Introduction: Ring chromosome 14 syndrome, or r(14), is a rare genetic disorder characterized by distinctive facial features, intractable epilepsy, delayed development, intellectual disability, and autism spectrum disorder. With less than 100 documented cases worldwide, the disease is not well known or fully studied. Furthermore, the literature offers little guidance to aid dentists in the management of these patients as r(14) remains undocumented in the dental literature.

Aim: To investigate the manifestations and challenges faced by a group of subjects suffering from r(14), to raise awareness of this syndrome, and to provide tips and suggestions that dentists may find helpful to manage r(14) children effectively.

Materials and methods: A voluntary survey was administered to the caretakers of 13 r(14) patients who, as of 2019, were registered in the NORD (National Organization for Rare Diseases) global data bank (Ring 14 USA Outreach). The patients were assessed for age, gender, geographic distribution, phenotype, physical appearance, maxillofacial characteristics, presence of oral conditions and abnormalities, malocclusion, epileptic seizures, cognitive abilities, speech, muscle tone, nutrition, autism, and other developmental and behavioral points of interest.

Results: Of the 13 patients queried, 7 were male and 6 were female. The age of the patients ranged from 5 to 49 years. Ten patients were of European ancestry and three were Hispanic, all residing across the U.S. The majority of patients were diagnosed as infants, shortly after commencement of uncontrollable seizures. All the patients had microcephaly and presented with Class II malocclusions. More frequent occlusal anomalies and conditions included diastemata of the anterior teeth, congenitally missing teeth, crowding, and drooling. The majority of subjects was unable to speak, suffered from intractable seizures, and frequently exhibited behavioral outbursts.

Conclusions: A child with r(14) may present a considerable challenge to the dentist and staff, but the dental problems of r(14) children are, for the most part, like those of any other patient and can often be handled by the dentist. Depending on the severity of symptoms, some children with r(14) may be as treatable in the dental office as any other child.

children, dental management, ring chromosome 14 syndrome, special needs

ring chromosome 14 syndrome [r(14)] is a rare chromosomal disorder distinguished by refractory epilepsy, intellectual disability, autism spectrum disorder, and a myriad of diverse health issues.^[1] Recurrent seizures, developing in infancy or early childhood, are often intractable and resistant to antiepileptic drugs. Other challenges faced by r(14) children include various intellectual and learning disabilities, as well as developmental delays in speech and motor skills such as sitting, standing, and walking.^[2]

Individuals with r(14) are typically short in stature and present with microcephaly and puffy hands and/or feet. Facial phenotype may also manifest with subtle differences. Recurrent respiratory infections due to immune issues are a common problem for many r(14) individuals. Abnormalities of the retina, which usually do not affect vision, have also been reported. Major birth defects are rare.^{[2, 3]}

The prevalence of r(14) is unknown, but less than 100 affected individuals have been reported in the literature worldwide. The syndrome is caused by one aberrant chromosome 14 whose broken ends fuse together to form a ring. In turn, the loss of several critical genes near the end of the long (q) arm of chromosome 14 (typically at band 14q32.2 or 32.3) during ring formation is believed to result in the major features of the syndrome (Fig. 1).^{[2, 3]}

Figure 1.

Breakpoints in chromosome 14 during ring formation can vary between patients. The p arm of chromosome 14 is small and may usually be deleted without consequence. The long q arm typically breaks at 14q32.2 or 14q32.3. Breaks at 14q31 and 14q24 may also occur. The loss of genetic material from the q arm is believed to cause the main features of r14.

Individuals with r(14) have one copy of the abnormal chromosome in some or all of their cells.^[3] However, the syndrome is almost never inherited and the ring chromosome probably occurs as a random event during early embryonic development or during the formation of male and female reproductive cells. Most affected individuals have no family history of the disorder, although at least two cases have been documented in which a ring chromosome 14 was passed on to the child from their mother.^{[3, 4]}

The symptoms among r(14) individuals may vary in type and severity. Abnormalities may include prenatal and postnatal growth delays, intellectual disabilities, diminished muscle tone, and feeding difficulties. The specific type of epileptic seizures may also vary. Seizures may be myoclonic or tonic-clonic. They may also manifest as sensory or behavioral disturbances or loss of consciousness, as well as loss of bowel or bladder control or other voluntary functions.^[5]

Children with r(14) may also present with a distinctive facial appearance, which results from characteristic dysmorphisms of the head and facial area. Besides microcephaly, these may include dolicocephaly, a high forehead, an elongated face, and a flat nasal bridge with a prominent nasal tip. The eyes may be widely spaced with downwardly slanting palpebral fissures and vertical skin folds covering the epicanthic folds. Affected individuals may also have a thin upper lip, downwardly turned corners of the mouth, a high-arched palate, micrognathia, and large, low-set ears (Fig. 2).^[1–5]

Figure 2.

The children were characterized as having a pleasant and affectionate demeanor. Most were short in stature and presented with distinctive features of the craniofacial area. Such features included microcephaly with a high forehead, an elongated face, widely spaced eyes, down-slanted palpebral fissure, thin upper lip, a flat nasal bridge with a prominent nasal tip, large low-set ears, micrognathia, and a high palate.

Since other chromosomal disorders may have similar features, chromosomal testing is necessary to confirm the diagnosis. Conventional cytogenetics can usually identify a ring chromosome once a terminal deletion of chromosome 14q is ascertained by molecular karyotyping.^[5] In some cases, r(14) may be diagnosed prenatally by ultrasound, amniocentesis, and/or chorionic villus sampling.^[5] 

Dentists see patients with all kinds of special needs, developmental conditions and disabilities. Children with r(14) need dental care just like every other child. As with other autism-related disorders, r(14) children need sameness and continuity in their environment.^[6–8] The dental literature, however, offers very little guidance to aid the dentist in the management of these children.

The article aims to make dentists aware of the disorder and provides tips and suggestions that dentists may find helpful to manage r(14) children more effectively.

In 2019, a medical student and dentist reached out to Ring14 USA Outreach, a non-profit organization founded by a group of mothers whose children have r(14). The mothers advocate not only for the children but also the doctors, caregivers, friends, and family who help to care for these children. They also work to raise public awareness about the disorder. The medical student asked if the mothers would be willing to answer some questions about their experience with the disease in the form of a survey. Participation by the mothers was voluntary and informed consent was obtained. The study conformed to the tenets of the Declaration of Helsinki as well as the requirements established by our institutional review board.

The survey was comprised of 26 questions, which included: five anthropometric questions related to gender, race, birth weight, current weight, current height; diagnostic tests conducted; type of doctor who delivered the diagnosis; onset of the disease; signs and symptoms at disease onset; current signs and symptoms; if other members of the family had the disease; whether microcephaly was present; and presence of lymphedema. Does the child experience any seizures? If so, when did they begin? How frequently do they occur? What type of seizure is experienced? Have any antiepileptic medications been administered? Was treatment effective in controlling the seizures? To what extent is the child capable of communicating?

Questions related to dentistry included: Has the child ever visited a dentist for an oral/dental examination? If so, how did the child respond to the dentist? At what age did the child begin to develop their permanent teeth? Does the child present with any oral abnormalities, for example, oral sores, ulcerations or patches, delayed eruption of teeth, bleeding and inflammation of the gums, missing or supernumerary teeth?

Two questions asked: Is the I.Q. of the child known? If so, what is the I.Q.? Finally, the mothers were asked: Are there any additional complications? What is the most challenging aspect of this disease for the child and the caregiver/parent/guardian? Is there any additional information, comments, signs, symptoms, behavioral patterns? If possible, the mothers were asked to attach photos demonstrating specific abnormalities related to their child’s condition, for example, facial dysmorphisms, misaligned teeth, etc.

Of the 13 patients queried, 7 were male and 6 were female. The age of the patients ranged from 5 to 49 years. Ten patients were of European ancestry and three were Hispanic, all residing across the U.S. In all 13 cases, the onset of disease was marked by seizures at infancy, at about 3 months and as early as 3 weeks. No other family members had a history of the disease. All the patients suffered from ‘global development delay’, taking longer than other children their age to reach key developmental milestones, such as walking or talking, acquiring fundamental movement skills, and learning to interact with others. The ability of the children to communicate was limited, some with a vocabulary limited to a few words and most very good at communicating with facial expressions, cries, or simply pulling at their parents to get their attention. Other complications included lung disease, scoliosis, tracheotomy, and feeding tube.

All the children were characterized as having a pleasant and affectionate demeanor. Most were short in stature, microcephalic, and presented with distinctive facial features. The face was generally elongated and presented with a high forehead. The eyes were widely spaced and distinguished by down-slanted palpebral fissures. The nasal tip was prominent and the nasal bridge was flat. The ears were set low and the upper lip was thin. Other craniofacial features included micrognathia and a high palate.

All the individuals suffered from epilepsy, which in most cases was drug resistant. The onset was varied, but usually presented during the first few months after birth. The seizures were mostly generalized, but could also be focal and spread to other areas. Seizures could occur when the children were awake or asleep. Cluster seizures were also possible, occurring over a period of 24 hours. However, status epilepticus was not indicated in any of the individuals. In two cases, the frequency of seizures gradually ameliorated by the time they became adolescents. In half the patients, however, the seizures were reported to be so intense that it would often set back previous gains in language and psychomotor skills.

Recurrent infections and episodes of exanthema could also trigger seizures. Seizures could eventually become less frequent, but they did not completely disappear. Antiepileptic drugs were frequently used, including carbamazepine, valproic acid, vigabatrin, topiramate, clobazam, and others. About half of the children developed some degree of drug resistance, while the other half had seizures under varying degrees of control. In two cases, where seizures seemed to disappear altogether and effective antiepileptic drugs were stopped, the seizures returned but would not respond to former medications.

One patient experienced complications of insomnia, mood disorder, neurogenic bladder, autism spectrum disorder, mild cerebral palsy, global development delay, chronic dehydration, chronic constipation, keratosis pilaris, allergies, and microcephaly. Her mother stated, “She can carry a simple conversation, but she cannot read or write and the pronunciation of the words is not always correct.” Another patient had low muscle tone, feeding issues, global delayed development and sometimes expressed aggressive behavior. One child was born with a heart murmur, high bilirubin, hypothyroidism, and feeding difficulties. Another child with brain malformations had GI issues, severe reflux, low tone, esophagitis, dysphagia, neuronal migration disorder, and global developmental delay. The child was completely non-verbal.

Moderate to severe intellectual disability was a consistent feature among the r(14) children studied. This condition appeared to correlate with seizure severity and time of onset. Autism spectrum disorder presented in children who experienced their first seizure very early on. Most of the children achieved postural control by their first birthday, while those who could walk took their first steps by 3 years of age. Unfortunately, two patients were not able to walk at all.

Language was the most common developmental disability. Behavior disorders were also reported in many of the children. Although the children were described as usually good natured, tantrums were also noted. Behavior characteristics of autism included anxiety, restricted or repetitive motor movements, obsessive routines, hyperactivity, and heightened or lessened excitability to sensory input.

Additional issues included feeding issues, slow gastric emptying, and pump feeds at night. One child, reported as having sensory processing disorder, was delayed in expressing when he feels pain. Another child, reported as having intractable epilepsy, OCD, sensory processing disorder (SPD), autism, pronated ankles, mental and growth delay, and compromised immune system was completely non-verbal. Behavior patterns such as sensory seeking seemed very common. Others suffered from strabismus, renal issues and were tube fed. In addition to seizures, some children experienced ataxia and body tremors, while others suffered from joint contractures.

Hypotonia was also common with the children and often involved the axial muscles. Physical therapy could help to gradually improve muscle tone in many. However, impaired motility beginning during infancy could result in muscle contractions, scoliosis, and flat foot.^[1]

Many of the r(14) children suffered from frequent upper respiratory infections, though cases of recurrent pneumonia were rare. Since many of the children also suffered from gastrointestinal issues, malnutrition was a serious concern. At times, the condition could be life threatening, especially when factoring in the role of seizures.^[1–5] Refractive issues such as myopia and astigmatism can also be observed in r(14) syndrome.^[1–5] However, strabismus was most often reported. Less frequently observed conditions included sleep disorders and arthritis, as well as congenital heart defects.

The r(14) children in this study have varying ability to comprehend dental treatment and cooperate with the dentist. Thus, detecting caries and other dental issues by means other than observation may be problematic. Obtaining an accurate dental history may be difficult due to limitations on the child’s ability to communicate effectively. R(14) children with autistic traits may have a higher pain threshold and, consequently, may not indicate to the dentist when they are experiencing major discomfort. Behavioral issues, including hyperexcitability and bursts of aggression may also hamper the delivery of treatment.^[10–15] Temper tantrums and other violent behaviors, triggered by invasive dental treatments, may expose the child to the risk of self-injury. Thus, in some cases, general anesthesia may be necessary to execute full mouth rehabilitation and allow the dentist to provide comprehensive treatment in a single appointment safely and without rushing.^[7] The child’s parents must also be made aware of the importance of routine dental check-ups and follow-ups. A successful long-term care plan should include routine oral prophylaxis, effective oral hygiene homecare that may require assistance from the parents, fluoride treatments, and consumption of non-cariogenic healthy foods such as cheese, nuts, and plain milk.‌^[7]