Elsevier

Sleep Medicine Reviews

Volume 24, December 2015, Pages 46-56
Sleep Medicine Reviews

Clinical review
Pediatric sleep-disordered breathing: New evidence on its development

https://doi.org/10.1016/j.smrv.2014.11.008Get rights and content

Summary

Sleep-disordered breathing (SDB) in children could be resolved by adenotonsillectomy (T&A). However, incomplete results are often noted post-surgery. Because of this partial resolution, long-term follow-up is needed to monitor for reoccurrence of SDB, which may be diagnosed years later through reoccurrence of complaints or in some cases, through systematic investigations. Children undergoing T&A often have small upper airways. Genetics play a role in the fetal development of the skull, the skull base, and subsequently, the size of the upper airway. In non-syndromic children, specific genetic mutations are often unrecognized early in life and affect the craniofacial growth, altering functions such as suction, mastication, swallowing, and nasal breathing. These developmental and functional changes are associated with the development of SDB. Children without genetic mutations but with impairment of the above said functions also develop SDB. When applied early in life, techniques involved in the reeducation of these functions, such as myofunctional therapy, alter the craniofacial growth and the associated SDB. This occurs as a result of the continuous interaction between cartilages, bones and muscles involved in the growth of the base of the skull and the face. Recently collected data show the impact of the early changes in craniofacial growth patterns and how these changes lead to an impairment of the developmental functions and consequent persistence of SDB. The presence of nasal disuse and mouth breathing are abnormal functions that are easily amenable to treatment. Understanding the dynamics leading to the development of SDB and recognizing factors affecting the craniofacial growth and the resulting functional impairments, allows appropriate treatment planning which may or may not include T&A. Enlargement of lymphoid tissue may actually be a consequence as opposed to a cause of these initial dysfunctions.

Introduction

Sleep-disordered breathing is related to upper airway collapse during sleep. In order to appreciate how this collapse occurs, it is important to have an understanding of the development and anatomy of the upper airway. The size of the upper airway and factors contributing to its narrowing can lead to increased risk of collapse and subsequent abnormal breathing during sleep. Because the upper airway is located below the skull and behind the face, any developmental changes in either of these two structures will impact the size of the upper airway. Facial growth is relatively rapid early in life. At birth, the face represents one-seventh of the craniofacial structures and 50% by 20 y of age. Eighty percent of this development is reached early in life, by the age of 5–6 y [1]. The two facial components that are key in determining the size of the upper airway are the naso-maxillary complex and the mandible.

The naso-maxillary complex is located at the anterior part of the skull, and its growth has been classified by Bjork [2] according to age. From infancy until the toddler period, growth is 1 mm/y. During the prepubertal period (5–11 y), growth slows down to 0.25 mm/y and then accelerates again during the peripubertal period (12–17 y) to 1.5 mm/y. Maximal growth is thus seen early in life and during puberty.

Facial growth is influenced during the fetal period by the brain growth and in humans, particularly by the vast development of the frontal lobe. The growth of the brain is critical in the development of the face. As indicated by Enlow and Poston [3], there is a distinct angle between the vertical axis of the brainstem and the spinal cord, known as the nevrax, and the cortical regions. This angle is more or less obtuse and impacts the development of the face and features distinct to the ethnic differences seen between Caucasians and Far-East Asians [4]. Genetics also play a role in the growth of the brain and thereby the skull and its base which then impact the size of the upper airway. This association is clearly demonstrated in that the posterior width of the middle fossa of the skull is the exact lateral size of the erect and awake adult pharynx. The development of these structures further defines the relationship between the maxilla and the mandible, categorizing subjects either as “Class II” or “Class III”, based on their relative position to each other in addition to the upper and lower teeth. A Class II malocclusion refers to a retrognathic abnormal posterior positioning of the maxilla or mandible, particularly the mandible, relative to the facial and soft tissue structures. The mesiobuccal cusp of the upper first molar is not aligned with the mesiobuccal groove of the lower first molar and instead sits anterior to it. Conversely, a Class III malocclusion is prognathic with the upper molars posterior to the mesiobuccal groove of the mandibular first molar.

The interaction between the development of the naso-maxillary complex and support of the head in an individual with vertical posture is a critical adjustment. The extremity superior and posterior of the odontoid must be aligned, and this involves exact placement of the spheno-palatine suture, the anterior part of atlas, and the superior limit of the odontoid. The spheno-palatine suture involves the “spenoidal angle” (Ba–S–Na) and the position of the naso-maxillary complex, i.e., the face. The sphenoidal angle can be easily traced on lateral cephalometry that is obtained in standardized conditions fixing the head in a defined position through usage of a cephalostat. Three structures easily recognizable on this form of imaging are the sella turcica (S), the nasion (N) and the posterior base of skull (basion-B). The Ba–S–N angle in a normal adult, is about 120°, although this measurement varies based on several factors including ethnicity. Delaire [5] defined a segment of this angle, the line from S to B, as C4. Calculation of the position of the superior and posterior part of the odontoid in relation to the two other landmarks in the occipital hole (anterior part of atlas and speno-palatine suture) allows to determine abnormal positioning of the odontoid. Any abnormalities in the development of this crucial junction may lead to well-known neurological syndromes such as hydrocephaly, Arnold-Chiari, Dandy-Walker and other conditions typically associated with abnormal breathing dominant during sleep. The placement of the face and the development and adjustment of the naso-maxillary complex is vital in maintaining the crucial protection of the neuro-vascular structures below the cerebellum. This complex interaction between growth of the face and the posterior skull-base is again a consequence of being erect and having a relatively large brain to support in this erect position Fig. 1.

The development of the face is thus a very closely regulated event, with continuous interaction between the development of the entire brain, the skull, and the skull-base.

The growth of the transversal portion of the naso-maxillary complex is influenced by three factors, the development of the nasal fossae during fetal life, the growth of the ocular cavities related to ocular development during fetal life, and the activity of the inter-maxillary suture that utilizes an enchondral mode of ossification and is active until about 16 y of age and undergoes complete synostose by the age of 25 y. The face is located at the anterior most point of the skull-base and is therefore especially dependent on the processes involved in its growth with maxilla and mandible been ”pushed forward” by the development of the skull-base.

Genetic factors are critical in such development. Most of the growth of the skull-base is cartilaginous growth, and growth occurs in relation to “synchondroses” [6]. These serve as the site of bone growth in the skull-base and are located in the sutures between the bones forming the skull and the skull-base. Synchondroses undergo three stages of growth and are particularly active during the “chondro-synostose” phase and early in life up to 5 y of age. If they are not stimulated, they may not induce growth. The spheno-sphenoidal chondrose is responsible for the vertical growth of the skull base. It has an oblique direction and lowers the location of the occipital lobe thereby affecting facial growth. The growth of the naso-maxillary complex is related not only to the sphenoido-occipital synchondrose but also to the activity of the synchondrose of the skull base and particularly the cleft at the following sutures: inter-malar, inter-maxillary, inter-palatine, maxillo-malar, and temporo-malar.

It is important to note that the inter-maxillary suture is active postnatilly as mentioned above, and is influenced by specific functions, such as suction, mastication, swallowing, and nasal breathing. These functions mobilize the facial muscles that play a clear role in facial growth.

The development of these functions is influenced by the quality of nasal respiratory roles, dental development which involves the position and height of alveoli and teeth position, and the activity and strength of the tongue and facial muscles. These facial muscles include the labial muscles, which influence not only the facial growth but also the position and height of the hard palate. As mentioned previously, the vertical growth of the naso-maxillary complex is related to the activity of the posterior skull base but also to that of the frontal-malar, frontal-maxillary, and maxillo-malar sutures. It is also related to the position of the hard palate and the alveolo-dental activity [6].

While the mandible is also involved in the space controlling the size of the upper airway, it is independent of the base of skull and instead associated with the cervico-thoraco-digestive axis. This structure involves many muscle and ligament attachments and dictates head posture. It has both membranous and enchondral growth. The mandible is comprised of two parts, the condyle and the body. Although both these parts determine the upper airway size, the condyle plays a significantly more important role.

Genetic factors influence mandibular development in fetal life; other factors, however, are involved after birth. Trauma impacting the condyle's function as a joint can occur in a variety of ways, such as from a vaginal delivery using or even not using forceps, from a fall, or from inflammation due to disorders such as juvenile idiopathic arthritis [7]. This disorder impairs growth through rapid ossification of the joint. Any changes in the position of the condyle will cause the growth region to migrate. An example of this is apparent in cases in which chronic buccal (mouth) respiration develops. The position of the condyle in the articulation changes, and therefore the growth location also changes, transferring cartilaginous production more posteriorly. This will alter the incline at which bone grows causing a posterior mandibular rotation during youth development and leading to narrowing of the upper airway.

Three phases exist in the condylar growth and activity: Phase 1: fetal and early postnatal life where the suction function will be vital to the postnatal growth. Phase 2: 1–20 y of age where the mastication function influences growth and there is a progressive but clear decrease in growth role. Phase 3: the joint no longer has a growth role [6].

Genetic abnormalities affecting membranous and cartilaginous craniofacial growth can lead to obvious malformation syndromes associated with sleep-disordered breathing (SDB) such as Appert, Crouzon or Traecher-Colin syndromes [8] In these disorders, abnormal breathing during sleep is recognized early in life.

However, in genetic impairments of endochondral growth leading to SDB, recognition is often delayed until after childhood. Ehlers Danlos syndrome (EDS) [9] is secondary to either an autosomal dominant, autosomal recessive, or X-linked mutation of genes located on proteins or enzymes, most commonly COL-1A1, COL 5A1, or 5A2. Several degrees of Ehlers Danlos syndrome have been described in humans, with one form not commonly recognized until adulthood as it manifests only with hyperextensibility of articulations and development of SDB. SDB may lead to complaints, but because the clinical symptoms are more of poor sleep, insomnia, daytime fatigue, rarely parasomnias, and attention difficulties in school or at work, they may not immediately be recognized as obstructive breathing during sleep. Regular evaluation of young family members of an adult case may uncover abnormal breathing during sleep when systematic polysomnography (PSG) is performed. In a report of our recently seen cases [9], clinical symptoms were as those mentioned above, with the most significant PSG finding being the degree of flow limitation [10], [11] during total sleep time more so than the apnea–hypopnea index (AHI). Clinical evaluation again demonstrated the presence of an abnormally long face, narrow and high hard palate, and frequently associated cross-bite. While initially only abnormalities of the naso-maxillary complex may be seen, as patients enter adulthood and develop worsening SDB, defects of the condyle may also be found Fig. 2.

The syndromic EDS with cardiac or other systemic complication and more importantly, the often unrecognized non-syndromic cases with only hyperlaxity, demonstrate that impairment of the normal naso-maxillary complex and mandibular growth during fetal life leads to abnormal breathing during sleep in childhood.

When teeth are absent or are extracted in early life during their growth, this can lead to bone retraction and affect the facial growth. Over the past seven years, we have collected data on 257 individuals of age 14–30 y, who underwent extraction of wisdom teeth and had associated symptoms of obstructive breathing during sleep. These patients had documented flow limitation [10], [11] between 50 and 90% of total sleep time and presence of obstructive sleep apnea (OSA) with a mean apnea–hypopnea index (AHI), as defined by the American Academy of Sleep Medicine (AASM)-2013 [12], of 7.5 ± 2.3 events/h.

During this initial investigation, it was revealed that some of these patients had prior recognition of wisdom teeth agenesis. After this discovery, a systematic search was done to retrospectively analyze, through collaboration with an orthodontist, an association between teeth agenesis and presence of OSA in non-syndromic children seen during the prior five years. Forty-one cases were found. Dental agenesis is linked to genetic mutations with a dental homeo-code for agenesis of canine, incisive, and molar teeth. These mutations involve certain transcription factors as demonstrated in mice investigations [13]. We identified varying degrees of agenesis of the molar, incisive, and canine teeth. Independent of the degree of dental agenesis, all 41 subjects, aged 4–14 y, referred to an orthodontist office for their teeth agenesis and not for any symptom associated with sleep-disordered breathing, presented with abnormal breathing during sleep with associated flow limitation for more than 50% of total sleep time, a mean AHI of 7.3 ± 2, and a mean minimum oxygen saturation of 90 ± 1.5% Fig. 3.

Clinical history revealed the presence of daytime fatigue more so than daytime sleepiness, poor sleep, and difficulty in school due to poor concentration and attention span. Less frequently (n = 18), there was a positive history of parasomnias. On clinical evaluation, all cases had an abnormally “long face” with an elongated lower facial third in addition to an abnormally narrow hard palate. In some cases, parents were hesitant to consider the possibility of abnormal breathing during sleep. This is likely due to poor recognition of abnormal facial features associated with SDB in the dentist-orthodontist and pediatric communities. The association between congenitally missing teeth and facial skeletal changes with “straight to concave profile, pointed chin, reduced lower facial height and altered dental inclination” was already noted by Ben-Bassat and Brin (2009) [14] but these authors did not investigate breathing during sleep.

Embryologic development and craniofacial studies have shown that at least one Homeobox gene [15], the muscle segment homeobox gene (Msx1), is involved in early embryological development of the facial aspects derived from the neuro-ectodermal stratus. While this gene is very active early in development, its expression becomes more limited in “progenetrical cells,” controlling proliferation and differentiation of cells involved in formation of the craniofacial skeleton.

Msx1 controls proteins diffusing outside the cell, such as growth factors, particularly the bone morphogenetic protein (BMP4) that also has an inductive role on Msx1 expression. Overexpression of Msx1 keeps bone and odontoblastic cells in an undifferentiated state. Msx1 controls specific cell populations, particularly the amount of mother cells involved in the formation of bones. Mutations of Msx1 are associated with presence of dys-genesis such as in Pierre Robin syndrome, a syndrome associated with SDB. The MSX1 and PAX9 proteins are highly correlated and the presence of mutations in these genes has been considered to lead to a haploinsufficiency (i.e., reduced amount of functional protein) allowing occurrence of abnormalities in odontogenesis [16]. The genes homeobox LHX 6/7 and Gsc are also involved in placement of the odontogenic cells and control the growth factor FGF8. This growth factor, through induction of a protein (Lf7), inhibits Gsc, and then the DLXs genes [13] induce odontogenesis, as do the genes LHX 6/7.

The DLX genes, as mentioned above, were well studied in mice [11] and shown to cause specific mutations altering dental development. In humans, the DLX genes are located on chromosome 7, showing a similar dental homeocode as that existing in mice. This dental homeocode, deciphered by Thomas and Sharpe [13], shows a link between specific dental agenesis and certain mutations of or elimination of one of these genes. For example, absence of DLX1 and DLX2 leads to absence of molars in the maxilla, and mutations of DLX 5 and 6 lead to absence of inferior molars. Other genes have been associated with dental agenesis and: Mutations on Pax 9 on chromosome 14 is associated with variable forms of oligodontia that mainly affect the molars and mutations involving AXIN2, WTA10, EDA genes have also been associated with hypodontia [8], [14], [17], [18], [19], [20], [21], [22], [23], [24], [25]. But potentially many other genes could be involved as several hundreds – up to 200-have been mentioned as directly or indirectly involved in the regulation of tooth development [14], [23]. Table 1 indicates the major families of genes that may be associated with genetic mutations leading to abnormal ondotogenesis.

Dental research has shown that tooth agenesis is a common congenital disorder, it may be associated with syndromes but it is also often seen in non-syndromic children and its prevalence has been variable depending of authors but findings oscillate between 10 and 20% of the studied population [20]. Most commonly only one tooth is agenetic but in 10% of the agenetic cases two are involved with the 2nd premolar and the lateral incisive being considered as more frequent agenesis and 1–2% having oligodontia.

In our children recognized with SDB there were at least two agenetic teeth. The clinical presentation was not obvious as snoring was not a chief a symptom as the more regularly mentioned mouth breathing [26]. During infancy, they were crying infants labeled as having colic, sleep disruption, poor development of long sleep phase with circadian clues [27] and difficulty in feeding. When older, the children and their parents, complained of daytime fatigue, impaired attention and focus in school, and poor and disrupted sleep more so than daytime sleepiness [28]. Clinical evaluation outlined presence of a high and narrow hard palate and an asymmetrical development most often involving the lower third of the face and frequently associated with a counter-clockwise rotation of the mandible. Evaluation of the upper airway shows an abnormal Friedman–Mallampati scale score [29], [30] of 3 or 4 and a high and narrow hard palate associated with a narrow maxilla with or without cross-bite. A deviated septum and mouth breathing are commonly found in association with a high and narrow hard palate, likely from hard palate elevation. The most significant PSG finding was the degree of flow limitation [10], [11] during total sleep time more so than the AHI. There was a progressively increasing AHI with age, with this latest finding suggesting perpetual worsening after birth with age.

Our cases demonstrate the important role of abnormal craniofacial growth in the development of pediatric SDB and involvement of synchondroses particularly those still active during childhood.

There is an interaction between muscle activities, particularly those of the face, and growth and normal development of the upper airway. Genetic abnormalities impairing normal activity of striatal muscles, including facial muscles, lead to SDB. The most studied genetic disorder involving mutations and generalized muscle impairment is myotonic dystrophy, both type I and type II [31]. The impact of abnormal facial muscle contractions present in myotonic dystrophy on the development of SDB in children was investigated and demonstrated many years ago. The studies showed a progressive worsening in AHI from the teenage years to adulthood. There was also increased worsening of daytime sleepiness documented by a multiple nap test; clinical features included presence of a long face and a high and narrow hard palate. The deduction from these studies is that the abnormal activity of muscles controlling the craniofacial structures also has an impact on the development of the naso-maxillary complex and the mandible leading to a small upper airway. Myotonic dystrophy is again related to genetic mutations that are already present during fetal life. Other genetic mutations that diffusely impact all muscles in the body may also lead to SDB, again due to impairment of normal facial muscle functioning: in our own clinical pediatric cases, Duchenne dystrophy was also associated with high narrow hard palate and with a combination of obstructed breathing and respiratory problems related to muscle weakness during sleep. Training in breathing and facial muscle activity is present during fetal life as demonstrated by ultrasonography [32], so abnormalities of craniofacial growth related to muscle impairments due to genetic mutations may begin in-utero.

Experiment done by Harvold et al. involving monkeys [33], demonstrates that non-genetic postnatal impairment may also have a similar impact as genetically induced muscle impairment. Between 1980 and 1990, a number of ground-breaking experiments on newborn rhesus monkeys were performed, whereby a small silicone head was placed within the nostrils of infant monkeys and held in place by a thin thread in order to induce nasal resistance for the first six months of life [33], [34], [35], [36]. The blockage of the nasal passages led to narrowing of dental arches, decrease in maxillary arch length, anterior cross-bite, maxillary overjet, and increase in anterior facial height [33], [34], [35]. Experimentally induced abnormal nasal resistance led to systematic changes in the orofacial muscles. The changes were noted in the recording of different muscles, in particular the geniohyoid, the genioglossal muscles of the tongue, the suprahyoid dorsal tongue fibers, the upper lip elevators, and the digastric muscles. EMG testing showed abrupt induction of rhythmic discharge patterns, a stark contrast to the nearly continuous and desynchronized discharges in most normal subjects. Tonic EMG discharges reverted back to the normal pattern when nasal breathing was restored at the end of the six-month experiment [34]. These experiments demonstrate that impairment of certain normal functions impact normal craniofacial growth. In this particular study, impaired nasal breathing had an impact on the inter-maxillary suture (as do mutations seen in Ehlers Danlos syndrome [9]), and secondary mouth breathing also had an immediate impact on the mandibular condyle position. This experimental manipulation impacting tongue and facial muscle activities consequently leads to craniofacial growth impairment and mouth breathing which narrows the size of the upper airway and further deteriorates normal nasal breathing, particularly during sleep.

The experimental data show presence of a continuous interaction between abnormal nasal resistance and orofacial growth through the intermediary of abnormal muscle tone and mouth breathing (with a change in the mandibular condyle position). The abnormal growth leads to further worsening of the nasal resistance. The consequence is a small upper airway.

In children, prematurity is often associated with generalized muscle hypotonia. Its severity is dependent on degree of prematurity. In our follow-up cohort of 400 premature infants born as early as 27 wk of gestational age, initial evaluations of 292 of these infants indicated progressive development of obstructive breathing during sleep. This was in spite of the disappearance of the diaphragmatic apneas of prematurity [37]. This atypical breathing pattern was associated with the development of mouth breathing and a high and narrow hard palate. Early premature infants have often abnormalities involving feeding functions such as suction, mastication, and swallowing with weakness of orofacial muscles that negatively alter the craniofacial growth, and lead to small upper airway.

Full term children are also at risk due to abnormal functional behavior early in life. These infants have no identifiable genetic or neurological disorder and have a normal oto-laryngological evaluation but are found to have abnormal mouth breathing or mild feeding difficulty despite a normal growth curve. Subsequent PSG in this subset of infants has shown flow limitation and a low but abnormal AHI with disrupted nocturnal sleep during the first six weeks of life [37]. It is possible that these infants have an unrecognized genetic problem despite thorough clinical evaluation, but the abnormal functional behavior, including the presence of mouth breathing during sleep, was the only evidence of increased risk for SDB. This suspicion was confirmed by PSG done in the ensuing 10 mo that showed a slow but progressive increase in flow limitation and secondary development of snoring sounds.

Some muscle activity limitations are easily recognized at birth such as the presence of a short anterior frenulum leading to abnormal feeding behavior and speech development. All our children with short mandibular frenulum had an association with SDB when seen untreated between two and six years of age. They all had a narrow and high hard palate Fig. 4.

Dental agenesis may be related to infection (e.g., rubella), chemotherapy, radiation or toxic substances (Thalidomide) [38], Schalk-van der Weide et al. [39] reported impact of extraction of temporary teeth and secondary permanent dental agenesis. We have studied a small group of 11 children with permanent teeth extraction (mostly second molar or lateral incisive) between age 10 and 13 y who developed symptoms of SDB within five years associated with abnormal maxilla-mandibular growth and small upper airway.

Chronic inflammatory diseases, such as rheumatoid juvenile arthritis, that lead to impairment of temporo-mandibular articulation leads to post-natal abnormal craniofacial growth with again progressive development of small oral cavity and presence of a high and narrow hard palate. In our children we observed presence of abnormal breathing during sleep as early as two-years of age associated with poor sleep [40]. Trauma on temporo-mandibular articulation has similar impact: in our own data-base we have three teen-agers with unilateral trauma that led to secondary impairment orofacial growth, narrow oral cavity, daytime fatigue and sleepiness and typical sleep-disordered breathing.

The above findings imply that there are pathways at play placing children at increased risk of development of SDB abnormal functional behavior during wake and sleep associated with craniofacial growth. There appears to be a continuous interaction between function and development involving the craniofacial region. Impairment of growth due to genetic mutations, environmental factors, and interaction between environmental factors and genes (epigenetics), leads to changes in facial growth patterns that influence facial tasks. These functional impairments have a negative feedback on orofacial growth, further impairing functions. The consequence is presence of a reduced upper airway size which in association with sleep leads to SDB.

Adenoids and tonsils are secondary or peripheral lymphoid organs that develop during fetal life with lymphoid tissues developing near the fifth week of fetal life [41]. They are the sites of lymphocyte activation by antigens. When activation occurs, there is a clonal expansion and affinity maturation. The mature lymphocytes recirculate between the blood and the peripheral lymphoid organs looking for the specific antigen that they have been matured to target. It is in these secondary lymphoid tissues, specifically the adenoids and tonsils, that the antigen (a foreign or altered native molecule) is placed in contact with the lymphocytes. The specific lymphocytes targeted are primarily in the follicles present in adenoids and tonsils. Reaction against foreign molecules may be related to genetic patrimony, exposure during fetal life, or even due to the temporary interaction between a mother's immune defense system and the infant's own genetic patrimony. An inflammatory reaction will be triggered by the interaction between an antibody and the foreign molecule. This reaction leads to subsequent enlargement of the organ. Viral infections, cysteinyl leukotrienes endogenous synthesis, history of wheezing and familial factors play also an important role in the pathogenesis of adenotonsillar hypertrophy. Nasal turbinates are not similar to adenoids and tonsils, but they are also a site of the allergen and antibody reaction and therefore also swell and enlarge as a result of this effect.

It has been assumed that the enlargement of lymphoid tissues (probably related to the underlying inflammatory reaction discussed above) was directly related to the development of SDB early in life. Systematic evaluation of palatine tonsils in 27–35 wk of age premature infants, however, indicates that tonsils are small early in life [37]. Adenoids could not be investigated in this study, and thus enlargement of adenoids could not be ruled out. It is important to note that children without tonsil and adenoid enlargement as documented by cephalometric X-rays but with dental agenesis also develop SDB in early childhood.

Based on these findings, it appears that adenotonsillectomy may not be the primary treatment modality in preventing the development of SDB. There is a balance between bone and tissue development. The importance of maintaining this relationship has been shown as discussed above, however, postnatally there is also interaction between specialized tissue size and function. Due to fetal processes, an individual may have a naso-maxillary build-up that does not allow a large pharyngeal space [3]. The pharynx relates specifically to the middle cranial fossa and the size of this specific fossa in humans determines the horizontal dimension of the pharyngeal space, and these spatial relationships are established during fetal life. Any reduction in skeletal dimensions will influence the space allocated for soft tissues. Similarly, enlarged adenoids will lead to impaired nasal breathing depending on the degree of bone development. Inflammatory reactions also play a role in influencing nasal breathing depending on the fetal development of the skull base and craniofacial structures.

Adenoids and tonsils influence function not necessarily because of their absolute size but due to their relative size compared to the available space. Because of their entrapment in a relatively small space due to adeno-tonsil enlargement, soft tissues will also become functionally impaired. If this impairment is counteracted by an increase in tongue and facial muscle activity, there may be no functional deficits of the soft tissue. If, however, this does not occur, the result will be continuous mouth breathing and nasal disuse [26]. Despite this absence of functional deficit, these children will still be vulnerable to sleep disruptions as discussed below. If the compensation is insufficient, there will be progressive development of a complete disuse in nasal breathing, leading to long-term consequences.

In the former situation in which there is adequate compensation of the tongue and facial muscles to offset soft tissue defects, children will not develop mouth breathing; putting them at time at a disadvantage should there ever be abrupt worsening of nasal flow during sleep. In this situation, they will not have the adapted tool of mouth breathing to compensate. This is commonly seen in very young infants where there is an increased effort to breathe nasally and no appropriate mouth breathing. This increased inspiratory effort will lead to increasingly negative intra-thoracic pressures with induction of the Muller maneuver and associated autonomic nervous system changes. Progression of these movements against a partially closed glottis will lead to a significant decrease in the already small tidal volumes of these infants. There will be development of asphyxia and potentially even death as documented on autopsies of infants with abrupt and unexplained deaths during sleep [42], [43]. In those with inadequate tongue and facial muscle strengthening to counteract soft tissue impairment, there will be absence of return to normal breathing during sleep post T&A, even with concurrent aggressive nasal allergy treatment. This lack of control of abnormal breathing during sleep post T&A has been well documented in numerous studies of older children [44], [45], [46], [47], [48], [49]. Interestingly, long-term prospective follow-up of children who appeared to have significant initial improvement following T&A [50] has shown reoccurrence over time despite absence of abnormal soft tissue in the upper airway. This finding has been confirmed in two retrospective studies [44], [45].

There are several reasons why abnormal breathing during sleep in these children post T&A goes unrecognized. Changes in skeletal growth may not be well investigated and at times difficult to recognize by non-specialists. Even if a diagnostic PSG is done, a poor understanding of abnormal breathing patterns during sleep in children may lead to underscoring of respiratory events. Inappropriate or limited usage of tools, such as the esophageal manometry and appropriately calibrated nasal cannula pressure transducers, also hinder appropriate detection of these events. There tends to be too much reliance on oxygen saturation recordings and lack of appropriate investigation of arousal patterns in the sleep electroencephalogram (EEG). Finally, no systematic effort is made to ensure that the functions altered by abnormal breathing during sleep are managed appropriately in order to restore nasal breathing during wake and sleep periods.

There are several questions regarding the development of enlarged tonsils and adenoids. As noted previously, enlarged tonsils in premature children were observed only after documentation of abnormal breathing during sleep and presence of an obstructive pattern on PSG. Questions then arise whether continuous mouth breathing secondary to impaired nasal breathing leads to lack of appropriate oral humidification and, as a result, a local inflammatory reaction. In addition to changes in humidification, temperature, and air turbulence, there is also micro-trauma related to the mouth breathing itself. Oral breathing also leads to functional changes, including abnormal swallowing, feeding, and occurrence of esophageal reflux. Increasing respiratory efforts affect the diaphragmatic movements causing augmented pressure on the stomach, particularly at feeding times. This may lead to recurrent micro-trauma of the oropharynx and the adenoids with secondary inflammatory reactions. Specialists trained in myofunctional reeducation of infants have documented the need to train young mothers on appropriate positions in which to breast or bottle-feed infants [51]. Finally, in some instances, food or other allergies documented early in life may be present concurrently with inflammatory reactions causing palatine tonsils, adenoids or nasal turbinate enlargement and thereby reducing the upper airway size. A negative cycle then ensues in which impairment of nasal breathing leads to functional impairment, affecting the skeletal growth. This is well documented in experiments done on Rhesus monkeys [33], [34], [35], [36].

In summary, it had been previously assumed without complete rationale that enlarged palatine tonsils and adenoids were the major cause of SDB in early childhood. There is a dependent relationship between appropriate nasal breathing and skeletal and soft tissue growth and distribution. Any defect in nasal breathing will affect many fundamental functions during early development and would lead to SDB. To ignore such interactions and focus on what may be the most visually recognizable abnormality, leads to inadequate and limited treatment.

Problems associated with abnormal nasal breathing were recognized prior to recognition of incomplete treatment with T&A for SDB [52], [53], [54]. The understanding of the relationships between function and growth of the craniofacial structures led to experiments on how the honing of the use of these functions would impact the craniofacial growth. Myofunctional therapy done in association with orthodontia and craniofacial surgery has been shown to correct the deficits caused by abnormal growth patterns [55], [56]. Myofunctional therapy was developed as a significant tool in Europe in the 1960s. Specialists of the craniofacial sphere recognized the continuous interaction between the facial muscle activity and orofacial development. Individuals such as Delaire in France and Planas in Spain created therapeutic protocols utilizing the stimulation of proprioception and motor activity in the orofacial region in children with craniofacial syndromic presentations and orthodontic problems [55], [56]. The extension of these myofunctional therapy protocols to those with SDB is more recent and has been shown to have limited benefit in improving outcomes in some centers. These published trials have been on adults in Brazil [57] and children in France, Northern California, and Taiwan [42], [43]. They suggest the possibility of strengthening in function and thus ensuing improvement in SDB. In children, improvement in SDB is accomplished through modification of craniofacial growth. In 2009, Guimares et al. [57] reported on the effects of tongue and facial muscle exercises in adults of age 25–65 y with OSA, with a mean AHI of 22.4 ± 6.48, i.e., moderate OSA. Outcome measures after three months of approximately 30 min of daily exercises showed not only improved PSG results (with an average AHI score of 13.7 ± 8.5), but also improved scores evaluating sleepiness, snoring, and sleep quality. Compared to the control group, subjects had significant improvement in all outcome measures.

Huang and Guilleminault [37] studied five premature infants at approximately 36 wk gestational age (GA), including a pair of twins born at 34 wk GA. The patients underwent myofunctional therapy from birth on, and at six months of age, were documented to have normal breathing during wake and sleep verified by nocturnal PSG. They had a normal craniofacial anatomy, normal hard palate, and normal nasal breathing, findings very different from all other studied premature infants who went on to develop obstructive respiratory patterns during sleep. Myofunctional therapy encompassed usage of primitive tongue reflexes to entice the tongue into a specific position. The children sucked on specially designed hard toys and also used a hard rather than soft nipple to feed. In doing so, the premature infants were forced to develop normal suction and swallowing responses. Guilleminault et al. [58], ∗[59] reported on the role of myofunctional reeducation in the development of nasal breathing and normal craniofacial development post T&A. These subjects acquired a normal naso-maxillary complex and mandible compared to those non-compliant with the exercise program in the control group. Recent studies have emphasized the importance of normal nasal breathing during sleep, most commonly associated with appropriate craniofacial growth and development of a normal upper airway.

Myofunctional reeducation hones the development of a normal and strong suction, mastication employing both sides of the jaw, normal swallowing, normal tongue position at rest against the upper and posterior face of the upper teeth, and normal nasal breathing with the lips in contact when at rest. The goals of reeducation programs are to eliminate abnormal swallowing, chewing, and speech articulation. They also aim to strengthen the posture and employ continuous usage of the nose when breathing whether the patient is awake or asleep. Reeducation techniques will vary depending on the age of the subject. Myofunctional therapy is applicable to subjects of any age, including premature infants, in whom exercises engage primitive reflexes present at birth. This may include having the infant close their lips around a finger gently placed in their mouth or having them touch their lips at different points in order to draw the tip of their tongue towards the sensory stimulated region [60]. Other techniques include utilizing specific nipples to reproduce the consistency and efforts demanded to pull milk from a mother's breast [61], [62] and special toys to aid infants and young children in exploring their tongue and mouth [51]. These modalities should be applied by the parents to their children daily or as often as possible [58], ∗[59], [60]. Myofunctional therapy is more advantageous compared to orthodontics in that it can be applied much earlier in life.

SDB has been described as a cause of not only poor development but also of failure to thrive. Obesity was not initially a key feature in these first reported cases. With the obesity epidemic beginning in the mid-1990s, increasing number of children were reported to also present with SDB. Certain ethnicities, particularly African American children, have a stronger association between obesity and SDB [63]. Obesity is a complex disorder leading to worsening supine ventilation secondary to restrictive chest-bellows syndrome [63]. This syndrome also leads to progressive fatty infiltration of the neck and upper airway. MRI studies have shown that a progressive fatty infiltration of the genio-hyoid and genio-glossal muscles occurs along with dissociation of muscle fibers with fat cells [64]. These fat cells also infiltrate the lateral walls of the pharynx in addition to other muscles. Such fatty infiltration leads to enlargement of the soft tissues, reduction in the size of the upper airway, and enlargement of the lingual tonsils. The reduction in tidal volume due to chest restriction from abdominal obesity also leads to mechanical changes that pull the trachea during inspiration. This constant pulling of the hyoid bone during inspiration leads to increased upper airway collapsibility. Obesity can thus result in abnormal breathing during sleep. Obesity is associated with a progressive dysfunction of the adipocyte. Preadipocytes differentiate into mature adipocytes and form adipose tissue in response to a positive energy balance. Adipose tissue not only stores energy, but also acts as a dynamic endocrine organ, vital for hormone and cytokine (adipokine) secretion. White adipose tissue (WAT), located in abdominal and subcutaneous deposits in mammals, performs the majority of energy storage and adipokine secretion [65]. Brown adipose tissue (BAT) mediates the non-shivering thermogenesis, well known to protect infants from cold exposure. Genetics play a role in the control and development of WAT and BAT. Specific animal models of obesity (such as the ob–ob mouse) have been developed showing such genetic role. The differentiation and maintenance of the two types of adipose tissue is interrelated, involving multiple signaling pathways and transcription factors whose expression varies over time. This includes the major genes implicated in WAT and BAT adipogenesis, such as hormones, adipokines, enzymes, transcription factors (particularly PPAR gamma and the C/EBP family), and signal transduction ligands, which are essential in studying the complex interactions between WAT and BAT. Dysfunction of the adipocyte leads to stimulation of adipokines, particularly TNF-alpha and interleukins 6 and 1. These defects lead to pivotal inflammatory responses, both local and general, in addition to abnormal secretion of peptides found not only in the adipocyte but also in the gut and brain. Peptides such as leptin, adinopeptin, obesin etc., are involved, and dysfunction of the adipocyte leads to leptin resistance and ghrelin dysfunction. These two peptides are crucial in food intake, insulin resistance, and dysregulation of glucose and lipid control [66]. Overweight and obese individuals, with or without SDB, will develop these dysfunctions. The consequences of these abnormalities affect the cardiovascular, respiratory, metabolic, and cerebral systems.

It is clear that the size of the upper airway has an impact on how quick obesity may lead to upper airway impairment and SDB. Initially, a smaller upper airway will have a faster infiltration than larger ones as shown many years ago by Jamieson et al. [67]; but the initial problem is related to two very distinct causes, thus if acute treatment in both cases utilizes positive airway pressure (PAP) therapy, etiogenic treatment and prevention will be very different. Sleep itself may be involved in the development of obesity. Sleep restriction, a consequence of new age electronics in the lives of children, has been shown to have a clear association with the obesity epidemic in children.

Sleep fragmentation, which occurs with abnormal breathing, will cause changes in metabolic controls in part through the process of epigenetics, by which environmental events trigger a genetic cascade that would not have otherwise occurred. Obesity along with the fatty infiltration of upper airway will always lead to SDB from simple flow limitation to frank OSA.

Treatment and prevention of SDB secondary to obesity, however, is very different from the ones in SDB in non-overweight children with impairment of orofacial growth. It is unfortunate that both syndromes are not clearly delineated as the ultimate goal should be prevention of SDB, and this requires a distinct therapeutic approach (Table 2).

Section snippets

Conclusion

It is important to understand how SDB develops and to separate the SDB seen in obese children from the one observed in non-overweight individuals particularly in its most common presentation of obesity. Understanding the development of the craniofacial structures, their interaction in the growth of the face, and the interaction between specific functions early in life and maxilla-mandibular growth is critical if we wish to prevent development of OSA and eliminate risk of reoccurrence in

Conflicts of interest

The authors do not have any conflicts of interest to disclose.

Support

No financial support.

Practice points

SDB in children persists and re-occurs after T&A.

Naso-maxillary and mandibular development has an important impact on the size of the upper airway, and any impairment in this development will consequently impact the size of the upper airway.

Development of the facial structure is under the control of genetic and environmental factors.

Two growth centers (synchodroses) are active postnatally (intermaxillary and alveolo-dental) and can be affected further by

Acknowledgment

We thank M Camacho MD, otolaryngol, Stanford Sleep Disordered Clinic for constructing Fig. 1.

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