Sleep in early life plays crucial roles in optimal neural and cognitive brain development, cortical maturation, and brain connectivity. Complex bidirectional relationships between sleep and development are observed in infants. Sleep (or lack of it) in typically developing fetuses, infants, and toddlers has lasting effects on later neurocognition. , , Sleep disturbances and disorders are highly prevalent in infants with particular neurogenetic syndromes; neurological and neurodevelopmental disorders (NDDs) contribute to worsening of their conditions.
Studies show that sleep/wake disorders (SWDs) in children with NDDs compared to typically developing (TD) children are: (1) far more prevalent; (2) multifactorial; (3) caused by an interplay of genetic, neurobiological, environmental, and epigenetic factors; (4) associated with worse functioning, increased parental stress and worse parental health; (5) more often persist into adolescence and adulthood; and (6) but do vary across disorders and individuals, and are often treatable. , Although NDDs affect only 2% of the general population, they represent a third of children referred to tertiary pediatric sleep clinics.
Here we will review what is known about SWDs in some of the most common neurogenetic, neurodevelopmental, and neurological disorders which present to pediatric sleep clinics or in-hospital in children <2 years of age. We will also review sleep-related movement disorders of infancy which are more often benign, remit, save again infants with NDDs.
Sleep need for optimal brain health and development
In 2016, the American Academy of Sleep Medicine (AASM) published consensus recommendations based on a systematic review which thought children ages 4 to 12 months need 12 to 16 hours per 24; and children ages 1 to 2 years 12 to 16 hours for optimal health. Two large prospective cohort studies found healthy infants between ages 4 and 12 months sleep slightly greater than 13 to slightly greater than 14 hours. , Forty percent of US infants aged 4 to 11 months sleep less than recommended amounts. Persistent short sleepers followed until age 7 tended to have poorer physical, emotional, and social health-related quality of life (QoL) than typical sleepers. TD children 12 to 35 months of age usually sleep 11 to 12 hours; sleeping <10 hours is associated with a greater risk for accidental injury.
Impact of premature birth on sleep, brain development, and later cognitive performance
Premature birth alone is a major risk for later neurodevelopmental disorders. Infants born preterm often have lower cognitive performance and more developmental disorders than those born at term. A 2018 metaanalysis (74 studies, 64,061 children) found that children born preterm compared to those born at term had: (1) lower cognitive scores for full scale, performance and verbal intelligence quotients (FSIQ, PIQ, and VIQ, respectively); (2) lower scores motor skills, behavior, reading, math and spelling at primary school age; persisted secondary school (except for mathematics); and (3) a 1.6-fold greater risk for attention-deficit/hyperactivity disorder (ADHD) with a differential effect according to the severity of prematurity.
Premature birth interrupts brain development preferentially occurring during sleep in the third trimester of pregnancy. Studies using polysomnography (PSG), electroencephalography (EEG), functional neuroimaging, and later neurodevelopmental testing have shown that premature birth is associated with impaired sleep ontogenesis, aberrant functional neuronal network connectivity, and poorer neurodevelopmental outcomes. Further, the Developing Human Connectome Project had showed that preterm birth is associated with disrupted formation of functional brain connectivity networks; and reduced cerebral gray and white matter volumes and neurocognitive deficits in adults born preterm. ,
Altered sleep architecture in preterm newborns impacts on later cognitive development
Premature infants sleep differently than infants born at term at similar postmenstrual age (PMA) with higher quiet/NREM sleep percentages, fewer arousals, fewer rapid eye movements, longer sleep cycle length, lower respiratory regularity, and lower beta EEG power. Infants born premature who had less REM sleep time on PSG had poorer developmental outcomes on the Bayley II at 6 months; whereas better neurodevelopmental outcomes were observed in those who had longer periods of sustained sleep, more REM sleep time, and more periods of REM sleep with rapid eye movements. Preterm born infants who slept poorly as neonates exhibited poorer attention and greater distractibility at 4 and 18 months than those who slept well. Sleep/wake transitions from NREM to W were associated with greater neonatal neuromaturation, less negative emotionality, and better verbal, symbolic, and executive competences at age 5 in 143 infants born mean age 32 weeks postmenstrual age (wPMA), while REM sleep and cry, short episodes of REM and NREM sleep with poorer outcomes.
Preterm birth increases risk for later pediatric obstructive sleep apnea
Premature birth also increases the risk for pediatric obstructive sleep apnea (OSA). A 2019 study found gestational age (GA) was the only significant predictor of SDB in a cohort of 98 children <2 years of age; premature birth increased the risk for OSA four-fold. Every additional week of gestation decreased the odds for SDB by 12.5%. SDB in those born preterm was associated with more severe nocturnal hypoxemia, increased frequency of central apnea, and altered sleep architecture. A recent study found premature birth was associated with a 2.97-fold higher likelihood of developing severe OSA, higher apnea-hypopnea index (AHI) and requiring more upper airway surgeries for OSA than children born at term.
Sleep disorders in neurogenetic syndromes which present in infancy
Sleep disorders are so common in infants with particular neurogenetic syndromes that they are considered phenotypic of the particular syndrome.
Down (trisomy 21) syndrome
Down syndrome (DS) is the most common genetic cause of intellectual disability (ID) accounting for approximately 30% of all cases of moderate-to-severe ID. DS is caused by a partial or complete duplication in chromosome 21q22.3 and occurs in approximately 1 of 1200 live births worldwide. , Phenotypic expression of the trisomy 21 genotype shows great interindividual variability modified by allelic variation, genomic imbalances, epigenetic, but also early intervention programs and parental nurturing. , ID in DS can vary from borderline to profound.
Obstructive sleep apnea highly prevalent in infants and toddlers with down syndrome
The most common sleep disorder in DS is OSA, highly prevalent in them across their life. A 2018 metaanalysis (18 studies, 1200 children with DS, mean age 7.7 years) found the prevalence of OSA based on AHI of 2, 5, and 10 events/hour were 75%, 50%, and 34%, respectively. AHI >5/h correlated inversely with age. OSA when present in infants with DS tends to be severe. , A study of 177 infants (≤6 months old) with DS attending a tertiary DS clinic suspected in 31%; PSG confirmed OSA in 95% of the severe in 71%.
Multiple factors predispose infants with DS to OSA and begin with craniofacial and upper airway abnormalities are common among them: midface and mandibular hypoplasia; a relatively large and/or posteriorly placed tongue in relatively small oral cavity; glossoptosis; small nose with a low nasal bridge; hypoplastic trachea; pharyngeal collapse; and increased secretions.
Hypotonia is a near universal finding in DS, most marked in infancy and affecting ligamentous laxity and gait. Poor tone in the airway predisposes them to glossoptosis, laryngomalacia, and hypopharyngeal collapse. When present, congenital heart disease, pulmonary arterial hypertension, hypothyroidism, and/or obesity further predispose them to OSA and often increase the severity of it found on PSG. , Risk factors for obesity in DS: increased leptin, decreased energy expenditure, subclinical hypothyroidism, and less favorable diets.
DS is the most common genetic syndrome associated with immune dysregulation. Children with DS have a 12-fold greater risk for infections especially pneumonia due to impaired cellular immunity and a four- to six-fold higher risk for autoimmune diseases than. Increased mortality from sepsis and increased oxidative stress are observed in people with DS.
Given the prevalence and predisposition for OSA in DS, the American Academy of Pediatrics (AAP) recommends all caregivers of children with DS receive information about the symptoms of OSA by 6 months of age and PSG be performed by age 4 years. Fig. 10.1 shows severe OSA recorded in an infant with DS.
Central sleep apnea also common in down syndrome especially those younger than two
A retrospective review of 158 children with DS found: (1) central sleep apnea (CSA) was common in children with DS <2 years old but rare after age 10; (2) if CSA persisted beyond age 2, it was more likely to occur in females; and (3) CSA was usually associated with concomitant OSA and hypoxemia. Another study of 60 infants and toddlers with DS (median age 1.5 years) found OSA in 61%, CSA 25%, and sleep-related central hypoventilation 32%.
Other sleep/wake disturbances in infants with down syndrome
Beyond SDB, infants with DS are at risk for other sleep problems. A large 2019 case-control study compared parent-reported sleep in 104 infants and toddlers with DS and 489 TD controls using the Brief Infant Sleep Questionnaire (BISQ). They found more parent-reported sleep problems in the children with DS compared to TD controls (45% versus 19%) including snoring (19% versus 2%), roomsharing (37% versus 17%), less nighttime sleep (55 minutes), and total sleep over 24 hours (38 minutes). Parents of an infant/toddler with DS were 4.4 times more likely to report needing to be present when their child fell asleep. A complaint of snoring increased reports of problematic nighttime awakenings.
A cross-sectional study recording actigraphy in 66 children with DS (aged 5–67 months) and 43 TD controls found infants born with DS exhibited worse sleep fragmentation than TD controls, but sleep efficiency and consolidation increased with age. Thirty-five percent of infants with DS showed a phase advance preference. Another study found more fragmented sleep and less leg movement activity when sleeping was observed in 3- to 6-months-old infants with DS compared to TD infants.
Impact of sleep disorders on development in children with down syndrome
A 2020 study of 10 children with DS (mean age 33 months) compared with 10 TD children and found more frequent parent-reported sleep problems were associated with more forgetfulness in the children with DS relative to TD. A prospective cross-sectional study found severity of SDB (AHI) correlated with more behavioral abnormalities (especially ADHD) and poorer development scores in 53 children with DS (ages 3–12). Fewer children with DS had nocturnal dipping of heart rate and blood pressure compared to TD children. A 2020 study found 30 children with DS had shorter nocturnal sleep duration and poorer sleep efficiency than 37 TD controls. Nocturnal sleep duration predicted receptive vocabulary size in the children with DS: for every 2 minutes more of nocturnal sleep, language comprehension in them increased by one word.
Autism spectrum disorders
Autism spectrum disorder (ASD) is the most prevalent NDD in the United States with a prevalence in 2018 of 17 per 1000 (1 in 59) 4-year-old children. ASD is a group of clinically heterogeneous neurological and NDDs associated with mild-to-severe impairments in socialization, communication, and/or reciprocal social interaction and often accompanied by restricted, ritualistic, and/or repetitive behaviors and interests. The male-to-female prevalence ratio of ASD is 3.4 to 1 and 52% had ID (IQ ≤70). , Twenty percent of cases of ASD are familial. More than 100 copy variants and point mutations have been identified in subjects with ASD; most de novo , and more often involved in gene regulation or synaptic connectivity.
Children with ASD often have: (1) difficulty understanding the intent of others; (2) decreased interactive eye contact; (3) atypical use and understanding of gesture; (4) atypical development of social communication, pretend play, and interest in other children; (5) repetitive behaviors or perseveration; and (6) sleep disturbances.
Sleep disturbances highly prevalent and persistent in children with autism spectrum disorders
Sleep problems are reported in up to 86% of children with ASD, still present in 50% in late adolescence. Sleep problems are reported as the most agonizing symptom for parents of children with ASD. Children with ASD often take longer than an hour to fall asleep, awakenings may last 2 to 3 hours and can begin with screaming or nightmares. Difficulty falling asleep, frequent night waking, and reduced nocturnal sleep duration are the most common sleep problems in children with ASD, but SDB, periodic limb movements (PLMs), restless legs (RLS), and nightmares were reported.
Problematic sleep in children with ASD is associated with repetitive ritualistic compulsive behaviors, ASD severity, and greater impairments in functional performance (mobility, self-care, and social function). Large cohort studies found sleep problems in ASD were associated with a higher prevalence of internalizing (anxiety, depression) and externalizing (aggression, defiance) daytime behaviors and lower overall intelligence, fewer verbal skills, less adaptive functioning, fewer daily living skills, communication, and socialization. , A study of 427 children with ASD admitted to psychiatric units found: (1) early morning awakening associated with higher autism symptom severity; (2) difficulty staying asleep/multiple insomnia symptoms scored low on adaptive behaviors (communication, self-care, socialization) and higher on maladaptive behaviors (irritability, hyperactivity, emotional reactivity, and dysphoria).
Core neurobehavioral deficits in children with ASD may contribute to their difficulty falling asleep: (1) impaired emotional regular may limit their ability to calm themselves; (2) difficulty transitioning from preferred or stimulating daytime activities because of fixation on daytime events; (3) inability to understand parental expectations related to bedtime and sleep due to impaired communication skills; (4) anxiety or fear about falling asleep; and (5) sensory processing issues. Abnormally low levels of melatonin and/or its urinary metabolic derivatives have been found in ASD and correlate with sleep problems and autistic behaviors.
Recognizing early signs of autism in infants
Prospective studies show the diagnostic features of ASD typically appear during the latter part of the first and second years of life. Earliest signs sometimes detected in infants <12 months old are: difficulties responding to name and/or attending to faces or social scenes; motor delay; and atypical visual orienting ( Table 10.1 ). Delays in acquiring language or disengagement of visual attention are red flags for ASD in children 12 to 18 months old. Regression in language or social behavior occurs in approximately a third of children with ASD, most often between 18 and 24 months of age. The Centers for Disease Control and Prevention (CDC) has a website which is useful for parents to identify symptoms and signs of ASD ( www.cdc.gov/ncbddd/actearly ). The Autism Navigator website provides a video glossary of early symptoms of ASD in toddlers ( www.autismnavigator.com ).
| Age | Warning Signs |
|---|---|
| 6 months | No affection for caregivers; does not squeal or laugh; does not make vowel sounds (eh, ah, oh) or respond to sounds; does not reach, or unusually stiff or floppy. |
| 9 months | Does not respond to name, babble, look where pointed, or recognize familiar people; does not sit with help, bear weight on legs with support, or transfer objects from one hand to other. |
| 12 months | Does not point to things, say single words, crawl, search for hidden objects, or stand when supported; does not learn gestures like shaking head yes or no, or waving bye-bye; losing skills once had. |
| 18 months | Does not point, imitate/copy others, notice/react when caregiver returns or leaves, walk, say at least six words, or know what familiar items are (phone, spoon, cup); losing skills once had. |
| 24 months | Does not know what familiar items are (phone, spoon, cup), walk steadily, follow simple instruction, imitate words/actions; use two-word phrases; losing skills once had. |
Sleep problems in infants and toddlers later diagnosed with autism spectrum disorder
Sleep patterns in children with ASD appear to diverge from typical development in the second or third year of life. One study found infants later diagnosed with ASD were much more likely to require ≥ two consult referrals for excessive crying, feeding, and sleeping problems compared to TD controls (44% versus 16%). A large prospective longitudinal study in 5151 children followed from 1.5 to 9 years of age found: (1) sleep problems did not precede autistic behavior but cooccurred with the development of autistic traits in early childhood; (2) sleep problems in children with ASD increased in severity with increasing age; (3) unlike sleep problems in TD children which tend to decrease with increasing age. A third study found toddlers with autistic features found they exhibited more bedtime resistance, abnormal circadian rhythms, and sleepiness outside of naptime than the TD toddlers.
A 2020 longitudinal neuroimaging study of 432 infants at high or low risk for ASD found sleep onset problem scores (derived from an infant temperament measure) were more prevalent at 6 to 12 months among infants who later developed ASD. Sleep onset difficulties at 6 to 12 months in infants at high risk for ASD were associated with weaker social communication skills by age 24 months and correlated with increased hippocampal volume trajectories from 6 to 24 months.
Treatment strategies for difficulty sleeping in children with ASD discussed elsewhere in this book in greater detail include: (1) behavioral therapy ; (2) extended release melatonin, alpha agonists, and gabapentin; , (3) identifying and treating SDB, PLMS, RLS, ferritin/iron/vitamin deficiencies, and gastrointestinal disturbances; (4) increased daytime physical activity. In-laboratory PSG should not be the first test for ASD unless symptoms of SDB, frequent atypical paroxysmal nocturnal behaviors, restless sleep disorder, and/or PLMs are suspected.
Of note, pediatric prolonged-release melatonin (PedPRM) is the first drug licensed for insomnia in children with ASD. , PedPRM treatment improves sleep onset, duration and consolidation, and daytime externalizing behaviors in children and adolescents with ASD and subsequently caregivers’ QoL and satisfaction with their children’s sleep. The coated, odorless, and taste-free minitablets are well-accepted in this population who often have sensory hypersensitivity and problems swallowing standard tablet preparations. The most frequent long-term treatment-related adverse events were fatigue (6%), somnolence (6%), and mood swings (4%) and with no evidence of delay in height, BMI, or pubertal development, or withdrawal effects. The starting dose is 2 mg once daily, independent of age or weight, escalated to 5 to 10 mg/day if predefined treatment success criteria are unmet. Slow melatonin metabolizers (approximately 10% of children) may require lower doses. Cognitive behavioral and behavioral treatment strategies used to treat insomnia in children with ASD and other severe NDDs are summarized in Box 10.1 .
Parents serve as active agents of change and are taught to:
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Create a quality sleeping environment:
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Dark, quiet, nonstimulating and perceived as safe (dim nightlight if needed);
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Eliminate visual and auditory stimuli (turn off electronics);
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Adjust ambient temperature if necessary (cool better than warm);
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Develop a successful bedtime routine which is consistently followed and tailored to the developmental age and abilities of the child;
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Promote self-soothing skills which allow the child to fall and return to sleep on own.
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Maintain a consistent sleep/wake schedule:
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Put to bed and get them up same time every day;
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Difficulty falling asleep:
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Temporarily delay child’s bedtimes by calculating the average sleep onset time during baseline then adding 30 minutes (e.g., average sleep onset 9:30 p.m. during baseline, initial bedtime 10 p.m.).
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Once child falls asleep within 15–20 minutes, gradually move the bedtime earlier in 30-minute increments as long as the child continues to fall asleep quickly until reaching a parent-determined goal bedtime (e.g., 8:30 p.m.).
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Do not allow the child to make up for lost sleep by going to bed earlier or sleeping later.
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Parent-child interactions:
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Parents avoid responding to the child’s disruptive bedtime behaviors (crying, tantrums, calling out, or leaving the bedroom);
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Parents who have difficulty ignoring the child can use the Excuse-Me Drill; parents periodically check on the child but only when the child is showing desire behaviors (calm, quiet, and in bed). This is repeated for nighttime awakenings.
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A bedroom pass (allowing only one bedroom exit per night) is often useful.
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Prader-Willi syndrome
Prader-Willi syndrome (PWS) is neurogenetic syndrome which occurs in approximately 1 of 15,000 births and most often due to a sporadic microdeletion in paternally derived chromosome 15q11-q13, less often when both copies of the chromosome are inherited from the mother (maternal uniparental disomy).
Recognizing infants with Prader-Willi syndrome
PWS is the most frequent cause of secondary obesity in children but the clinical presentation of PWS is striking different in infants. The prenatal features of PWS include: decreased fetal activity; polyhydramnios, breech presentation; and an abnormal posture on ultrasound: elbows flexed; feet dorsiflexed. Infants with PWS typically present with: severe central hypotonia; weak cry and difficulty feeding due to poor suck; growth retardation; and dermal and ocular depigmentation; and genital hypoplasia. A 2020 study of 134 infants with PWS found that 99% had severe central axial hypotonia and feeding difficulties; 98% weak (or even no) cry; 95% failure to thrive (FTT) requiring feeding tubes in 66%. This most often prompts genetic testing confirming the diagnosis.
After infancy, children with untreated PWS often exhibit hyperphagia, obesity, short stature, pubertal delay, hypogonadism, and behavioral and learning problems. Distinctive facial features in people with PWS: almond-shaped eyes, thin upper lip with down-turned corners of the mouth; and narrow nasal bridge. Hypothalamic dysfunction in PWS predisposes them to: temperature instability; high pain thresholds; and deficiencies in growth hormone, thyroid stimulating hormone, and central adrenal insufficiency. Mild-to-moderate ID, temper tantrums, resistance to change, manipulative tactics, food foraging, skin picking, and compulsiveness are common in them.
Sleep apnea more often central in infants with Prader-Will syndrome
CSA is the predominant type of SDB in children with PWS <2 years old, OSA >2 years. CSA tends to remit with increasing age in PWS, often replaced by OSA and/or sleep alveolar hypoventilation.
CSA was initially present in 53% of 28 infants with PWS but at a median follow-up of 2 years only 4 had residual CSA, and 3 had developed OSA CSA (but no OSA) on overnight PSG in 72% of children with PWS <2 years of age.
Another study found: (1) CSA in 43% of 23 children with PWS who were <2 years old versus 5% of 21 who were >2 years old; (2) OSA alone in 17% < age 2 years; (3) OSA sole type of SDB in 53% >2 years old versus 5% <2 years. CSA in infants with PWS often responds to supplemental oxygen. , Fig. 10.2 shows CSA recorded on a PSG in an infant with PWS.
Benefits of exogenous growth hormone therapy in infants with Prader-Willi syndrome
Infants diagnosed with PWS are typically offered exogenous growth hormone (GH) therapy. GH therapy in infants with PWS has many beneficial effects. One study found 21 children with PWS treated with GH for 6 years (beginning at age 13 ± 6 months) had lower body fat (mean 36% versus 45%), greater height (131 versus 114 cm), greater motor strength, and better lipid profiles compared to 27 children of a similar age (ages 5–9 years) prior to GH treatment.
A prospective study showed starting GH in infants with median age of 9.6 months resulted in less fat/more muscle body composition and them walking earlier by 15 months of age. Children with PWS who started GH during infancy (median age 1.4 years) had greater vocabularies and higher total intelligence quotient (IQ) than those who started GH later (median age 8.1 years).
However, GH (especially at higher doses) can accelerate the growth of lymphoid tissue and tonsillar hypertrophy; this may be related to insulin-like growth factor 1 (IGF-1) levels and contribute to development of OSA. A 2020 longitudinal PSG study found OSA develops independently of GH therapy in PWS. Pathological OSA increased significantly during the first 3 months of GH therapy but dropped below baseline after 1 year. A 2022 retrospective multicenter study of 112 patients with PWS followed from a mean age of 1.9 years found the mean obstructive AHI (oAHI) was 0.4/hour at baseline; 35% >1/hour. After GH initiation, there was no change in central AHI. The median oAHI did not increase significantly, but 12 children (13%) developed moderate/severe OSA. The AAP recommends PSG be repeated 6 to 10 weeks after starting GH therapy. Children with PWS treated with GH need regular follow-up screening for emergence of SDB.
Increased risk for sudden death in Prader-Willi syndrome
Individuals with PWS are at increased risk for sudden or premature death and have an annual all-cause death rate of 3%. Sudden death in PWS during infancy is more often secondary to milk aspiration; viral infections when sleeping in older children and adolescents; and respiratory failure, pulmonary embolism, cellulitis, or other complications of morbid obesity in the adults. Initial reports raised great concern that exogenous GH therapy contributed to/caused sudden death in PWS. Subsequent studies by in large refute this. A long-term study of 48 treated children suggests that the benefits of treatment with GH greatly exceed the risks.
Central hypersomnia common in Prader-Willi syndrome
Infants, children, and adults with PWS often have excessive daytime sleepiness (EDS) unrelated to SDB, attributed to hypothalamic dysfunction. , However, longer sleep needs in infants with PWS may not prompt complaints from caregivers.
Smith-Magenis syndrome
Smith-Magenis syndrome (SMS) is a neurogenetic complex multisystem disorder caused by a heterozygous deletion at chromosome 17p11.2 in the retinoic acid-induced 1 gene ( RAI1 ) or a heterozygous RAI1 pathogenic variant. The prevalence is estimated to be 1 in 15,000 to 25,000 live births.
SMS is characterized by developmental delay with ID, short stature, a deep hoarse voice, obesity, scoliosis, peripheral neuropathy, a distinctive neurobehavior syndrome and often severe sleep problems. The particular neurobehavioral phenotype seen in SMS (usually not recognizable until 18 months of age or older) is characterized by: (1) severe maladaptive sleep behaviors with inverted circadian rhythm of melatonin secretion; (2) self-injury with low sensitivity to pain (hitting, biting, skin picking, inserting foreign objects into body orifices, yanking nails); (3) peculiar motor stereotypies (upper body self-hugging, compulsive finger licking, and book or magazine page flipping); (4) temper tantrums, oppositional defiant behaviors, and attention-deficit/hyperactivity disorder (ADHD); and (5) emotional maturity delayed beyond intellectual functioning.
Recognizing infants with Smith-Magenis syndrome
Infants with SMS have feeding difficulties, FTT, hypotonia, hyporeflexia, prolonged napping (often need to be awakened to feed), generalized lethargy, relative insensitivity to pain and a mild 6 to 8 Hz intention tremor of the upper extremities. Crying in infancy is infrequent and often hoarse. The majority show markedly decreased babbling and vocalization for age with/without hearing loss. Head banging, which may begin as early as age 18 months is also frequent. ,
Infants with SMS are often described as having a cherubic face with DS-like features: a characteristic downturned tent-shaped vermilion of the upper lip; up-slanting palpebral fissures, short upturned nose, broad forehead; mild micrognathia, brachycephaly, and a fair (hypopigmented) complexion with rosy pudgy cheeks. Childhood onset obesity and scoliosis predispose older children and adolescents to OSA when older.
Sleep problems in Smith-Magenis syndrome are often severe and persistent
Caregivers of children with SMS usually do not recognize significant sleep problems before age 12 to 18 months, although fragmented sleep with reduced total sleep time has been documented as early as age 6 months. SWDs in children with SMS are characterized by fragmented and shortened sleep cycles with frequent nocturnal and early morning awakenings, daytime sleepiness, and sleep attacks.
A 2020 actigraphy study of 20 children with SMS (mean age 8.7 ± 2.7) and 20 TD controls found children with SMS had shorter total sleep times, shorter total sleep time (TST), extended night waking, shorter sleep onset, more daytime naps, and earlier morning waking compared to the TD group. In the SMS group, increased afternoon sleepiness was associated with increased irritability and hyperactivity.
Inverted circadian rhythm of melatonin secretion in Smith-Magenis syndrome
The RAI1 gene is a crucial transcriptional regulator gene of the mammalian circadian clock. The RAI1 gene loss of function in SMS is thought to be a significant factor contributing to SWDs in them. Seminal studies in children with SMS (20 ages 4–17 years) showed all had a phase shift of their circadian rhythm of melatonin with onset of melatonin secretion at 06:00 ± 2 hours, peaking at 12:00 ± 1 hours. Sleep/wake complaints in these children improved by giving early morning oral acebutolol (a beta-blocker to suppress the daytime melatonin secretion) and evening melatonin (to replace the normal nighttime peak). , Another study showed the 24-hour circadian rhythm of body temperature was phase advanced by about three hours (not inverted) in patients with SMS relative to controls.
Effective treatment of SWDs in SMS is best achieved by combination of behavior intervention techniques, oral extended release melatonin, and/or other medications including melatonin receptor agonists, beta1-adrenergic antagonists, and stimulant medications, to improve sleep outcomes. A multicenter double-blinded randomized placebo-controlled crossover study showed tasimelteon modestly increased TST in people with SMS.
Williams syndrome (7q11.23 duplication syndrome)
Williams syndrome (WS) is a multisystem genetic disorder which occurs in one in 7500 births and is caused by a contiguous gene deletion of the Williams-Beuren syndrome critical region on chromosome 7q11.23 that includes the elastin gene (ELN). WS is characterized by: usually mild ID (IQs in 60s and 70s), visual spatial deficits, relatively preserved expressive language, and a distinctive personality profile (social, friendly, gregarious, empathetic, loquacious, difficulty interpreting social cues, and prone to worries and fears). People with WS also have: cardiovascular diseases (elastin arteriopathy, peripheral pulmonic stenosis, supravalvular aortic stenosis, hypertension), endocrinopathies (hypercalcemia, hypothyroidism, hypercalciuria, early puberty), hypotonia, hyperextensible joints, and particular facial features (full cheeks and lips, broad nasal tip, widely spaced teeth). ,
Recognizing infants with Williams syndrome
Infants with WS are often born postterm and small. Impaired suck and swallow, textual aversion, GERD and vomiting often lead to failure to gain weight. Prolonged colic (>4 months) in infants with WS warrants consideration of GERD, chronic constipation, and/or hypercalcemia. Hypotonia and hyperextensible joints predispose to motor milestone delay; walking usually occurs by age 24 months. Other medical problems that often occur in the first year include: strabismus, chronic otitis media, rectal prolapse, umbilical and/or inguinal hernia, and cardiovascular disease. Speech delay and fine motor difficulties are common.
Sleep problems in infants and toddlers with Williams syndrome
Parents of 16 infants and toddlers with WS reported sleep problems in 31%. Large case-control studies have shown that children with WS have: greater bedtime resistance; sleep anxiety; nighttime awakening; sleep-onset insomnia; enuresis; body pain; and decreased sleep efficiency, increased respiratory-related arousals, increased slow wave sleep, more difficulty falling asleep, greater restlessness, and more arousals from sleep.
A 2020 study assessed sleep in 13 with WS and 25 TD controls at 18, 24, and 30 months of age. Parents of children with WS reported they had more nighttime waking, longer settling times, and required higher levels of parental involvement. Sleep duration measured using actigraphy was shorter in WS at all ages. Sleep quality with age improved in the TD controls but persisted in those with WS. Infants and toddlers with WS are at increased risk for SDB. A 2020 case-control study of 96 2 year olds with WS found SDB in 16% and EDS in 30%.
Children with WS children with SDB symptoms had significantly more behavior problems and those with EDS more attention/hyperactivity, stress, and externalizing problems. Shorter nighttime sleep duration correlated with language difficulties and internalizing problems; daytime sleepiness with externalizing problems. Another study found sleep problems correlated with a proportion of variance in language development scores in infants and toddlers with WS. Behavioral treatment strategies are needed to treat insomnia in WS, often supplemented by extended release melatonin. A less pronounced rise in nocturnal melatonin levels was found in children with WS compared with TD controls.
Angelman syndrome
Angelman syndrome (AS) is a neurogenetic disorder caused by loss of loss of function of the maternal copy of ubiquitin-protein ligase E3A (UBE3A) of chromosome 15q11-13. AS occurs one in 12,000 to 20,000 live births. Clinical features characteristic of AS include: global developmental delay; severe ID; lack of speech; and a unique behavior of frequent inappropriate laughter, smiling easily, excitability, epilepsy, hand-flapping coupled with a peculiar ataxic gait prompting them to be called “happy puppets.” Medically refractory epilepsy is particularly common in AS and usually begins before age 3 years. Also observed are: hyperactive lower-extremity deep-tendon reflexes; wide-based gait with pronated/valgus positioned ankles and an uplifted flexed arm when walking; attraction/fascination with water, paper, and plastics. Abnormal EEG awake and asleep with characteristic very high amplitude rhythmic 2 to 4 Hz slow waves (sometimes intermixed with spikes) are characteristic of AS ( Fig. 10.3 ).
Recognizing with infants with Angelman syndrome
Infants with AS have a normal prenatal and birth history, normal head circumference at birth and no major birth defects. Delay in developmental milestones first appear by age 6 to 12 months, eventually classified as severe without loss of skills. Feeding problems and/or hypotonia, tongue thrusting, suck/swallowing disorders, frequent drooling, excessive chewing/mouthing behaviors, and tremulousness and jerky limb movements should prompt consideration of the diagnosis and genetic testing. Delayed or disproportionately slow growth in head circumference usually results in absolute or relative microcephaly by age 2 years. Features which suggest AS in infants: minimal or no use of words; open mouth; tongue protrusion; ataxic gait and/or tremulous movements of limbs; frequent laughter/smiling, hand-flapping, hypermotor behavior, microcephaly; fair skin and hair; and problem sleeping.
Sleep problems so pervasive in Angelman syndrome to be considered part of clinical phenotype
Sleep problems in children with AS are so common that they are regarded as part of the syndrome and include: difficulty falling and staying asleep; frequent nighttime and early morning awakenings; irregular sleep/wake cycles; reduced sleep duration with increased WASO; heightened sensitivity to their sleep environment, being easily aroused by noise; and a variety of disruptive nocturnal behaviors (including periods of laughing), sleepwalking/sleep terrors, bruxism, seizures, and PLMs. , A 2018 metaanalysis found daytime sleepiness, frequent arousals sleeping, and short sleep duration were the most common sleep/wake complaints in people with AS. A recent study found low serum ferritin levels common in children with AS, often associated with periodic limb movements of sleep (PLMs) and sleep quality improved by iron supplementation. Separation anxiety and aggressive behavior correlated with sleep difficulties in another study of children with AS.
Mucopolysaccharidoses
Mucopolysaccharidoses (MPS) are a group of inherited autosomal recessive lysosomal storage disorders caused by the deficiency of hydrolases involved in the degradative pathway of glycosaminoglycans. MPS are progressive disorders in which the concentration of glycosaminoglycans in cells increase over time. The incidence of MPS in the United States was found to 0.98 per 100,000 live births (prevalence 2.67 per 1 million).
Infants are usually born without the clinical features of MPS but progressively develop clinical signs. Symptom onset and severity vary between subtypes, but coarse facial features, organomegaly, skeletal and joint abnormalities, dysfunction in vision and hearing, and cardiorespiratory problems are common across all MPS subtypes.
People with MPS are at great risk for multifactorial upper airway obstruction and often severe obstructive SDB. , Risk factors for OSA in them: macroglossia, excessive glycosaminoglycans deposited in tracheobronchial mucosa, restrictive lung disease due to a small thoracic cage, and reduced abdominal dimension due to hepatosplenomegaly and lumbar hyperlordosis. OSA is most often severe in MPS I (also known as Hurler syndrome), II (Hunter), and IV-A (Morquio) and VI (Maroteaux-Lamy). , Chronic hypoxemia may result in polycythemia, pulmonary hypertension, cor pulmonale, chronic respiratory failure and premature death.
Guidelines for managing MPS VI were published in 2019 and recommend overnight PSG at diagnosis (and no later than 2 years of age) and every 3 years thereafter or when signs and symptoms of OSA are noted. One study in 19 children with MPS found OSA in 95% and typically severe (AHI >10/hour 11; 5–9/hour 2; 1–4/hour 5; and normal in 1). Snoring, witnessed apnea, pectus carinatum, and macroglossia were the main clinical findings. Pulmonary hypertension was present on cardiac echo in 68%. Another study found OSA in all 24 children with various MPS, moderate/severe in 20.
Treatment strategies for OSA in MPS: AT, PAP, tracheotomy, supraglottoplasty, and bone marrow transplantation. Guidelines for managing MPS VI were published in 2019 and recommend overnight PSG at diagnosis (and no later than 2 years of age) and every 3 years thereafter or when signs and symptoms of OSA are noted. Sadly, OSA usually remains following enzyme replacement therapy and/or hematopoietic stem cell transplantation.
Sleep disorders associated with brainstem and cervicomedullary dysfunction
Particular neurological disorders (often with a genetic basis) are associated with SBD related to either brainstem respiratory dysfunction or compression of medullary respiratory centers. SDB in them prompt referrals to pediatric sleep specialists.
Chiari malformations
Chiari malformations (CM) are various rhombencephalic anomalies of cerebellar tonsillar herniation of increasing severity which present with varying combinations of spina bifida, meningomyelocele, syringomyelia, bilateral abductor vocal cord paralysis, SDB, prolonged breath-holding spells, and sudden death due to cervicomedullary junction (CMJ) compression. CM are classified by severity: (1) Chiari 1 (CM1) characterized by caudal displacement of the cerebellar tonsils inferior to the plane of the foramen magnum by 3 to 5 mm; (2) Chiari 1.5 by tonsillar descent into the foramen magnum accompanied by brainstem descent ; (3) Chiari 2 by caudal herniation of the brain stem, caudal cerebellar vermis, and 4th ventricle through the foramen magnum into the cervical spinal canal; and (4) Chiari 3 by features of CM2 and occipital encephalocele. ,
CM1 malformations occur in 1 in 1000 to 5000 births. The clinical presentation of symptomatic CM1 malformation (with/without syringomyelia) in children <3 years old is characterized by neck and cervical pain, short-lasting occipital “cough” headache, dizziness, gait impairment, feeding problems, signs of myelopathy, and sleep apnea. Most infants with CM2 or CM3 are recognized at birth (many earlier by fetal ultrasound). Patients with CM2 are more likely than those with CM1 to have spina bifida, meningomyelocele, and spastic paraparesis with neurogenic bladder. Syringomyelia (central cavitation or tubular fluid-filled cavity in several spinal cord segments) is present in 40% to 75% of cases of CM1 (occurring as early as 12 months). Conversely, 90% of patients with syringomyelia have CM.
People with chiari malformations at risk for symptomatic cervicomedullary junction compression
People with CM are at risk for cervical medullary junction (CMJ) compression. Symptoms and signs of CMJ compression include: (1) suboccipital headache may increase with coughing, sneezing, or bowel movement; (2) myelopathy can cause mono-, hemi-, para-, or quadriparesis which may develop acutely following a seemingly mild head or neck injury; (3) downbeat nystagmus, hearing loss or uni- or bilateral paralysis or dysfunction of soft palate or pharynx; (4) apneic episodes and often severe breath-holding spells awake when upset; and (5) sudden death in sleep.
Sleep disordered breathing common in people with chiari malformations
SDB is common in individuals with CM and can be central and/or obstructive sleep apnea, bradypnea, sleep-related alveolar hypercapnic hypoventilation, or sleep-exacerbated restrictive lung disease causing sleep-related hypoxemia with apnea or hypercapnia. SDB can be a sole or concomitant feature of CMC compression in CMs but is challenging to recognize in those unable to speak. A retrospective study of 16 infants and toddlers with CM1 diagnosed and surgically treated for CMJ compression found: (1) 75% presented with signs of headache with irritability, inconsolable crying, head grabbing, and/or arching back; (2) 63% presented with emesis, choking, gagging, snoring, sleep apnea, breathing pause, and/or vocal cord palsy.
Sleep disordered breathing may not remit following posterior fossa decompression in chiari malformations
Varying degrees of symptomatic improvement occurred following decompression, second surgeries were needed in seven. Infants with myelomeningocele and symptomatic CM2 are at increased risk for death especially in the first 3 months of life, low APGAR scores, large myelomeningocele defects, large head circumference at birth, and early CSA.
Overnight PSG with CO 2 monitoring is warranted to evaluate for CMJ compression and/or SDB in CM. Unexpectedly observing long runs of central apnea and/or marked bradypnea during NREM sleep in a PSG warrants ordering a brain MRI to exclude posterior fossa compression. Fig. 10.4 shows a PSG we recorded in an infant with Chiari 2 showing central apneas and bradypnea. Brain MRI is the initial best choice for neuroimaging (evaluates soft tissue structures, ligaments, and brain) to assess for the presence and severity of CMJ compression.
Treatment with CPAP, BPAP, BPAP-ST, and/or supplemental oxygen is often needed and tried depending upon the SDB found. Posterior fossa decompression in patients with symptomatic CM1 often improves or stabilizes symptoms including the SDB and headache. Syrinxes would usually stabilize (and sometimes decrease) in size. Acute hydrocephalus sometimes develops in the first week following surgery, heralded by worsening of the SDB. PAP therapy is often then needed or resumed. Better outcomes follow if decompression is performed while symptoms are present for less than 2 years. Another 2021 retrospective analysis of 15 children with symptomatic CM1 who underwent posterior fossa decompression for OSA and/or CSA found SDB improved but persistent SDB required PAP therapy in 47%.
Achondroplasia
Achondroplasia (AC) is the most common cause of severe disproportionate short stature and short-limbed skeletal dysplasia (dwarfism) with an estimated birth incidence of 1 in 10,000 to 30,00 live births and affects >250,000 individuals worldwide. , The diagnosis of AC should be suspected in the newborn with proximal shortening of the arms, large head, narrow chest, and short stubby trident hands.
The diagnosis of AC is based on clinical characteristics (short stature, macrocephaly, trident hand configuration, and a long near-normal length trunk) and specific radiographic findings (square pelvis, small sacroiliac notch, short vertebral pedicles with interpedicular narrowing from lower thoracic through the lumbar region, proximal shortening of long bones, proximal femoral radiolucency, and a characteristic chevron shape of the distal femoral epiphyses). AC is suspected prenatally when fetal ultrasound shows macrocephaly, long bone foreshortening, and disproportionate small stature which is usually not noticeable until after 26 weeks’ gestation. , Molecular confirmation of the FGFR3 mutation can be done by droplet digital polymerase chain reaction (PCR) combined with mini-sequencing from maternal blood.
AC is due to a heterozygous mutation in the FGFR3 gene on chromosome 4p16.3 that codes for production of the FGFR3 (fibroblast growth receptor-3) protein. FGFR3 (a membrane-spanning tyrosine kinase receptor) binds various fibroblast growth factors to regulate the normal endochondral bone growth. Gain of FGFR3 function in people with AC results in inhibition of endochondral ossification and which severely inhibits bone and cartilage growth. The gene mutation has 100% penetrance. Approximately 75% to 80% of AC are spontaneous new mutations of the FGFR3 gene but anyone with AC has a 50% chance of passing the mutation to their offspring given it has an autosomal dominant pattern of genetic transmission. FGFR3 mutation testing should be considered in infants/children with atypical AC since some may have a second genetic condition and/or other FGFR3 gene mutations (such as hypochondroplasia or thantophoric dysplasia. Confirming these can be clinically important because GH therapy can be an effective treatment for hypochondroplasia (not AC). Thantophoric dysplasia is often lethal in the prenatal or early postnatal period and associated with severe thoracic and lung hypoplasia; survivors usually require significant respiratory support.
Recognizing infants with achondroplasia
Distinctive features of AC evident at birth: macrocephaly, frontal bossing, saddle nose, midfacial hypoplasia, short cranial base, short proximal limbs, and short squat long bones. Infants with AC also have: mild-to-moderate hypotonia which contributes to delayed motor development; thoracolumbar kyphoscoliosis; delayed self-feeding and fine motor development; and some may exhibit unusual patterns of motor development such as snowplowing (using head and feet to leverage movement). Infants with AC are usually able to hold up their heads by 4 to 7 months of age, sit by 9 to 10 months, and walk unassisted by 16 to 22 months. Respiratory problems in infants with AC can be due to chest deformity, upper airway obstruction, airway malacia, SDB, and craniocervical compression of lower brainstem and upper cervical spinal cord from foramen magnum stenosis and bony overgrowth in occipital skull regions. Compression of the spinal cord at the foramen magnum in AC occurs because of premature fusion of the four segments of the occiput.
Sleep disordered breathing and respiratory difficulties in infants with achondroplasia
Studies evaluating SDB in infants and children with AC have been few, all retrospective, and most have found that the most frequent SDB in AC is predominantly obstructive in type. A 2020 retrospective chart review of 22 children with AC (median age 12 months) found that 73% had severe OSA on PSG (median preoperative OAHI 14/hour). Adenotonsillectomy was performed in 14, others required other upper airway surgeries. Following surgeries, OSA improved in 73% but only completely resolved in only 18%. Moderate/severe OSA was found on overnight PSG in all nine toddlers with AC (mean age 21 months) with varying degrees of CMC due to FMS; four underwent cervicomedullary decompression and SDB improved in three. SA was found on overnight PSG in 59% of 43 consecutive children with AC (mean age 3.9 ± 3.5 years) followed at a national referral center for skeletal dysplasia. OSA was moderate (AHI 5–9/hour) in 9%, severe (AHI ≥10) in 16%.
Important to evaluate for symptomatic foramen magnum stenosis in infants with achondroplasia
Overgrowth of bone in the occipital skull predisposes infants with AC to foramen to CMJ compression due to foramen magnum stenosis (FMS) and potentially sudden death. CMJ compression in AC often peaks around 12 months of age. Sudden death in infants with AC is now most uncommon. In 1987, the prevalence of sudden death in infants with AC was reported as 7.5%, 0.3% in 2018 with proactive screening for symptomatic CMJ compression. Nevertheless, the AAP 2020 revised clinical guidelines for managing the health of children with AC recommend neurological evaluation, craniocervical junction magnetic resonance imaging (MRI), and overnight PSG evaluating for symptomatic CMJ compression.
When significant symptomatic CMJ compression is present, suboccipital decompression is performed. A 2020 longitudinal study of 114 people with AC found that 50% had craniocervical stenosis (involving the foramen magnum with/without cervical vertebrae C1 and/or C2) but only 6% had suboccipital decompressive surgeries. Best predictors of need for suboccipital decompression include: (1) lower limb hyperreflexia and/or clonus; (2) radiographic evidence of CMJ compression/brainstem distortion at the level of the foramen magnum and/or T2-weighted signal abnormality with the cervical cord evident on MR; and (3) central hypopnea on PSG. , , , A 2020 longitudinal study of 114 people with AC found that 50% had craniocervical stenosis (involving the foramen magnum with/without cervical vertebrae C1 and/or C2) but only 6% had suboccipital decompressive surgeries.
A 2021 study compared cervical spinal cord abnormalities on MRI and overnight PSG in 36 infants with AC. They found: 6% had no FMS on MRI (graded AFMS-0); 36% had FMS but preserved cerebrospinal fluid (CSF) spaces (AFMS1); 8% loss of CSF space but no spinal cord distortion (AFMS2); 36% FMS flattening of the cervical cord without signal change (AFMS3); and 14% cervical cord signal change (AFMS4). Severity of total AHI on overnight PSG were 3.4, 6.4, 2.97, 10.5, and 25.8/hour for AFMS 0 to 5, respectively. Severe AHI had an 89% specificity but only 59% sensitivity for AFMS grades 3 or 4. The neurological examination was normal in 94%.
Central congenital hypoventilation syndrome
Central congenital hypoventilation syndrome (CCHS) is a neurogenetic disorder with an incidence of 1 in 50,000 to 200,000 live births which is almost always due to pathogenic variants in the transcriptional paired-like homeobox 2B ( PHOX2b ) gene. , The PHOX2b gene encodes a transcription factor crucial for the early development of the central autonomic nervous system (ANS).
More than 90% of patients with CCHS have in-frame tandem duplications of polyalanine repeat mutations (PARMs) in the exon 3 of PHOX2B gene producing genotypes of 20/24 to 20/33 (normal number of repeats is 20). CCHS. Remaining CCHS patients have frameshift, missense, or nonsense mutations in exons, 1, 2, or 3 of the PHOX2B gene (so-called non-PARMS). Two consanguineous CCHS families were recently found to have mutations in MYO1H and LBX1 genes.
Infants with CCHS most often present in the first 30 days of life with duskiness or cyanosis upon falling asleep accompanied by progressive rise in carbon dioxide (CO 2 ) and fall in oxygen (O 2 ) which does not trigger breathlessness, an increase in respiratory rate, ventilatory effort, arousal or awakening. Central hypoventilation in CCHS is typically most severe during NREM sleep but some hypoventilate awake and asleep, especially in the first few months of life.
Other infants with CCHS can present later (more often around age 3 months) with cyanosis, edema, and signs of right heart failure. At first these findings are mistaken for cyanotic congenital heart disease until only pulmonary hypertension found on cardiac catheterization. A few other infants with CCHS (again most often around 3 months of age) present with: brief resolved unexplained events (BRUE); repeated oxygen desaturations; or episodes of tachycardia, diaphoresis, and/or cyanosis during sleep. , Another chapter in this text covers CCHS in detail and we encourage you to review it. Table 10.2 summarizes neurological disorders presenting as sleep-related central hypoventilation in infants.
