Craniofacial Conditions

Diagnosis and Etiology

The triad of micrognathia, glossoptosis, and airway obstruction is known as Robin sequence (RS) or Pierre Robin sequence . Cleft palate is a common feature of RS, although not obligatory to the diagnosis. Approximately one-quarter of infants with cleft palate (CP) were found to have RS in a population-based, case-control study. RS is an etiologically and phenotypically heterogeneous disorder. In a large cohort study of 191 children with RS, 38% had isolated RS, 9% had a chromosome anomaly, 29% had a Mendelian disorder, and 24% had no detectable cause. Twenty-two Mendelian disorders were diagnosed, of which Stickler syndrome was the most frequent. The tremendous heterogeneity and lack of uniformly accepted diagnostic criteria for, or definitions of, RS make it challenging to know the true prevalence. In a review of 42 international studies, the estimated birth prevalence for RS ranged between 1:3900 and 1:122,400 (0.8 to 32.0 per 100,000), with a mean prevalence of 1:24,500.

Phenotype

While there is great variation in severity, RS is characterized by the following phenotypic features: micrognathia, glossoptosis, and resultant base of tongue-level upper airway obstruction ( Fig. 88.1A, B ). Cleft palate is a common additional feature, occurring in approximately 90%. A wide, U-shaped cleft is classic in RS and should prompt the provider to evaluate for any signs of micrognathia or airway obstruction, while the narrow, V-shaped cleft palate is more typical in infants without RS. Micrognathia, or a small and symmetrically receded mandible, is a subjective diagnosis, although assessing the maxillomandibular discrepancy (distance between the maxillary and mandibular alveolar ridges in the midline) can help with recognition. Glossoptosis is dynamic and defined as displacement of the tongue base into the oropharynx and hypopharynx. Tongue size varies across the spectrum of RS, and the severity of glossoptosis does not always correlate with the degree of micrognathia. Intraoral examination of the infant with glossoptosis may reveal a posteriorly positioned tongue, occasionally pulled up into a palatal cleft. Upper airway obstruction (often presenting with stertor, increased effort, or obstructive apnea) in infants with RS can be associated with feeding difficulties and challenges gaining weight. Clinical judgment can be made about whether the patient represents “isolated RS,” “RS plus (RS with other anomalies)” or a syndromic form of RS.

Intensive Care Unit Concerns

Upper airway obstruction in RS is a result of tongue displacement toward the posterior pharyngeal wall or up into the cleft. The tongue can act as a ball valve, leading to inspiratory obstruction. The principal physiologic sequelae of RS are the inability to effectively feed and breathe due to airway obstruction. In the immediate neonatal period, patients with RS may have increased inspiratory work of breathing, cyanosis, and apnea. Rising CO ₂ levels may be a signal of worsening airway obstruction and often precedes hypoxemia in the neonate with RS. Obstruction is more common in the supine position and can be exacerbated during feeding and in sleep or in any state where there is loss of pharyngeal tone. Chronic obstruction can lead to failure to thrive, carbon dioxide retention, pulmonary hypertension, and eventually right-sided heart failure (cor pulmonale). Airway exposure is often compromised in the infant with RS, which impacts the ability to safely intubate the neonate with RS.

Airway obstruction is the main cause of feeding and growth issues in infants with RS. Feeding problems can also be related to abnormal coordination, primary swallowing dysfunction, pharyngeal hypotonia, and suction mechanics are complicated by the presence of a cleft palate. Increased energy expenditures because of the increased work of breathing may lead to failure to thrive if the infant is not receiving adequate caloric intake. Gastroesophageal reflux is common in infants with RS, as it is in other infants who have increased work of breathing, and may contribute to episodes of distress and aspiration or apnea.

Management

First and foremost, the airway must be addressed. Placement of a nasopharyngeal (NP) airway or endotracheal tube may be required in an emergency, and it is important to realize that severe, life-threatening airway obstruction can present in the delivery room. RS features are not commonly noted before birth; however, if microgathia or maternal polyhydramnios is a prenatal concern, there should be heightened suspicion for worse airway obstruction. Although uncommon, a prenatal diagnosis of micrognathia allows the involvement of neonatologists and otolaryngologists before and during delivery.

Key members of the craniofacial team are shown in Box 88.1 . Treatment protocols differ across institutions, and an example of the initial evaluation and clinical team discussion for the neonate with tongue-based airway obstruction is provided in Box 88.2 . While the threshold for intervention and the management options differ substantially, most neonates with RS can be treated nonsurgically. A number of therapeutic maneuvers can be used to stabilize the upper airway in RS, ranging from positioning to surgery. Placing the baby in the prone or lateral decubitus position can improve airway patency to some degree, and has the potential to decrease work of breathing. When prone positioning fails to stabilize the airway, alternative approaches include the use of an NP airway, intraoral device such as the Tubingen palatal plate (TPP) or orthodontic airway plate (OAP), noninvasive positive pressure, treatment with tongue–lip adhesion (TLA), and mandibular advancement through distraction osteogenesis. An NP airway provides a temporary way to bypass the infant's airway obstruction (see Fig. 88.1C ). An endotracheal tube can be modified so that it can be passed through the nares into the hypopharynx above the epiglottis, bypassing the obstruction at the base of the tongue. The NP airway can be both diagnostic of isolated base of tongue level airway obstruction, and therapeutic, and in some institutions, the infant is discharged home with an NP airway in place. Infants are monitored with oximetry, and parents are taught NP airway suctioning and replacement. The TPP or OAP is a newer therapy in the United States but well established in Europe. This intraoral device can bring the tongue forward to improve airway patency in neonates and infants, allow for full oral feeding, and safe discharge home. Airway compromise and stability are assessed by physical examination, CO ₂ levels, oxygenation, overnight sleep studies, and growth, monitored over time. While trending oxygen and CO ₂ levels is considered the minimum assessments for RS, some centers recommend sleep studies routinely to aid in decision making and to assess the success of interventions. Improved infant normative sleep data, access to quality sleep studies, and understanding long-term outcomes will impact approaches to neonates at risk for early obstructive sleep apnea.

The infant’s clinical status, a perceived need for long-term respiratory support, and failure of less invasive interventions will determine whether invasive surgery is recommended. Tracheotomy is considered a gold standard to bypass severe tongue-based airway obstruction, and the preferred option for infants who are not candidates for less invasive treatments, for example, those with multilevel airway obstruction and those who need longer-term mechanical ventilation. However, other surgical interventions may avoid a tracheostomy tube.

Children with isolated airway obstruction at the base of the tongue without other medical comorbidities may be considered for mandibular distraction osteogenesis (MDO). The surgery consists of surgical osteotomy and placement of a distraction device to slowly increase mandibular length and bring the base of the tongue forward, thereby increasing the airway space. This procedure will not achieve respiratory stabilization in patients with concomitant airway anomalies, lung disease, central apnea, or the need for positive pressure ventilation. In some institutions, TLA may be a temporizing measure to reduce base of tongue-level obstruction while allowing for mandibular growth.

Airway endoscopy helps to delineate the level of obstruction, and computed tomography (CT) of the facial skeleton provides optimal understanding of jaw anatomy and tooth bud position before MDO. For many infants with RS needing an ICU, the patterns of obstruction are more complex. In addition to glossoptosis, other mechanisms may contribute to airway obstruction in individuals with RS, such as pharyngeal hypotonia and/or compromised airway clearance in the infant with a concomitant neurological disorder. Recognition of other causes of respiratory compromise, for example, poor secretion handling, laryngotracheomalacia, or ventilatory muscle weakness, affects treatment decisions. Children with RS associated with syndromes, skeletal dysplasia, or neurologic conditions may have multiple causes of respiratory compromise such that a tracheostomy may be the best approach to alleviate respiratory compromise. Thus infants with RS who have airway obstruction unresponsive to positional techniques for whom surgical options are being considered should have a comprehensive airway evaluation as well as a diagnostic evaluation for an underlying syndrome or associated malformations that might impact respiratory status and response to therapies. The multidisciplinary approach and considerations of all therapeutic options and potential outcomes should be considered for the neonate with RS requiring airway escalation.

Nutrition can be maintained with a fortified breast milk or formula given by side-lying feeding using a cleft feeder, or via a feeding tube; placement of a surgical gastrostomy tube is more common among infants with a syndromic form of RS. Oral feeding can and should be introduced when the airway is stable, and consultation with a feeding therapist is crucial. As tone and tongue position improve, and growth ensues, swallow coordination and safe feeding can also improve. A formal swallow evaluation may be helpful for the infant with persistent feeding challenges. Close observation for symptoms of gastroesophageal reflux with proactive treatment to prevent reflux and aspiration should also be considered.

Genetics consultation is recommended, as identification of an associated syndrome will have implications for treatment decisions and additional screening.

Screening and Surveillance

Syndrome diagnoses may become more apparent over time, and reassessments investigating a unifying diagnosis should be continued as the child with RS grows. Associated anomalies can impact respiratory function, including skeletal dysplasias.

CNS anomalies and hypotonia will impact care needs and prognosis. Congenital heart defects are present in up to 25% of babies with RS who die in early infancy. It has been reported that a portion of individuals with RS experience developmental delay, cognitive impairment, and poorer school achievement. Overall morbidity and mortality are higher in syndromic RS, RS plus, and RS with associated neurological anomalies compared with isolated RS. Diagnostic work-up should include investigation of common associated anomalies and syndromes. Specific genetic and syndrome diagnosis will guide surveillance protocols, but for all infants and children with RS, we recommend:

• An eye exam in the first 6 months of life to evaluate for ocular features of Stickler syndrome

• Hearing assessment annually, more frequently if hearing loss is detected

• Close monitoring of development and referral to early intervention services for developmental assessment, monitoring, and support

• Monitoring for obstructive sleep apnea, with a low threshold for a sleep study referral

• Monitoring dental eruption, occlusion and facial growth over time; most children will benefit from orthodontic management, and some will be candidates for mandibular or bimaxillary advancement surgery in adolescence

Diagnosis and Etiology

Cleft lip and palate is the most common type of orofacial clefting, followed by cleft lip, then CPO. Less prevalent are atypical clefts (macrostomia or lateral cleft, Tessier or oblique, and midline clefts). Unilateral CL±P is more common than bilateral involvement. A bifid uvula can be a normal variant, found in 2% to 4% of births, but can also be a sign of an associated submucous cleft palate, which can have the same functional impact as an overt CP.

The causes of most orofacial clefts are unknown and are nonsyndromic (isolated) in 70% to 75% of infants with CL±P and approximately 55% of those with CPO. Neonates with orofacial clefting who are born prematurely or have low birth weight may have a higher incidence of associated congenital malformations. Racial and ethnic variation in the prevalence of clefts has been described. In the US, rates are closest to those of the area from which the population originated with the highest prevalence of CL±P found in Native Americans, followed by whites and Hispanics, and the lowest overall prevalence of CL±P demonstrated in African Americans. The cause of nonsyndromic clefts is complex and multifactorial, likely resulting from an interaction between environmental and genetic factors. Known environmental risk factors include maternal tobacco and alcohol use, anticonvulsant treatment, and nutritional status. There is some evidence showing a protective association with preconception folate supplementation in preventing nonsyndromic orofacial clefts. Although many candidate genes have been described, in the absence of a family history of cleft or lip pits, routine clinical genetic testing for a child with isolated CL±P is not recommended. Recurrence risk information for the parents of a child with CL±P or for the affected individual depends upon either the specific syndrome/genetic diagnosis or the empiric risks for those with nonsyndromic clefts. Recurrence risk for nonsyndromic clefts differs based on the cleft phenotype and the number of affected individuals in a family (see Table 88.3 ).

Anatomy

Embryologic development of the primary palate begins early in gestation, and the upper lip and primary palate have usually fused by the seventh week of gestation. A failure of fusion of the medial and lateral nasal processes with the maxillary process produces CL±P. Clefts can affect the primary palate (lip, alveolus, or anterior portion of the hard palate that extends to the incisive foramen) and secondary palate (posterior hard palate and soft palate). Clefts of the primary and secondary palate can be unilateral or bilateral and complete or incomplete. A complete cleft of the primary palate leaves no residual tissue between the alar base and the lip, whereas an incomplete cleft does not extend through the floor of the nose ( Fig. 88.3A–C, F ). A submucous cleft palate is a defect in the musculature of the palate with intact overlying mucosa.

Phenotype

The cleft of the primary and secondary palate affects facial shape and growth (see Fig. 88.3A–C ). Children with cleft palate (CP) are at increased risk of eustachian tube dysfunction, recurrent otitis media, acquired hearing loss, as well as speech issues in childhood. Feeding difficulties, nasal regurgitation of feeds, and difficulty gaining weight may also occur in infants with a CP (submucous and overt clefts of the palate). Associated dental findings include hypodontia and natal teeth.

Lateral facial clefting or macrostomia is pathogenically distinct from isolated CL±P and is often associated with syndromes, including craniofacial microsomia and Treacher Collins syndrome. Amniotic rupture sequence can be associated with oblique facial clefts and may be associated with underlying central nervous system (CNS) malformations and transverse limb anomalies.

A true median cleft of the upper lip is the rarest type of facial cleft (see Fig. 88.3D ). Midline clefts can be associated with other congenital defects as can be seen in orofaciodigital syndrome and frontonasal dysplasia, and CNS malformations are common in children with midline clefts. Some midline clefts are not true clefts but represent hypoplasia or agenesis of the primary palate or premaxillary agenesis, which can be associated with holoprosencephaly (HPE) sequence (see Fig. 88.3E ). Infants with HPE often have a depressed nasal tip and a short columella and appear hypoteloric (compared with FND or frontonasal encephalocele, where a midline cleft may be present, but the infant has a broad nasal tip, wide columella and hypertelorism).

Orofacial clefts are rarely associated with clefting of airway structures, such as cleft larynx or extension of clefting into the trachea. Opitz G/BBB syndrome is a multiple congenital anomaly syndrome characterized by facial anomalies (100% are hyperteloric and 50% have CL±P), genitourinary abnormalities (90% have hypospadias), and laryngotracheoesophageal (LTE) defects (present in 70%). Autosomal dominant and X-linked recessive forms of Opitz G/BBB syndrome are recognized. Pallister–Hall syndrome (PHS) is characterized by a constellation of findings that include hypothalamic hamartoma (resulting in seizures and pituitary dysfunction), polydactyly, airway clefting, and other anomalies (genitourinary, renal, pulmonary, and imperforate anus). Bifid epiglottis is the most common airway manifestation in PHS, although LTE clefts have been reported. LTE defects may range from LTE dysmotility in mild forms to laryngeal or tracheoesophageal clefts in more severe forms.

Syndromes Associated With Cleft Lip and/or Palate

It is estimated that there are more than 400 syndromes associated with orofacial clefts. Associated malformations occur in about 30% of children with CL±P. In considering a diagnosis of a syndrome, one should categorize the type of cleft (CL±P, U-shaped or V-shaped cleft palate, or more atypical orofacial cleft) and look for any other malformations. Table 88.1 describes the syndromes most commonly associated with clefting, their key features, and potential ICU issues. A referral to a clinical geneticist is recommended when an underlying diagnosis is suspected.

Intensive Care Unit Concerns

Most infants with CL±P do not require ICU care. Thus an infant with an apparently isolated cleft who develops significant respiratory or electrolyte abnormalities requiring ICU care should be considered syndromic until proven otherwise. In these infants, a genetics consultation should be pursued.

The newborn with a midline cleft or premaxillary agenesis is at risk of serious underlying CNS anomalies, including HPE. In the presence of HPE, the detection of associated medical issues is essential. Endocrine abnormalities can arise because the midline malformation affects the development of the hypothalamus and the pituitary gland. Clinical manifestations include growth hormone deficiency, adrenal hypoplasia, hypogonadism, diabetes insipidus, and thyroid deficiency. Neurologic manifestations warrant close attention, including seizures, hypotonia, spasticity, autonomic dysfunction, and developmental delays.

With an LTE cleft, there is communication between the airway and the esophagus, allowing tracheal aspiration of oral contents, including saliva and feeds. Clefting of the larynx may result in stridor, a hoarse cry, respiratory distress, swallowing dysfunction, feeding difficulties, regurgitation, aspiration, hypoxia, recurrent pneumonias, and eventually severe respiratory compromise if unrecognized. An infant boy with hypertelorism, hypospadias, orofacial clefting, and symptoms of airway obstruction or aspiration should be evaluated for Opitz syndrome. Infants with PHS may also have respiratory distress due to airway clefting, as well as other potentially life-threatening clinical manifestations such as seizures and severe panhypopituitarism. Genetic evaluation and consideration of molecular testing for Opitz syndrome and PHS can be coordinated through a geneticist.

Management

The specifics of management of orofacial clefting are center-specific. Because of the potential impact of the orofacial cleft on breathing, eating, hearing, speech, facial growth, and dental health, it is recommended that infants and children with clefts be referred to a multidisciplinary care team for long-term management. Infants cared for with a multidisciplinary cleft or craniofacial team have better long-term functional and aesthetic outcomes. The nearest cleft team may be found through the American Cleft Palate-Craniofacial Association (ACPA) team listings. Overviews of recommended team care for patients with cleft lip/palate can be accessed electronically.

On the initial assessment, the provider should assess the cleft and examine the infant for dysmorphic features and other anomalies. Hearing should be evaluated by evoked otoacoustic emissions or by brainstem auditory evoked response if the newborn does not pass the initial hearing screen. Although this finding is often attributed to middle ear effusion because of the high prevalence of middle ear disease in children with CP, the incidences of sensorineural hearing loss, conductive hearing loss, and mixed hearing loss are higher in children with clefts. A neonate with a complete cleft lip should be evaluated by a craniofacial or cleft team in the first 2 weeks of life, and some centers offer taping or presurgical molding (such as nasoalveolar molding) that can be initiated in early infancy. Many mothers will be able to breastfeed an infant born with an isolated cleft lip. Breastfeeding a baby with CP (with or without cleft lip) will prove extremely challenging because the open palate will not generate the negative pressure needed for sucking. Thus the mother of infants with CP with or without cleft lip should be encouraged to provide expressed breast milk with the use of a specialized cleft feeder. Lactation counselor support should be offered to all mothers to discuss feeding at the breast or pumping to provide expressed breast milk to the infant. A variety of cleft nipples/bottles exist to allow oral feeding ( http://www.cleftline.org/who-we-are/what-we-do/feeding-your-baby/ ). There are assisted milk delivery systems such as the Medela special needs feeder (formerly known as the Haberman) and the Mead Johnson squeeze bottle. There are also infant-driven systems, such as the Dr. Brown’s specialty feeding system (with valve and varied nipple sizes allowing flow variation) and the Pigeon system. Infants with CP tend to swallow more air during feedings and should feed in an upright position, as gravity will help prevent nasal regurgitation. If the child is still having difficulty feeding safely or efficiently, a feeding therapist should be consulted. If a feeding specialist is not available, a lactation counselor or the nearest ACPA Cleft/Craniofacial team’s nurse coordinator can be an additional helpful resource for feeding support.

Adequate weight gain is important for overall health, development, and readiness for the surgical procedures that occur in the first year of life. Newborns with clefts are considered nutritionally high risk, but a child with an isolated orofacial cleft should be expected to follow typical growth charts. Infants with suboptimal weight gain may require additional nutrition support from a dietitian to help determine caloric needs and to closely monitor growth.

Surgical timelines and approach differ between teams but often span from infancy into early adulthood. In general, surgery to repair the cleft lip and associated nasal deformity occurs within the first 6 months of life. Palatoplasty typically occurs between 9 and 12 months of age with the primary goal to normalize palate muscle function to facilitate normal speech development.

Newborns with orofacial clefting should have a follow-up with their primary care pediatrician and be evaluated by a cleft/craniofacial specialist as soon as possible after discharge from the birth and NICU hospitalization, ideally within 1 week from discharge.

Screening and Surveillance

Routine screening laboratory and imaging studies are not typically recommended in the neonate with an isolated cleft. For children with syndromes, surveillance is guided by syndrome-specific protocols, with some special considerations noted here:

• Although rare, airway or laryngeal clefts can cause respiratory distress, coughing, choking, stridor, recurrent croup, and recurrent aspiration. Recommended evaluations include a clinical swallow evaluation, videofluoroscopy, functional endoscopic evaluation of swallow, and the gold standard for diagnosis is microlaryngoscopy and bronchoscopy. Given the risk of gastrointestinal manifestations such as gastroesophageal reflux, dysmotility, and aspiration, anti-reflux precautions should be initiated in infants with suspected or confirmed LTE defects. Early diagnosis and proper repair of the laryngeal cleft are essential to prevent injury to the lungs. Significant LTE defects will need to be managed surgically, and tracheostomy may be necessary initially to ensure airway stability and safety.

• In the presence of a midline cleft, it is important to evaluate the neonate for underlying CNS malformations such as HPE. In any child with a midline cleft or facial features consistent with premaxillary agenesis/hypoplasia, CNS imaging (CT or MRI) is recommended. Consultation with a geneticist or genetic counselor may provide insight into the genetics, molecular testing options, and recurrence risk of HPE. Treatment of HPE is supportive and based on symptoms. The outcome depends on the severity of HPE and the associated medical and neurologic manifestations.

Diagnosis and Etiology

22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion syndrome, with an estimated prevalence of 1 in 4000 births, in which affected individuals are missing a region (typically 3 Mb, encompassing approximately 40 genes) on one copy of chromosome 22. 22q11.2DS is associated with more than 180 clinical features, and phenotypic variation is a hallmark of this genetic condition. In some cases, this condition is diagnosed prenatally. Testing may occur as part of the evaluation for fetuses with congenital heart disease or because of a parental history of 22q11.2DS. The clinical indications for genetic testing for this condition in neonates include congenital heart malformations (particularly conotruncal anomalies), hypocalcemia, dysphagia, CP, other palatal dysfunction (e.g., submucous CP, velopharyngeal insufficiency with intact palate), and immunodeficiency identified on newborn screening or by noting thymic hypo-/aplasia, such as during heart surgery. Overt CP is less common than submucous CP and velopharyngeal insufficiency; genetic testing is more definitively indicated for CP when other features associated with 22q11.2DS are also observed.

Phenotype

22q11.2DS commonly presents with multiorgan system involvement, including cardiac and palatal abnormalities, immune differences, endocrine and gastrointestinal problems, developmental delay, and later-onset conditions across the life span, including variable cognitive deficits and psychiatric illness.

Several craniofacial features have been observed in individuals with 22q11.2DS; however, many of these are subtle and may not be apparent in the newborn period. Common features identified include small ears with overfolded helices, a long face, tubular conformation of the nose, nasal alar hypoplasia, and hooded eyelids. In neonates, some of the most indicative findings include dysphagia and/or nasal regurgitation (including in the absence of an overt CP, due to palatal dysfunction), congenital heart disease, and hypocalcemia.

Intensive Care Unit Concerns

About two thirds of patients with 22q11.2DS have congenital heart disease, sometimes severe, which often leads to prolonged neonatal hospital stays. If a seizure occurs in the neonatal period, especially in the setting of known congenital heart disease, 22q11.2DS and hypocalcemia should be strongly suspected. Hypocalcemia is most common in the newborn period and is triggered by physiologic stressors (e.g., peripartum period, surgery, infection). Importantly, hypocalcemia and neonatal seizures caused by it have been linked with worse intellectual outcomes for patients. Feeding challenges can be due to cleft palate, palatal dysfunction, and dysphagia. Rarely, severe immunodeficiency can be present, increasing the risk for serious infections. It can be identified on newborn screening for T-cell receptor excision circles (TRECs). About one-third of patients with 22q11.2DS have structural urinary tract abnormalities. Cervical spine anomalies can occur; routine screening in infancy is not recommended, but neonates should be monitored for symptoms of cord compression and cervical spine instability. In addition, infants with 22q11.2DS often have airway obstruction, most commonly due to tracheomalacia, subglottic stenosis, laryngomalacia, glottic web, and bronchomalacia; this is most commonly observed in patients who also have congenital heart disease.