Conclusion
The current recommendations aim to improve the judgement of signs and symptoms in anyone with PTHS, to better serve the caregivers and families in caring for the child or adult with PTHS.
The diagnostic pathways (judgement process) has been done in such a way that a judgement can be made universally, so with or without the access to modern technology, and recommendations are meant to be cost effective and avoid any unnecessary measures.
We realise that local circumstances such as medicolegal environments (medicine related legal systems) may cause changes to the recommendations. Together with the various national
PTHS support groups we aim to go on and review the guidelines from time to time, to better the recommendations.
Acknowledgements
The authors are very grateful to all individuals with PTHS, their parents, and other caregivers who attended the 2018 International PTHS World Conference. The guidelines for lay persons have been translated with great help from Sue Routledge. Many parents from different countries have helped to translate the guidelines from English into the various other languages, and we are grateful for this.
Some important literature references on PTHS
- Pitt D, Hopkins I. A syndrome of mental retardation, wide mouth and intermittent overbreathing. Austr Paediatr 1978;14:182-184.
2. Marangi G, Ricciardi S, Orteschi D, et al. The Pitt-Hopkins syndrome: report of 16 new patients and clinical diagnostic criteria. Am J Med Genet 2011;155A:1536–1545, 155.
3. Whalen S, Heron D, Gaillon T, et al. Novel comprehensive diagnostic strategy in Pitt-Hopkins syndrome: clinical score and further delineation of the TCF4 mutational spectrum. Hum Mutat 2012;33:64-72.
4. De Winter CF, Baas M, Bijlsma EK, et al. Phenotype and natural history in 101 individuals with Pitt-Hopkins syndrome through an Internet questionnaire system. Orphanet J Rare Dis 2016;11:37.
5. Van Balkom IDC, Vuijk PJ, Franssens M, et al. Development, cognition, and behaviour in Pitt–Hopkins syndrome. Develop Med Child Neurol 2012;54:925–931.
Major research issues in PTHS recognized at the PTHS World Conference
- What is the natural history of Pitt-Hopkins syndrome in adults and older individuals?
- Breathing anomalies: what are the long-term consequences of breathing anomalies, both physically and cognitively? What is the prevalence of obstructive sleep apnoea? Can breathing anomalies be decreased if needed?
- Seizures: are seizures primary or consequences of breathing anomalies?
- Other symptoms caused by autonomic nervous system dysregulation: what is the exact pathogenesis? If needed, can consequences (especially drooling and constipation) be
influenced?
- Immune system: what are the consequences of PTHS variants causing Pitt-Hopkins syndrome for immunological functioning, including reactions to vaccination?
- Motor functioning: what is the pathogenesis of the foot position anomalies? Can physical therapy, drugs or surgical procedures effectively influence these anomalies?
- Communication: what are the communication abilities? Are there biomarkers that predict these abilities? Which approach best increases communicative abilities?
- Behaviour: what are the specific characteristics of autism or autism spectrum disorder in individuals with Pitt-Hopkins syndrome? In which way do factors such as autonomic dysregulations, food or other environmental factors influence behaviour?
Is it possible to address behavioural difficulties effectively through psychotherapy, contextual adjustments and/or drugs if needed?
- Genotype – phenotype correlations
- Molecular characteristics: can a functional study be developed that indicates with sufficient certainty causality of a Pitt-Hopkins phenotype? Can the mRNA derived from the wild type allele be stabilized in vitro? Does this lead to increase protein formation and if so, does this influence the consequences of haplotype insufficiency for TCF4 in animal models?
