General Health

Feeding problems

Early muscle weakness (hypotonia) in infants with PTHS may lead to feeding problems. Typically, the new-born feeding is closely monitored and if needed the paediatrician will offer advice how to deal with these for each child. This is done like in any new-born with feeding problems. Generally, the problems sort themselves out as the children get older.
Feeding difficulties at a later age, such as gagging, refusing to eat, and only eating at a certain time or place, or a certain type of food, may occur, but in general those with PTHS are described as excellent eaters. 

Digestion problems

Digestion problems are common in children and adults with PTHS. Constipation occurs in the majority of children. In adults it occurs a bit less, but still frequently. Gastroesophageal reflux disease occurs in about 40% of PTHS children and adults, and burping occurs in a third of them. Hyperbreathing can lead to swallowing air into the stomach causing lots of discomfort as the stomach swells and lots of burping. This was the case for just under half of those present at the World Congress in 2018. One child had this so badly that she had had a gastrostomy to let air escape a few times a day which fixed her problems, and we have a similar good experience in some others as well. When the swelling of the stomach is causing problems in a child or adult this should be considered.

The 47 attending the World Congress did not seem to show more food intolerance than would be expected in the general population. Other gut problems include pyloric stenosis and malrotation, but are not common. They can be treated in the same way as in children and adults without PTHS.

Reflux

The treatment for gastroesophageal reflux is similar to that of the general population. The first thing to try is the proton pump inhibitor. People with PTHS respond well to these if the medication is given in high enough doses (omeprazole 0.7-3.5 mg/kg/day to keep everything well (R10).

Constipation

Many with PTHS have severe constipation all their lives. Hirschsprung Disease (when nerves are missing in parts of the intestine), is causing very severe constipation and has been associated with PTHS but it is very rare and has only been seen in one child with PTHS. It may well be this should be explained by coincidence.  A study with mice that had a TCF4 deletion similar to those with a deletion in a human showed slower movement from the mouth down to the beginning of the large intestines and from end of the large intestines. There is not much data on the speed of food going through the bowel in humans.

The treatment for constipation is similar as for the general population (R8). (Toilet timing eg regular toilet sitting for a set period after every meal and using positive reinforcement through a reward system is also helpful. Effective control of constipation includes using constipation diaries, the Bristol stool form scale, and the section C of the Questionnaire on Paediatric Gastrointestinal Symptoms and seeing a doctor when necessary (QPGS) (R9).

Recommendations
R8 Constipation, both chronic and occasional can often occur in individuals with PTHS and should be monitored and assessed.  This can be done by keeping a diary or by using a dedicated questionnaire.

R9 Treatment for constipation will follow the same treatment that would be given to anyone else.  This might include some behavioural modification strategies.

R10 If the PTHS individual encounters problems with reflux, again the treatment will not differ from any other person.  Sometimes anti-reflux medications will be prescribed and should be used to their maximum dosage.

Disturbed regulation of respiration is one of the main criteria of PTHS. It is most probably part of the general dysautonomia that occurs in PTHS. Dysautonomia means that all processes which are automatically steered by your nervous system are no longer regulated well. This means it might also show in characteristics such as dilated pupils with sluggish response to light, instability of temperature, decrease circulation in hands and feet, constipation, or not emptying urine completely from the bladder urinary retention.
Respiration problems can start at a variable age. We gathered data on 256 children and adults with PTHS and found that 123 (48%) had hyperbreathing which started at a mean age of 6 years, but it could start as early as 3 months or as late as 37 years. The true frequency of a disturbed respiration may well be higher, as affected individuals may have been reported at an age where they may not yet have developed the abnormal breathing. When checking this for each age group the incidence of respiration problems was 20% before 2 years of age, 23% between 3 and 5 years, 22% between 6 and 10 years, 69% between 11 and 15 years, and present in over 90% of older individuals. Rarely, hyperbreathing has started to occur in a young child and then, after months or even years, disappeared again for several years. We did not see a relation between the change in the gene and the occurrence of hyperbreathing.
The typical breathing pattern consists of rapid breathing, sometimes regular sometimes irregular, followed by a pause in breathing. It usually takes 2 to 5 minutes. It may occur several times per hour to a few times per year. The spells are not reported during sleep. Apnoea’s and hyperbreathing may also occur independent of each other. Periods of hyperbreathing may be triggered by excitement, stress, or anxieties, but may also occur without clear issues that makes it arise. A period of apnoea may be followed by cyanosis (blue discoloration of lips and pale blue skin) and rarely loss of consciousness. Oxygen saturation (the amount of oxygen in the blood) may be decreased during a spell of abnormal breathing.  We are not aware of any instance that the heart stopped beating provoked by a spell of apnoea (R11). Sometimes the epilepsy occurs first and after months or years the breathing abnormalities follow, but the reverse occurs as well, but only infrequently a spell is followed immediately by a seizure. Many affected individuals develop clubbing of fingers (broadening of the tips of the fingers) within a few years after the start of the breathing irregularities. Clubbing was present in 9 of 49 individuals with PTHS in whom the hands were evaluated during the 2018 PTHS World Conference. In some the clubbing had been noted before the hyperbreathing had started but it is more likely the hyperbreathing had gone unnoticed before.
Other consequences of the abnormal breathing are excessive burping and swelling of the abdomen. Breathing spells may cause anxieties in a child or adult with PTHS and appear quite concerning, but many do not seem to be disturbed and remain comfortable. Others stop what they are doing, some sit down to prevent a fall, and in a minority loss of consciousness occurs. Infrequently, irregular breathing at night and catathrenia (an apnoea at the end of inhaling air and groaning when exhaling, both during sleep) has been reported. Parasomnias (unusual behaviour during sleep like nightmares and sleepwalking) were reported in 10 of the attendees of the 2018 PTHS World Conference. Although polysomnographies are not available for evaluation, it has been suggested that the breathing problems at night may also have a different cause and be obstructive in nature (R12).
There is a report from Belgium on two children with PTHS and marked spells of hyperbreathing which decreased in number and duration when using acetazolamide, and in another adult it did work too. Acetazolamide is a carbonic anhydrase inhibitor and is used in acute mountain sickness which resembles the breathing problems in PTHS to some extent. However, how it may work in PTHS is still uncertain. A major side effect may be low potassium levels which has been a reason to stop the medication in several children and adults with PTHS. In individuals without PTHS, other medications such as triazolam and zolpidem have been used for central sleep apnoea, but we must assume the effect in PTHS to be low due to the different origin of the respiratory problems in PTHS. In a mouse model of another syndrome, Rett syndrome, in which breathing problems also occur, sarizotan has been shown to reduce the incidence of apnoea and hyperbreathing, and a clinical trial is now underway. If successful it may hold promise for the breathing problems in PTHS.

Recommendations
R11 It should be explained to caregivers that spells of hyperbreathing, despite being disturbing to witnesses, are unlikely to be harmful.

R12 If breathing disturbances occur at night, polysomnography should be considered in individuals with PTHS to exclude obstructive sleep apnoea.

Which problems occur with eyesight? How often should this be checked? Which occur with hearing and how often should these be checked? Are there problems with other senses such as smell, feeling temperature and pain?

7.1 Vision

The structure of the eyes (lens, iris) of PTHS children is usually normal. About 10% of children may have blocked tear ducts. If it causes prolonged problems, it can be treated in the usual way.
Sight issues are common, with about 2/3rd of PTHS kids needing glasses, frequently before the age of 2 years. Short-sightedness (50%), strabismus (cross-eyed, 45%) and nystagmus (eyes rapidly moving side to side, 14%) are the most common problems. Rarely a slow reaction of wide pupils to light occurs. As sight problems are so common in PTHS, every child should be seen at a young age and regularly followed up by an ophthalmologist (R13).

7.2 Hearing

Hearing loss is not very common (10%) in PTHS. Still, as it is so important for speech development, it is wise to check the hearing in all children with PTHS (R14). There are tests that can be carried out that do not need any type of feedback from the child (in medical terms: optoacoustic emission and auditory evoked potential), so testing can be done reliably in every child, also the ones who are not willing or able to cooperate.. 

7.3 Other senses

Smell

There have not been any studies of the sense of smell in children with PTHS. Maybe some have a decreased sense of smell and others are sensitive to some smells, but this is not yet certain.

Pain

Recognising and dealing with pain is challenging in children and adults with PTHS as the majority cannot tell us this. Apparently, they can react in a different way to pain. Some parents have said that their child is more bothered by and sensitive to minor pain, such as a small scrape or cut, while they seem less bothered by something others would find far more painful such as pain after surgery. Others are showing less pain anyway. This is important to realize if the behaviour of a child has changed as for instance a fracture can go unnoticed (R15). It can be that the cause is a different pain sensation: the gene, TCF4, makes a protein that works in pain signalling in the Pitt-Hopkins mouse.
There are questionnaires such as the FLACC that have been developed to recognise and assess pain in children with special needs and it is advised they are used with children with PTHS if there is any doubt whether or not someone has pain (R15).

Recommendations
R13 Every child with PTHS should have their eye-sight checked on diagnosis and then regularly monitored

R14 Hearing should be tested regularly in everyone with PTHS.

R15 Parents and carers should be aware of the various types of pain felt by those with PTHS; if in doubt specific questionnaires can be used to assess pain.

It has been found that up to half of people with PTHS have epilepsy with different types of seizures that vary in severity. Someone with PTHS may have a first seizure as early as the first year of life or as late as early adulthood. Seizures can easily be misdiagnosed when there is apnoea (see glossary) as in both the lips and skin can go blue. Children with PTHS may show apnoea or hyperbreathing just before a seizure, but the abnormal breathing is not itself part of the seizure. Electroencephalographic (EEG) patterns in people with PTHS are typically abnormal, and the patterns will change over time. If the EEG is normal one should be careful not to miss that in fact, there is no seizure, but it is an apnoea. The EEG patterns usually are not specific to a certain type of seizure. As it is difficult to tell the difference between seizures and apnoea it is suggested that an EEG be carried out if in doubt and looked at with this in mind (R16). There is no need to make an EEG in everyone with PTHS. Valproic acid, levetiracetam, lamotrigine, and carbamazepine are the most commonly used seizure drugs but there are not enough data to say whether one drug is better than another (R17)

Other neurological (glossary) problems are not very common in people with PTHS. Seven of the 47 people with PTHS who attended the 2018 PTHS World Conference were shown to have a tremor (shake) that did not get worse over time. The common wide standing position and movement may be linked to problems with a person’s nervous system, but there has not been enough study on it. There is a noticeable difference in muscle tone in people with PTHS: three-quarter will have truncal (torso) hypotonia, and less than 10% has a high muscle tone (hypertonia). One-third has this high muscle tone in arms and legs. It has been suggested the difference in muscle tone is due to the autonomic nervous system being disrupted (see section 6).
Sleep problems are seen in a small number of those with PTHS with many parents saying that their child sleeps extremely well. Some parents mention that their child does not sleep through the night or have night terrors. Melatonin had been used by 10 of the 51 attendees of the World Conference in 2018: in two it had worked well, in six it had no effect and in the remaining two the result was uncertain. Sleep has not been looked at in full detail yet and further studies are needed.
Different brain scans (MRI) have been done and smaller changes in the formation of the brain have been seen in some but in most the scans just show normal results. Almost invariably the results are not important in how a child with PTHS should be looked after. So, it is suggested that an MRI is only needed when there are neurological signs and symptoms, such as repeated seizures but not in all children with PTHS. An MRI is also not needed just because a child has microcephaly (small head) (glossary) (R18)

Recommendations
R16 EEG studies should only be carried out when there are clear seizures or when one remains in doubt if someone with PTHS shows seizures or apnoea’s.

R17 Clinical seizures can be treated just the same as in the general population; there is no evidence that one specific drug works better than others.

R18 MRIs need only be carried out if there are neurological signs and symptoms that this would be useful. Microcephaly (small head) on its own does not mean a child should have an MRI.

Musculoskeletal problems occur frequently in both children and adults with PTHS.

The hands are quite small and slender, and the fingers are often tapering. But this does not appear to cause major problems. The thumbs can be bowed less than usual in half of the children and rarely even not at all. Usually no therapy is needed. Also rarely someone with PTHS cannot move all fingers in the normal way; then physical therapy in the first year of life might make this better.

Major problems occur frequently in the feet: these are almost always slender and flat and can be turned outwards. Also, a pes cavus (high arch) occurs. Overlapping toes are not uncommon.
Minor limb anomalies do not require therapy, but the shape and function of the feet and ankles often require special footwear, inserts, or orthotics (R19). In selected cases, surgical procedures may be beneficial, for example, flat foot reconstruction.

Scoliosis (curving of the spine to one side) has been reported in 18% of children with PTHS (RH20). It can arise during puberty but also at younger ages. There is no study available on the results in larger groups on the management of scoliosis. Our joint experience indicates that the way a doctor deals with the scoliosis should be as for the general population (R21). Someone with a scoliosis can best be followed regularly, as that is the best way to show if treatment is needed or not.

Very infrequently other orthopaedic problems occur such as kyphosis (forward bending of the upper part of the spine), pectus excavatum (chest bone running inward), and decreased mobility in a knee. Each can be treated as in anyone with this problem without PTHS.

In the first year of life most children with PTHS have a low muscle tone and a delayed development. Motor skills are delayed: about one-third walk unaided between 3 to 5 years of age, and three-quarter between 6 to 10 years of age. They walk typically with a wide‐based, unsteady (in medical terms: ataxic) gait. Some may walk only with help, and still others never learn to walk on their own.  Of those who are unable to walk alone, some achieve independent mobility by using a wheelchair. 

Speech is frequently markedly delayed, with many remaining non‐verbal. Up to 55% of individuals speak single words before 10 years of age, and only a minority (less than 10%) use whole sentences. Of the 47 individuals present during the 2018 PTHS World Conference 39 used 0 to 5 words, two 10 to 20 words, and six were able to use short sentences. 

Few children develop dressing or toileting skills. One in five children will be toilet trained for urine between 11 and 15 years of age.

Growth in length and weight is usually normal at birth; less than 10% is small at birth. After birth height drops below the lowest lines in one-third of the children, and head circumference will be just below the lowest line of the curve in half of the kids. 

No major teeth anomalies have been reported, and teething and the loss of milk teeth occur at a normal age. Increased spacing of teeth is common. It is prudent to have children with PTHS evaluated regularly (usually once per 6 months) by a dentist as children with developmental disabilities are more likely to have unmet dental needs (R22).

Burping (28%), reflux (38%), and constipation (80%) are common in children. During feeding they may gag, choke, and not chew properly. Some refuse food, or have very strict rituals during feeding. , In general however, many are described as excellent eaters. 

Drooling is seen in 80%, usually more prominent in young children, and teeth grinding occurs in one-third. Repeated infections of the airways (otitis media, tonsillitis, bronchitis) and kidney and bladder have been reported in one‐third, occurring mainly in childhood. 

An abnormality in the way the children and adults deal with infections (in medical terms: immunological disturbances) are reported only a few times and include low levels of several proteins needed to fight infections (in medical terms: low IgA, IgM, and IgG levels). Of 49 affected individuals at the 2018 PTHS World Conference immunological testing was performed in seven, and abnormalities in immune‐globulin levels were found in three. 

Vaccinations should be given according to national schemes (R23). There are still many things not explained in infections in PTHS, and it seems wise to perform detailed immunological studies in everyone with repeated infections.

Abnormalities of heart, lungs, kidneys, liver and intestines are quite infrequent, and ultrasounds of the heart and kidneys are only indicated in case of suggestive symptoms (R24). 

One-third of boys has non descended testicles, and infrequently small or fused (glued together) labia majora, and a small womb occur in girls.  As far as we know now puberty develops at a normal age and pace.

The paediatrician, preferably one with experience in PTHS, should play a central role in the clinical care for children with PTHS. He or she should regularly check for health problems (surveillance), coordinate multidisciplinary care, and oversee the social support system surrounding the child (R25).

About one-fifth of adults is just below the expected height. 

There are no reports of related endocrine issues such as shortage of growth hormone or abnormal functioning of the thyroid gland. Some become somewhat overweight as time goes on, but excessive weight gain is not often a problem in most with PTHS. 

Mild microcephaly is seen in a quarter of adults. Adult facial characteristics do not change much from those in in infancy.

Feeding problems are not common in adults with PTHS. Problems with drinking and swallowing solids is seen in about 10%. Constipation is very common and occurs in three-quarter of adults (see Section 5). Gastroesophageal reflux is present in one‐third and usually responds well to anti‐reflux medication. 

Flat feet (pes planus) and turned out feet (pes valgus) are seen in half of the adults. These should be checked for as orthopaedic shoes or other orthotic devices, physiotherapy, or other specific treatments may be needed (R26). When an adult with PTHS has limited mobility, physiotherapy is required to prevent the mobility to become permanently affected (contractures). 

Other, usually less important problems can be overriding toes, scoliosis, and limited thumb mobility. 

Although frequent infections are not common, urinary tract infections can be missed or manifest as unusual behaviour changes (R27).

Adults with PTHS have widely spaced teeth. Many grind their teeth and drooling is seen often. A protruding jaw (prognathism) may develop and can cause problems with chewing. Advice from a speech therapist may be helpful (R28). If there are unexplained behavioural changes, the teeth should be checked as they could be a cause of pain.

In about a third of those with PTHS genital differences are seen such as undescended testes (cryptorchidism), a small penis, and unusual labia. Adult males should be checked for cryptorchidism, as this may have been missed when they were younger. If present, management is as in the general population (R29).

It is hard to give an accurate idea of the life span in PTHS as only few older people have been diagnosed, and most are still young adults. It is thought that they will have a typical life span. Three adults are known who have developed a form of cancer: two with Hodgkin lymphoma, and one with medulloblastoma; there is also a child with a rhabdomyosarcoma. It is uncertain whether there is a relation between these tumours and PTHS as this can well be explained by coincidence. Data on cardiovascular functioning, osteoporosis, and dementia in adults with PTHS are not available.