, and deputy coordinator of the Brazilian leg of the study. Affiliated with the National Healthcare System (SUS), the hospital is one of the main cleft palate centers in Brazil. It currently conducts surgery for cleft palate between 12 and 18 months of age. “For the child, resolving speech issues translates to better quality of life, less difficulty fitting in, and a lower likelihood of bullying at school,” she explains.
In the August-published study, 558 children at 23 centers across Europe and South America were randomly assigned to undergo surgery at two different time points: 281 were operated at 6 months of age, and 277 at 12 months. The researchers then followed up on participants until their fifth year, subjecting them to periodic tests to measure speech performance. Not all operated children completed the follow-up cycle.
In both groups, the overwhelming majority (85% to 90%) of operated children developed the ability to produce speech adequately, including pressure consonants—or consonants requiring increased air pressure in the mouth, such as “p,” “b,” “t,” “d,” as well as “f,” “v,” “s,” and “z.” However, the proportion of subjects who had no difficulties pronouncing these consonants was higher in the early-operated group than in the late-operated group.
Upon turning 5, 461 children underwent a test for velopharyngeal insufficiency, a condition that results from incomplete closure of the air passage between the back of the mouth and the posterior portion of the nose, leading to nasalized pronunciation of syllables with those consonants. Of the 235 who underwent surgery at 6 months, only 21 (9%) still had velopharyngeal insufficiency. In the group operated at 12 months, 34 (15%) of the 226 children still exhibited the disorder at 5 years of age. Even the outcome with late surgery was superior to previous studies, where speech problems persisted in about 30% of operated children.
One possible explanation for the current positive results is the surgical technique used in both the operations at 6 and at 12 months: the Sommerlad technique, which was used for nearly all participants. Developed by Australian plastic surgeon Brian Sommerlad, this technique is more difficult to perform and demands a higher level of skill from the surgeon. Using a microscope, the surgeon dissects and repositions the muscles of the soft palate—the posterior part of the roof of the mouth—bundle by bundle. Another study, conducted by researchers from HRAC and published in September in the Journal of Craniofacial Surgery, confirmed the superiority of this technique over two others in repairing clefts affecting both the lip and palate.
Early correction of palate malformation also seems to help children develop the ability to pronounce their first simple syllables, typically formed by a consonant and a vowel, such as “ba,” “da,” or “gu,” or repetitions such as “da-da-da-da-da.” Although lacking communicative function, this ability, known as canonical babbling, typically emerges between 7 and 10 months of age and is a milestone in language development. According to the NEJM study, 84% of children operated on at 6 months of age were able to produce canonical babbling by the end of the first year of life, whereas the same was true for only 64% of those who underwent surgery at 12 months. “Closing the palate earlier provides the baby with a greater ability to produce their first sounds and reduces long-term speech alterations,” says Fukushiro.
Surgical treatment also enables children born with orofacial clefts to enjoy a level of quality of life comparable to those without the deformity. In a recent literature review, researchers from the ABC School of Medicine/University Center (FMABC) combined data from 14 studies comparing psychological indicators of quality of life between two groups of children and adolescents: 1,558 without orofacial clefts and 1,185 born with the malformation who later underwent surgery and other treatments. According to the results, published in September in BMC Oral Health, quality of life in the first group was not significantly superior to that of the second. “Children and teens appear to adapt well,” says researcher Erik Montagna, who coauthored the study. “This underscores the importance of conducting interventions as early as possible, as recommended by international protocols.”
Those born with any of these malformations encounter challenges in carrying out everyday activities as trivial as eating or speaking. The difficulties vary in degree depending on the type and severity of the cleft. The classification most commonly used by specialists categorizes the pathology based on the affected structures: lip, palate, or lip and palate—each type representing about one-third of cases (see infographic on page 59). Clefts that are confined to the lip can create aesthetic discomfort due to alterations in facial features and are typically resolved through surgery between 3 and 6 months of age. However, they may extend to the gums and affect tooth alignment, requiring surgical and dental interventions.
The effects of clefts in the palate are more severe. Infants may struggle to breastfeed due to being unable to generate enough pressure to draw out the milk, and breastfeeding may require adjustments. These children also face a higher risk of speech impairment and hearing loss due to ear inflammations resulting from malfunctioning palate muscles. “No matter the extent or location, if the palate is affected, it is almost certain that the child will experience functional issues,” notes speech therapist Melissa Antoneli from HRAC, a coauthor of the studies published in the NEJM and the Journal of Craniofacial Surgery.
Over the past two decades, just over 33,600 cases of patients with orofacial clefts (lip, palate, or cleft lip and palate) have been identified in Brazil, averaging almost 1,500 cases per year. Valéria Freitas, a professor of dentistry at the State University of Feira de Santana (UEFS) in Bahia, and her colleagues arrived at these numbers by compiling cases identified in the Brazilian Ministry of Health’s National Live Births System (SisNac) from 1999—the year the malformation began to be recorded—to 2020. The data revealed that in 82% of instances (or 27,700 cases), clefts occurred in isolation, unrelated to other illnesses. Experts refer to these cases as non-syndromic, distinguishing them from those in which the deformity is associated with other diseases—occurrences of clefts in the mouth and face have been documented in over 600 syndromes.
Over the 22-year period analyzed in the study, there was a significant (though fluctuating) increase in the occurrence of non-syndromic clefts in Brazil. The problem affected 3.3 children out of every 10,000 in 2000 and rose to 5.3 per 10,000 in 2020. According to the data, published in September in Revista Paulista de Pediatria, the average rate of non-syndromic cases in the country was 4.2 cases per 10,000 children. This number is significantly lower than the global average of 15 cases per 10,000.
For reasons not yet understood, both non-syndromic and syndromic cases are concentrated in hinterland cities. Of the 27,600 cases of isolated clefts, 95% (26,300) were identified in babies born in cities far from the coast, as were 98% of the 6,022 syndromic cases. The study—conducted in collaboration with Alexandre Vieira, a dentistry researcher at the University of Pittsburgh, and published in September in The Cleft Palate Craniofacial Journal—did not attempt to elucidate the causes of such a significant difference. However, Vieira has a suspicion. “The best explanation I can think of is the social disparities observed between rural and urban environments,” he told Pesquisa FAPESP. “Housing conditions, access to healthcare, the quality of nutrition, and stress levels, for example, are environmental factors that can influence fetal development during pregnancy.”
There have been known to be cases resulting from alterations in a single gene, typically associated with syndromic forms of the malformation. However, experts believe that, most of the time, orofacial clefts occur as a result of alterations in multiple genes affecting facial formation and the conditions under which the baby is gestated.
At the USP campus in São Paulo, geneticist Maria Rita Passos-Bueno and her team have been investigating the hereditary basis of orofacial clefts for several years. In a recent study, they identified a situation where the deformity arises due to the interaction between genes and the environment. Analyzing cases within certain families, the researchers observed that most individuals with the malformation shared an alteration in a single gene, CDH1. This gene encodes E-cadherin, a protein involved in cell-cell adhesion and the formation of certain tissues. The mutations found in these families involved changes in a single pair of nitrogenous bases—the chemical units that form DNA—among the thousands that make up this gene. However, this alteration was sufficient to cause a minor deformity in E-cadherin, preventing it from functioning properly.
The unaltered form of E-cadherin plays a crucial role in early life. In the initial stages of embryo development (up to the 12th week of pregnancy), this protein is essential for the formation of facial bones, cartilage, and muscles, as well as the fusion of structures that give rise to the lips and the roof of the mouth. In experiments with mice, frogs, and human cells, in collaboration with Chilean embryologist Roberto Mayor at University College London, Passos-Bueno’s group observed that the CDH1 mutation found in these families caused alterations in tissue formation consistent with the occurrence of orofacial clefts.
However, there was an interesting detail. A mutation in the CDH1 gene alone was not always sufficient for the malformation to manifest in these families. In experiments with frog embryos in Mayor’s laboratory and with mouse embryos and human cells in Passos-Bueno’s laboratory, biologist Lucas Alvizi found that the formation of facial tissues was even more impaired when, in addition to the altered gene, the embryo developed in the presence of inflammation—experimentally induced by adding bacterial fragments to the culture medium. Published in Nature Communications, their findings help explain why not everyone with the altered gene presented with cleft lip and palate, and confirm that, in these cases, the condition instead resulted from interaction between the gene and the environment. “Pregnant women who are obese, have uncontrolled diabetes, or have an imbalanced diet rich in carbohydrates and poor in proteins may expose the embryo to an inflammatory environment that can exacerbate the effect of this mutation,” suggests Passos-Bueno.
Projects
1. HUG-CELL – Human Genome and Stem Cell Research Center (nº 13/08208-1); Grant Mechanism Research, Innovation, and Dissemination Centers (RIDC); Principal Investigator Mayana Zatz (USP); Investment R$56,159,521.51.
2. Interaction of genetic and epigenetic factors in response to inflammation in the predisposition to cleft lip and palate (nº 17/11430-7); Grant Mechanism Postdoctoral Fellowship in Brazil; Supervisor Maria Rita Passos-Bueno (USP); Beneficiary Lucas Alvizi Cruz; Investment R$627,834.87.
Scientific articles
GAMBLE, C. et al. Timing of primary surgery for cleft palate. The New England Journal of Medicine. Aug. 31, 2023.
ANTONELI, M. Z. et al. Speech outcomes audit for unilateral cleft lip and palate after 2-stage palate repair: Preliminary results. The Journal of Craniofacial Surgery. Sept. 1, 2023.
SILVA, A. M. et al. Epidemiologic profile and prevalence of live births with orofacial cleft in Brazil: A descriptive study. Revista Paulista de Pediatria. Sept. 15, 2023.
SILVA, A. M. et al. Coast-or inland residence and differences in the occurrence of cleft lip and cleft palate. The Cleft Palate Craniofacial Journal. Sept. 24, 2023.
ALVIZI, L. et al. Neural crest E-cadherin loss drives cleft lip/palate by epigenetic modulation via pro-inflammatory gene–environment interaction. Nature Communications. May 24, 2023.
OLIVEIRA JUNIOR, A. G. et al. Oral health-related quality of life in patients aged 8 to 19 years with cleft lip and palate: A systematic review and meta-analysis. BMC Oral Health. Sept. 16, 2023.
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