Clinical Description
Pitt-Hopkins syndrome (PTHS) is characterized by distinctive facial features, significant developmental delays with moderate-to-severe intellectual disability, neurobehavioral/psychiatric manifestations (e.g., stereotypic hand movements, autism spectrum disorder), and autonomic dysfunction (e.g., episodic hyperventilation and/or breath-holding while awake). Speech is significantly affected. Although most individuals are nonverbal, receptive language is often stronger than expressive language. Other common findings are sleep disturbances, seizures, constipation, and severe myopia (see Table 2).
Table 2.
Pitt-Hopkins Syndrome: Frequency of Select Features
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Feature | % of Persons w/Feature |
---|
Facial gestalt | 90%-95% |
Developmental delay / intellectual disability | 100% |
Delayed motor milestones | 100% |
Neurobehavioral/psychiatric manifestations | 100% |
Speech & language delay | 90%-100% |
Excessive drooling | 80% |
Hypotonia | 73%-90% |
Autonomic dysfunction | Constipation | 78%-95% |
Respiratory | 54%-75% |
Urinary retention | 40% of adults |
Myopia or strabismus | 50%-60% |
Seizures | 32%-50% |
Cryptorchidism | 33% |
Sleep disturbances | 33%-43% |
Microcephaly | 23%-60% |
Musculoskeletal | Pronated ankles / flat feet | ~100% |
Scoliosis | 20%-25% |
Short stature | 15% |
Developmental delay / intellectual disability. Children with PTHS typically present in the first year of life with hypotonia and global developmental delay.
Hypotonia is noted in most infants and young children. Poor balance often causes difficulty with learning to walk. Fine motor skill acquisition is also delayed and variably achieved.
Motor milestones are delayed in all individuals, most of whom are not ambulatory until after age three years [Goodspeed et al 2018]. The mean age of walking is four to six years (range: 27 months to 7 years); some individuals may walk only with assistance, and a minority do not achieve independent ambulation [Whalen et al 2012]. Those who walk independently often have a wide-based, unsteady gait. Most individuals require orthotics to stabilize the ankle.
Speech and language. Speech is significantly delayed in practically all individuals. Because most individuals are nonverbal, important means of communication include interpretation of body language and use of gestures or leading behaviors. Although some individuals develop a few words, later in life they regress, becoming nonverbal. Rare individuals can combine words into sentences.
Receptive language is generally stronger than expressive language; many individuals understand and follow simple commands. The use of augmentative communication devices and alternate forms of communication including signs often improve communication, thus helping to reduce frustrations and behaviors and to improve learning (see Management). Although all individuals with PTHS have significant intellectual disability, poor communication skills may result in underestimation of cognitive abilities.
Self-care skills are also delayed; few individuals develop consistent dressing or toileting skills.
Neurobehavioral/psychiatric manifestations include features of autism spectrum disorder (ASD) such as impairments in communication, behavior, and social interactions.
Some individuals meet diagnostic criteria for ASD. Eight of ten participants scored at or above the social, behavioral, and communication criteria for ASD using the Autism Diagnostic Interview Revised (ADI-R) [Van Balkom et al 2012]. All participants had repetitive hand or finger movements and high scores for self-absorption. Six of the ten had fixations that prompted repetitive exposure to a specific object, listening to the same song, or viewing the same video repeatedly. Many individuals love water play (with a fascination with running water), spinning objects, and lights [D Sweetser, personal observation].
By contrast, most individuals with PTHS often seek attention and enjoy being with people. Most individuals generally have an easygoing, happy temperament [Marangi et al 2011, Goodspeed et al 2018], frequently smiling and seemingly content. Unprovoked laughter may occur. However, they commonly exhibit periods of behaviors that may be set off by anxiety, frustration, or pain [D Sweetser, personal experience]. Given the frequent underlying anxiety, Whalen et al [2012] proposed that an anxious disposition with a smiling appearance is a more apt description.
Individuals may be shy or anxious in new situations (such as disruptions of routines) and can show self-aggression such as hand biting and head banging, pinching, or hitting themselves [de Winter et al 2016].
Many individuals have outbursts of aggression or bouts of shouting associated with frustration or unanticipated changes in routine [Andrieux et al 2008, Giurgea et al 2008, de Pontual et al 2009]. The onset of puberty can also be associated with increased aggression and behavioral issues [D Sweetser, personal observation].
Stereotypic head movements (e.g., head rotation) and hand movements (e.g., flapping, clapping, washing movements, hand to mouth, finger crossing) are common [Takano et al 2010, Marangi et al 2011, Whalen et al 2012]. Although three individuals were reported to have lost hand skills [Armani et al 2012, Whalen et al 2012], this is not generally seen.
Individuals with PTHS invariably have a profound affinity for music. Families report that during episodes of anxiety or frustration, music is often soothing.
Respiratory dysregulation is common [Zweier et al 2007, de Winter et al 2016, Goodspeed et al 2018]. Breathing abnormalities tend to develop between ages three and seven years. Although rare, neonatal presentation occurs [Tas et al 2022]. In one study, 30% of individuals with PTHS exhibited symptoms by age 15 years [de Winter et al 2016].
Breath-holding episodes of varying severity and independent of hyperventilation may occur. Breath-holding/apnea episodes are not typically related to seizure activity and generally do not occur during sleep [Maini et al 2012].
Apnea from birth to age three months, not associated with prematurity or seizures, is seen in about 6% of infants [D Sweetser, personal observation].
Subtle breathing pauses are common. Overt breath-holding with hypoxia and cyanosis can be seen, and in rare cases syncope may occur [Whalen et al 2012]. Chronic hypoxia presumably underlies the clubbing seen later in life in some individuals. Note: Parents/caregivers may need to be queried directly about breath-holding (which typically is not serious enough to seek medical attention) [Takano et al 2011; D Sweetser, personal observation].
In some children, hyperventilation and/or breath-holding episodes are observed for only a few months or years; however, in most individuals breathing abnormalities persist to some degree. It is difficult to make conclusive statements about frequency or severity of such episodes in adults, as to date too few adults with PTHS have been described.
Chronic hypoxemia and associated finger clubbing has been reported in 7%-19% of individuals [Whalen et al 2012, Goodspeed et al 2018]. While the etiology of digital clubbing is not well elucidated, it may be related to cumulative periods of hypoxemia. Detailed studies of pulmonary function, including diffusing capacity, are not possible given behavioral barriers.
Disorders of sleep-related breathing, such as obstructive apnea, hypoxemia, and hypoventilation, can have significant long-term effects on health, behavior, and development. Children with developmental disorders may be more susceptible to the deleterious effects of these disorders than neurotypical children [Menzies et al 2022].
Episodic hyperventilation, usually in the context of heightened emotion such as anxiety or excitement, occurs in 40-60% of individuals [Giurgea et al 2008, Whalen et al 2012, Steinbusch et al 2013, de Winter et al 2016, Goodspeed et al 2018]. Rare children manifest repeated episodes of hyperventilation immediately followed by apnea and syncope.
Other signs of general autonomic dysfunction observed in some individuals or reported by families include the following [Zollino et al 2019]:
Dilated pupils with sluggish response to light
Decreased distal circulation
Urinary retention
High external pain tolerance with visceral hyperesthesia
Dysregulation of body temperature
Gastrointestinal. Feeding issues related to hypotonia can present in the first months of life with poor feeding and poor coordination of suck and swallow resulting in poor weight gain. Most of these issues resolve with age.
Constipation, which is common (75%), often starts in infancy, may be severe, and generally is lifelong.
Dysmotility of the gastrointestinal tract and autonomic dysfunction resulting in gastroparesis and chronic intestinal pseudo-obstruction are thought to contribute to frequent and significant abdominal pain. Constipation or intestinal dysmotility is a common source of pain. Effective control of constipation and improving gastrointestinal motility may lessen such spells [Comisi et al 2023], as can institution of pain management [Reaney & Collins 2024] (see Table 5).
Visceral hyperalgesia can be a cause of abdominal pain [Reaney & Collins 2024], which contrasts with individuals with PTHS having a higher tolerance in general for cutaneous pain. Due to impaired communication, it can be difficult to determine the cause of unexplained crying episodes, though an intestinal cause should be suspected.
Aerophagia (i.e., excessive air swallowing) can be caused by dysregulated breathing, leading to abdominal bloating. While aerophagia is generally benign, it can cause abdominal pain; rarely, it has been associated with colonic volvulus and/or bowel perforation [Zollino et al 2019, Koppen et al 2023]. Fatal gastrointestinal complications have been reported in which aerophagia may have been a contributing factor [Koppen et al 2023].
Malrotation, reported in up to 16% of individuals [Goodspeed et al 2018], can predispose to the serious complication of intestinal volvulus.
Gastroesophageal reflux disease (GERD), reported in fewer than half of individuals with PTHS [de Winter et al 2016], can be associated with manifestations of impaired swallowing but often improves with age.
Bruxism is also common [de Winter et al 2016, Zollino et al 2019].
Excessive drooling is seen in most individuals with PTHS [de Winter et al 2016]. Drooling can decrease in early childhood in some children due to improved oral motor coordination; however, it can continue even into adulthood, indicating sialorrhea as a possible cause. Drooling can also be a manifestation of GERD.
Eyes. Myopia, strabismus, and/or astigmatism are common.
Myopia can be severe (>6 diopters) and evident before age two years [Giurgea et al 2008, Stavropoulos et al 2010]. Retinal detachment has not been reported. Most individuals can tolerate glasses to correct their myopia.
Cerebral visual impairment has been diagnosed in about 14% of individuals [D Sweetser, personal observation].
Seizures vary in type and severity. Onset ranges from early infancy to as late as age 18 years [de Pontual et al 2009].
In an internet-based questionnaire involving 101 families, 37.6% reported epilepsy [de Winter et al 2016]. The majority (51.4%) had involuntary motor movements or tonic-clonic seizures often with absence seizures, 16.2% had only absence seizures, and the rest could not accurately describe their family member's seizures. Since this was a questionnaire study, it is unclear whether "absence" events were true absence seizures or focal-onset seizures with no motor component. Of those with a history of epilepsy, 23.7% became seizure-free at a mean age of 6.4 years.
In a study of 38 individuals with PTHS, Maini et al [2012] reported that the breathing abnormality observed did not appear to be a manifestation of seizure activity; however, seven individuals with seizures had apnea or hyperventilation shortly before their seizures.
Although seizures are usually well controlled with standard anti-seizure medications, presumed sudden unexplained death in epilepsy has been observed [D Sweetser, personal observation].
EEG findings in four individuals reported no specific patterns other than occipital and central delta waves in the two younger individuals. Pseudo-/quasiperiodic complexes present during wakefulness over the central and occipital regions were at times admixed with slow spike and wave in the two older individuals [Amiel et al 2007].
Of 11 EEGs in individuals with PTHS with seizures, the most common EEG findings were generalized background slowing in six individuals, focal spikes and discharges in three, and focal slowing in two [D Sweetser, personal observation].
Genital abnormalities. Small penis or cryptorchidism in males and abnormal clitoris or labia in females have been noted in 30% of individuals. Rare instances of absent vagina or uterus and ovaries have been noted [Whalen et al 2012, Zollino et al 2019].
Sleep disturbances, reported in 33%-43% of individuals, can include difficulties with sleep initiation and maintenance, circadian disorders, sleep-disordered breathing, and sleep-related movement disorders [Whalen et al 2012, de Winter et al 2016, Gandhi et al 2021].
Some infants with PTHS have been described as quiet and "unusually good," with excessive sleeping [Giurgea et al 2008].
Musculoskeletal. Hyperpronation of the ankles with flat feet is nearly universal.
Mild-to-moderate scoliosis has been noted in about 20% [Goodspeed et al 2018].
Minor hand and foot anomalies such as slender or small hands and feet, broad fingertips, clinodactyly, tapered fingers, transverse palmar crease, prominent heels, overriding toes, and short metatarsals have been reported [Goodspeed et al 2018]. Absent interphalangeal flexion creases of the thumbs with limited or absent voluntary thumb flexion generally without thumb ankylosis has been observed in about 9% of individuals [D Sweetser, personal observation]. A thumb tendon was not found in one individual during attempted surgical correction [D Sweetser, personal observation].
Many affected individuals have prominent pads (i.e., persistent fetal pads) on fingertips and/or toes [Lehalle et al 2011, Goodspeed et al 2018].
Other
Hands and feet are reported to be cold and cyanosed in some individuals.
In addition to the craniofacial features (see , , , , and ), cherry-red lips have been noted infrequently [
Ghosh et al 2012].
The initiation and progression of secondary sexual characteristics appear to be unaffected [D Sweetser, personal observation].
Adult-onset features. Relatively few older teens or adults have been reported; thus, it is not yet known what, if any, other adult-onset findings may be of concern. Several adults have had significant hand tremors. Several had chronic urinary retention requiring intermittent catheterization. One 34-year-old had bipolar disorder [D Sweetser, personal observations].
Other. Hodgkin lymphoma was reported in a 29-year-old [Zweier et al 2007]. While TCF4 has a role in lymphocyte development [Zhuang et al 1996], the lack of other reports of individuals with PTHS with lymphoma suggests that this might be a coincidental finding.