Pierre Robin Sequence

Pierre Robin sequence, also known as Pierre Robin syndrome or simply Robin sequence, is a condition in infants that is characterized by a smaller-than-normal mandible, a tongue Tongue The tongue, on the other hand, is a complex muscular structure that permits tasting and facilitates the process of mastication and communication. The blood supply of the tongue originates from the external carotid artery, and the innervation is through cranial nerves. Oral Cavity: Lips and Tongue that retracts back into the throat, and difficulty breathing. The exact etiology of the Pierre Robin sequence is unknown, although some contributing factors have been identified. The abnormal development of the lower jaw Jaw The jaw is made up of the mandible, which comprises the lower jaw, and the maxilla, which comprises the upper jaw. The mandible articulates with the temporal bone via the temporomandibular joint (TMJ). The 4 muscles of mastication produce the movements of the TMJ to ensure the efficient chewing of food. Jaw and Temporomandibular Joint during gestation, along with certain genetic mutations, can be the first of a series of steps leading to breathing and feeding problems in the neonate.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Definitions

The Pierre Robin sequence (PRS) is a triad of congenital micrognathia (small lower jaw Jaw The jaw is made up of the mandible, which comprises the lower jaw, and the maxilla, which comprises the upper jaw. The mandible articulates with the temporal bone via the temporomandibular joint (TMJ). The 4 muscles of mastication produce the movements of the TMJ to ensure the efficient chewing of food. Jaw and Temporomandibular Joint), glossoptosis (retraction of the tongue Tongue The tongue, on the other hand, is a complex muscular structure that permits tasting and facilitates the process of mastication and communication. The blood supply of the tongue originates from the external carotid artery, and the innervation is through cranial nerves. Oral Cavity: Lips and Tongue into the pharynx Pharynx The pharynx is a component of the digestive system that lies posterior to the nasal cavity, oral cavity, and larynx. The pharynx can be divided into the oropharynx, nasopharynx, and laryngopharynx. Pharyngeal muscles play an integral role in vital processes such as breathing, swallowing, and speaking. Pharynx), and airway obstruction Airway obstruction Airway obstruction is a partial or complete blockage of the airways that impedes airflow. An airway obstruction can be classified as upper, central, or lower depending on location. Lower airway obstruction (LAO) is usually a manifestation of chronic disease, such as asthma or chronic obstructive pulmonary disease (COPD). Airway Obstruction.

Pathophysiology of the pierre robin sequence

Pathophysiology of the Pierre Robin sequence, justifying its classification as a sequence and not a syndrome.

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  • Pierre Robin is a sequence, not a syndrome!
    • Sequence = a series of sequential developmental malformations produced by a single cause
    • Syndrome = a group of signs and symptoms that occur together and that underlie a particular abnormality or condition
  • Sequence progression: micrognathia → glossoptosis → airway obstruction Airway obstruction Airway obstruction is a partial or complete blockage of the airways that impedes airflow. An airway obstruction can be classified as upper, central, or lower depending on location. Lower airway obstruction (LAO) is usually a manifestation of chronic disease, such as asthma or chronic obstructive pulmonary disease (COPD). Airway Obstruction
  • Presents in an isolated form or as part of another syndrome (syndromic PRS), such as:
    • Stickler syndrome
    • DiGeorge syndrome DiGeorge syndrome DiGeorge syndrome (DGS) is a condition caused by a microdeletion at location q11.2 of chromosome 22 (thus also called 22q11.2 syndrome). There is a defective development of the third and fourth pharyngeal pouches, leading to thymic and parathyroid hypoplasia (causing T-cell immunodeficiency and hypocalcemia, respectively). DiGeorge Syndrome
    • Fetal alcohol spectrum disorder Fetal alcohol spectrum disorder Fetal alcohol spectrum disorder (FASD) is a group of neonatal pediatric disorders caused by maternal alcohol consumption during pregnancy. The term entails a range of physical and neurodevelopmental effects. Classification is based on severity and clinical presentation. Fetal Alcohol Spectrum Disorder
    • Treacher-Collins syndrome: Patients with this syndrome also have mandibular hypoplasia but to different degrees than PRS.
    • Patau syndrome Patau syndrome Trisomy 13, or Patau syndrome, is a genetic syndrome caused by the presence of 3 copies of chromosome 13. As the 3rd most common trisomy, Patau syndrome has an incidence of 1 in 10,000 live births. Most cases of Patau syndrome are diagnosed prenatally by maternal screening and ultrasound. More than half of the pregnancies result in spontaneous abortions. Patau Syndrome (Trisomy 13)
    • Velocardiofacial syndrome
    • Beckwith-Wiedemann syndrome
    • CHARGE (Coloboma, Heart defects, choanal Atresia, Retarded growth and development, Genital abnormalities, and E ar AR Aortic regurgitation (AR) is a cardiac condition characterized by the backflow of blood from the aorta to the left ventricle during diastole. Aortic regurgitation is associated with an abnormal aortic valve and/or aortic root stemming from multiple causes, commonly rheumatic heart disease as well as congenital and degenerative valvular disorders. Aortic Regurgitation anomalies) syndrome
    • Cleft lip Cleft lip The embryological development of craniofacial structures is an intricate sequential process involving tissue growth and directed cell apoptosis. Disruption of any step in this process may result in the formation of a cleft lip alone or in combination with a cleft palate. As the most common craniofacial malformation of the newborn, the diagnosis of a cleft is clinical and usually apparent at birth. Cleft Lip and Cleft Palate and/or palate Palate The palate is the structure that forms the roof of the mouth and floor of the nasal cavity. This structure is divided into soft and hard palates. Oral Cavity: Palate
Pierre robin sequence

Progression of triad of events that underlies the Pierre Robin sequence clinical presentation

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Epidemiology and Etiology

Epidemiology: 1 in 8,500–14,000 live births in the United States

Etiology:

  • Deletions in the loci 4p, 4q, 6q, and 11q have been associated with micrognathia, which is believed to be the first step in this sequence of malformations. 
  • Duplications in loci 10q and 18q have also been linked to micrognathia. 
  • Some external factors during intrauterine life (e.g., oligohydramnios Oligohydramnios Oligohydramnios refers to amniotic fluid volume less than expected for the current gestational age. Oligohydramnios is diagnosed by ultrasound and defined as an amniotic fluid index (AFI) of ‰¤ 5 cm or a single deep pocket (SDP) of < 2 cm in the 2nd or 3rd trimester. Oligohydramnios) may play a role in micrognathia. 
  • Isolated PRS is believed to arise sporadically via de novo mutations in the SOX9 gene/protein, which plays a critical role in skeletal development.
    • Familial cases of isolated PRS are rare and inherited autosomal dominantly.
  • Syndromic PRS follows the same inheritance pattern as the associated syndrome.

Clinical Presentation

  • Pierre Robin sequence consists of a triad:
    1. Micrognathia:
      • Hypoplastic abnormalities of the mandible
      • Radiographic findings of micrognathia are the basis of the diagnosis
    2. Glossoptosis: abnormal placement of the tongue Tongue The tongue, on the other hand, is a complex muscular structure that permits tasting and facilitates the process of mastication and communication. The blood supply of the tongue originates from the external carotid artery, and the innervation is through cranial nerves. Oral Cavity: Lips and Tongue in the posterior part of the mouth/ pharynx Pharynx The pharynx is a component of the digestive system that lies posterior to the nasal cavity, oral cavity, and larynx. The pharynx can be divided into the oropharynx, nasopharynx, and laryngopharynx. Pharyngeal muscles play an integral role in vital processes such as breathing, swallowing, and speaking. Pharynx
    3. Airway obstruction:
      • The abnormal position of the tongue Tongue The tongue, on the other hand, is a complex muscular structure that permits tasting and facilitates the process of mastication and communication. The blood supply of the tongue originates from the external carotid artery, and the innervation is through cranial nerves. Oral Cavity: Lips and Tongue is responsible for airway obstruction Airway obstruction Airway obstruction is a partial or complete blockage of the airways that impedes airflow. An airway obstruction can be classified as upper, central, or lower depending on location. Lower airway obstruction (LAO) is usually a manifestation of chronic disease, such as asthma or chronic obstructive pulmonary disease (COPD). Airway Obstruction.
      • Severe airway obstruction Airway obstruction Airway obstruction is a partial or complete blockage of the airways that impedes airflow. An airway obstruction can be classified as upper, central, or lower depending on location. Lower airway obstruction (LAO) is usually a manifestation of chronic disease, such as asthma or chronic obstructive pulmonary disease (COPD). Airway Obstruction may result in hypoxia, cerebral impairment, and failure to thrive Failure to Thrive Failure to thrive (FTT), or faltering growth, describes suboptimal weight gain and growth in children. The majority of cases are due to inadequate caloric intake; however, genetic, infectious, and oncological etiologies are also common. Failure to Thrive
  • Suprasternal retractions and the use of accessory muscles of respiration are common findings in infants with PRS, and are activated in an attempt to forcefully relieve the airway obstruction Airway obstruction Airway obstruction is a partial or complete blockage of the airways that impedes airflow. An airway obstruction can be classified as upper, central, or lower depending on location. Lower airway obstruction (LAO) is usually a manifestation of chronic disease, such as asthma or chronic obstructive pulmonary disease (COPD). Airway Obstruction
  • Pierre Robin sequence is also commonly associated with feeding difficulties, which lead to failure to thrive Failure to Thrive Failure to thrive (FTT), or faltering growth, describes suboptimal weight gain and growth in children. The majority of cases are due to inadequate caloric intake; however, genetic, infectious, and oncological etiologies are also common. Failure to Thrive and malnutrition Malnutrition Malnutrition is a clinical state caused by an imbalance or deficiency of calories and/or micronutrients and macronutrients. The 2 main manifestations of acute severe malnutrition are marasmus (total caloric insufficiency) and kwashiorkor (protein malnutrition with characteristic edema). Malnutrition in children in resource-limited countries.
  • Commonly, the glossoptosis can produce a U- or V-shaped cleft palate cleft palate The embryological development of craniofacial structures is an intricate sequential process involving tissue growth and directed cell apoptosis. Disruption of any step in this process may result in the formation of a cleft lip alone or in combination with a cleft palate. As the most common craniofacial malformation of the newborn, the diagnosis of a cleft is clinical and usually apparent at birth. Cleft Lip and Cleft Palate, as it impedes the fusion of the 2 palatal shelves.

Diagnosis and Management

Diagnosis

  • Mainly based on the clinical assessment and radiographic findings of micrognathia
  • Genetic testing (e.g., fluorescence in situ hybridization) is important to determine if PRS is isolated or associated with another syndrome.

Management

  • Patients with PRS may be treated non-surgically. 
    • Placement in the prone or lateral position will resolve the airway obstruction Airway obstruction Airway obstruction is a partial or complete blockage of the airways that impedes airflow. An airway obstruction can be classified as upper, central, or lower depending on location. Lower airway obstruction (LAO) is usually a manifestation of chronic disease, such as asthma or chronic obstructive pulmonary disease (COPD). Airway Obstruction in two-thirds of cases. 
    • A nasopharyngeal tube can be inserted to avoid frequent oxygen desaturation.
    • A nasogastric tube can be inserted for feeding assistance.
  • Patients who do not respond to these conservative measures should undergo surgical procedures to relieve the airway obstruction Airway obstruction Airway obstruction is a partial or complete blockage of the airways that impedes airflow. An airway obstruction can be classified as upper, central, or lower depending on location. Lower airway obstruction (LAO) is usually a manifestation of chronic disease, such as asthma or chronic obstructive pulmonary disease (COPD). Airway Obstruction
    • Tongue-lip adhesion
    • Distraction osteogenesis or mandibular distraction
    • Tracheostomy (in severe cases)
  • Patients with cleft lip and/or palate Palate The palate is the structure that forms the roof of the mouth and floor of the nasal cavity. This structure is divided into soft and hard palates. Oral Cavity: Palate may also require corrective surgical interventions.

Differential Diagnosis

The following conditions are differential diagnoses for isolated or syndromic Pierre Robin sequence:

  • Velocardiofacial syndrome (Shprintzen-Goldberg syndrome): also called chromosome 22q11.2 deletion syndrome, a disorder presenting with congenital heart disease, palate Palate The palate is the structure that forms the roof of the mouth and floor of the nasal cavity. This structure is divided into soft and hard palates. Oral Cavity: Palate abnormalities, immunologic dysfunction (e.g., autoimmune disease), hypocalcemia Hypocalcemia Hypocalcemia, a serum calcium < 8.5 mg/dL, can result from various conditions. The causes may include hypoparathyroidism, drugs, disorders leading to vitamin D deficiency, and more. Calcium levels are regulated and affected by different elements such as dietary intake, parathyroid hormone (PTH), vitamin D, pH, and albumin. Presentation can range from an asymptomatic (mild deficiency) to a life-threatening condition (acute, significant deficiency). Hypocalcemia, endocrine conditions (e.g., growth hormone deficiency), gastrointestinal problems, feeding difficulties, kidney malformations, hearing loss Hearing loss Hearing loss, also known as hearing impairment, is any degree of impairment in the ability to apprehend sound as determined by audiometry to be below normal hearing thresholds. Clinical presentation may occur at birth or as a gradual loss of hearing with age, including a short-term or sudden loss at any point. Hearing Loss, seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures, minor facial abnormalities, and learning disabilities. 
  • Stickler syndrome: a rare connective tissue Connective tissue Connective tissues originate from embryonic mesenchyme and are present throughout the body except inside the brain and spinal cord. The main function of connective tissues is to provide structural support to organs. Connective tissues consist of cells and an extracellular matrix. Connective Tissue disorder that presents as myopia, retinal detachment Retinal detachment Retinal detachment is the separation of the neurosensory retina from the retinal pigmented epithelium and choroid. Rhegmatogenous retinal detachment, the most common type, stems from a break in the retina, allowing fluid to accumulate in the subretinal space. Retinal Detachment, hearing loss Hearing loss Hearing loss, also known as hearing impairment, is any degree of impairment in the ability to apprehend sound as determined by audiometry to be below normal hearing thresholds. Clinical presentation may occur at birth or as a gradual loss of hearing with age, including a short-term or sudden loss at any point. Hearing Loss, a characteristic facial appearance with mid-facial flatness, and joint pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain. Affected individuals may also have features of PRS (micrognathia, glossoptosis, and cleft palate cleft palate The embryological development of craniofacial structures is an intricate sequential process involving tissue growth and directed cell apoptosis. Disruption of any step in this process may result in the formation of a cleft lip alone or in combination with a cleft palate. As the most common craniofacial malformation of the newborn, the diagnosis of a cleft is clinical and usually apparent at birth. Cleft Lip and Cleft Palate).
  • Treacher-Collins syndrome (mandibulofacial dysostosis): a rare autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance condition characterized by significant craniofacial deformities and conductive hearing loss Hearing loss Hearing loss, also known as hearing impairment, is any degree of impairment in the ability to apprehend sound as determined by audiometry to be below normal hearing thresholds. Clinical presentation may occur at birth or as a gradual loss of hearing with age, including a short-term or sudden loss at any point. Hearing Loss. Treacher-Collins syndrome is strictly a physical disease; it does not affect cognition or other spheres of development. 
  • Beckwith-Wiedemann syndrome: a cancer-predisposition disorder caused by changes on chromosome 11p15.5. Associated features include above-average birth weight (large for gestational age), macrosomia, macroglossia, organomegaly, omphalocele Omphalocele Omphalocele is a congenital anterior abdominal wall defect in which the intestines are covered by peritoneum and amniotic membranes. The condition results from the failure of the midgut to return to the abdominal cavity by 10 weeks' gestation. Omphalocele, umbilical hernia, and/or diastasis recti.
  • CHARGE syndrome CHARGE Syndrome CHARGE syndrome is a rare genetic condition with autosomal dominant inheritance in which almost all body systems are affected. The acronym CHARGE stands for the constellation of clinical features seen with this condition: Coloboma, Heart defects, Atresia choanae, Growth retardation, Genetic Abnormalities, and Ear abnormalities. CHARGE Syndrome: a rare genetic disorder in children that affects almost all body systems due to impaired gene expression as a result of inherited mutations.
  • Childhood sleep Sleep Sleep is a reversible phase of diminished responsiveness, motor activity, and metabolism. This process is a complex and dynamic phenomenon, occurring in 4-5 cycles a night, and generally divided into non-rapid eye movement (NREM) sleep and REM sleep stages. Physiology of Sleep apnea: a sleep Sleep Sleep is a reversible phase of diminished responsiveness, motor activity, and metabolism. This process is a complex and dynamic phenomenon, occurring in 4-5 cycles a night, and generally divided into non-rapid eye movement (NREM) sleep and REM sleep stages. Physiology of Sleep disorder in which a pediatric patient’s breathing is partially or completely obstructed repeatedly during sleep Sleep Sleep is a reversible phase of diminished responsiveness, motor activity, and metabolism. This process is a complex and dynamic phenomenon, occurring in 4-5 cycles a night, and generally divided into non-rapid eye movement (NREM) sleep and REM sleep stages. Physiology of Sleep. While adult sleep Sleep Sleep is a reversible phase of diminished responsiveness, motor activity, and metabolism. This process is a complex and dynamic phenomenon, occurring in 4-5 cycles a night, and generally divided into non-rapid eye movement (NREM) sleep and REM sleep stages. Physiology of Sleep apnea usually presents with fatigue and daytime sleepiness and is due to obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity, childhood sleep Sleep Sleep is a reversible phase of diminished responsiveness, motor activity, and metabolism. This process is a complex and dynamic phenomenon, occurring in 4-5 cycles a night, and generally divided into non-rapid eye movement (NREM) sleep and REM sleep stages. Physiology of Sleep apnea is more likely to present with behavioral disorders and is usually due to an enlargement of the adenoids and tonsils.
  • DiGeorge syndrome DiGeorge syndrome DiGeorge syndrome (DGS) is a condition caused by a microdeletion at location q11.2 of chromosome 22 (thus also called 22q11.2 syndrome). There is a defective development of the third and fourth pharyngeal pouches, leading to thymic and parathyroid hypoplasia (causing T-cell immunodeficiency and hypocalcemia, respectively). DiGeorge Syndrome: a condition caused by a microdeletion at location q11.2 of chromosome 22. DiGeorge syndrome DiGeorge syndrome DiGeorge syndrome (DGS) is a condition caused by a microdeletion at location q11.2 of chromosome 22 (thus also called 22q11.2 syndrome). There is a defective development of the third and fourth pharyngeal pouches, leading to thymic and parathyroid hypoplasia (causing T-cell immunodeficiency and hypocalcemia, respectively). DiGeorge Syndrome is associated with defective development of the 3rd and 4th pharyngeal pouches, leading to thymic and parathyroid hypoplasia. Features also include congenital heart defects, characteristic facial features, cleft palate cleft palate The embryological development of craniofacial structures is an intricate sequential process involving tissue growth and directed cell apoptosis. Disruption of any step in this process may result in the formation of a cleft lip alone or in combination with a cleft palate. As the most common craniofacial malformation of the newborn, the diagnosis of a cleft is clinical and usually apparent at birth. Cleft Lip and Cleft Palate, frequent infections, developmental delay, learning problems, and psychiatric disorders.
  • Fetal alcohol spectrum disorders: a group of conditions that can occur in neonates whose mothers consumed heavy amounts of alcohol during their pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care. Problems may include characteristic craniofacial changes, short height, low body weight, small head size, poor coordination, low intelligence, behavior problems, and problems with hearing or seeing. 
  • Pectus excavatum: a congenital malformation of the rib cage featuring a sternal depression usually beginning at the manubrium and progressing down to the xiphoid process. Can occur sporadically or be associated with connective tissue Connective tissue Connective tissues originate from embryonic mesenchyme and are present throughout the body except inside the brain and spinal cord. The main function of connective tissues is to provide structural support to organs. Connective tissues consist of cells and an extracellular matrix. Connective Tissue disorders (e.g., Marfan syndrome Marfan syndrome Marfan syndrome is a genetic condition with autosomal dominant inheritance. Marfan syndrome affects the elasticity of connective tissues throughout the body, most notably in the cardiovascular, ocular, and musculoskeletal systems. Marfan Syndrome).
  • Cleft lip Cleft lip The embryological development of craniofacial structures is an intricate sequential process involving tissue growth and directed cell apoptosis. Disruption of any step in this process may result in the formation of a cleft lip alone or in combination with a cleft palate. As the most common craniofacial malformation of the newborn, the diagnosis of a cleft is clinical and usually apparent at birth. Cleft Lip and Cleft Palate and palate Palate The palate is the structure that forms the roof of the mouth and floor of the nasal cavity. This structure is divided into soft and hard palates. Oral Cavity: Palate: a congenital defect of the face that can include the upper lip and/or the palate Palate The palate is the structure that forms the roof of the mouth and floor of the nasal cavity. This structure is divided into soft and hard palates. Oral Cavity: Palate and that can be unilateral, bilateral, complete, or incomplete. A cleft lip is caused by the failure of fusion of the maxillary prominence with the medial nasal prominence, while a cleft palate cleft palate The embryological development of craniofacial structures is an intricate sequential process involving tissue growth and directed cell apoptosis. Disruption of any step in this process may result in the formation of a cleft lip alone or in combination with a cleft palate. As the most common craniofacial malformation of the newborn, the diagnosis of a cleft is clinical and usually apparent at birth. Cleft Lip and Cleft Palate is caused by the failure of fusion of the palatine prominences. Presents as difficulty with speech development, feeding, swallowing, and tooth eruption, as well as visible malformation of the face.

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