Constitutional pathogenic variants in TP53 are associated with a significant paediatric tumour risk with up to 41% of affected people developing their first tumour by the age of 18 [1]. Recently published UK Clinical Genetics Group Guidelines recommend childhood surveillance for carriers of TP53 pathogenic variants including annual whole-body and brain MRI, 3-4 monthly abdominal ultrasound and review in a dedicated clinic [2]. Such surveillance has been ongoing at Great Ormond Street Hospital (GOSH) for over three years. Through seeking parental views, we demonstrated that the surveillance is generally acceptable for children and their families, with high levels of expressed satisfaction.

It has long been recognised that hospital procedures may present a source of anxiety and psychological distress for children and their families [3]. Recent work by SIGNIFY reported in this journal has demonstrated that adult carriers of TP53 pathogenic variants generally experienced low levels of psychological morbidity around whole-body MRI and found it to be an acceptable intervention [4]. However, comparable data around children’s experiences did not exist. We were keen to understand more about children's and parents’ experience of this surveillance clinic, including any associated burden.

24 families representing a total of 41 children under the care of the TP53 carrier clinic at GOSH were invited by telephone to take part in a semi-structured anonymous online survey. The survey started with demographic questions and continued to questions about the levels of anxiety, optimism and satisfaction associated with clinic visits, scans, and being part of the surveillance clinic overall. Each question started with a structured format but also invited free-text comments.

All families agreed to receive the survey and 16/24 families completed it. Of these, six had children affected with a tumour, all of which were identified prior to starting the surveillance programme. 13 respondents had wider familial experience of tumours, including ten with an affected parent.

A majority of the respondents (eleven) had been part of the clinic for at least one year.

Overall, parents reported a very high degree of satisfaction associated with being part of the surveillance clinic. One respondent had not yet had an MRI and one had not yet had any surveillance.

Of those whose children had started surveillance scans, 14/15 parents (93%) reported being satisfied or very satisfied with the clinic visits, the ultrasound scans and the service as a whole. Levels of satisfaction with the MRI scans were comparable, with 13/14 respondents (93%) reporting being satisfied or very satisfied.

Half of parents reported higher levels of optimism about their child’s diagnosis since being invited to join the surveillance clinic. Of those whose child had started surveillance scans, just 3/15 (20%) felt anxious or very anxious about attending. Comments by parents suggested that this was associated with waiting for results, and that it was preferable to the alternative of no surveillance:

‘[I feel] anxiety when waiting for results.’

‘[I feel anxious about] not knowing what could be detected.’

‘The alternative of no clinic/surveillance is a million times worse.’

Only 2/15 children were felt by their parents to be anxious or very anxious about attending. Parents expressed that their children were comforted by the atmosphere in the hospital:

‘[S]he enjoys visiting the hospital as it is set up to make children feel at ease.’

Others expressed that their children were too young to understand the implications.

All parents expressed that they felt the surveillance was valuable and that they had a good understanding of its aims. Some mentioned that they were aware the surveillance may not improve outcome but they felt supported by being part of the clinic and ‘having somewhere to turn.’

‘I understand that it may not impact long-term outcomes but it is hugely beneficial mentally compared to the alternative of being left completely on your own.’

‘[I value the] ability to access top class care at short notice in the event of issues’

‘[Being part of the clinic is] incredibly powerful in terms of coping with the continual mental challenge of being a family with LFS and numerous early-deceased relatives. It is vital to have this help in order to cope.’

‘[The team …] are there should I need them’

However, some families’ distance from the hospital meant that they did not feel GOSH would be a practical primary contact point in case of problems.

‘The ability to contact the team isn’t all that important [for us] because of the distance, GOSH is about 250 miles away so wouldn’t be our first port of call’

With respect to the issue of childhood testing in the context of surveillance, 3/16 respondents said they would not have chosen for their child to have testing, had surveillance not been available. One parent commented that the existence of the surveillance programme had influenced her decision to conceive naturally.

Parents’ experiences of the disease in the family appeared to influence their beliefs about the value of surveillance; there was a theme of concern about what would happen when children aged out of the programme, and ‘what if’ reflections about whether relatives’ outcomes might have been different, had this surveillance been available to them.

‘LFS is terrifying. You feel alone. Adult surveillance is non-existent and alarming in the UK.’

‘[Surveillance] may have helped in other cases.’

‘This is incredibly powerful in terms of coping with the continual mental challenge of being a family with LFS and numerous early-deceased relatives. It is vital to have this help in order to cope. I am deeply alarmed about what happens at age 18 though. Suddenly there will be zero help in the UK...this is our experience as family with adults who have LFS.’

In summary, our work shows that the degree of burden associated with the TP53 surveillance programme is acceptable for children and families and that there appears to be a significant psychological benefit. It is likely that shared-care or local surveillance will be helpful for patients travelling long distances to access this service.

Further work will clarify the longer term impact, aided by the new UK CGG Guidelines.

References

1. Bougeard G, Renaux-Petel M, Flaman JM, et al. Revisiting Li-Fraumeni Syndrome From TP53 Mutation Carriers. J Clin Oncol. 2015;33(21):2345-2352. doi:10.1200/JCO.2014.59.5728

2. Hanson H, Brady AF, Crawford G Consensus Group Members, et al UKCGG Consensus Group guidelines for the management of patients with constitutional TP53 pathogenic variants J Med Genet 2021;58:135-139.

3. Bachanas P J, Roberts MC. Factors affecting children's attitudes toward health care and responses to stressful medical procedures, J Ped Psychol, 1995, vol. 20 (pg. 261-275)

4. Bancroft EK, Saya S, Brown E, et al. Psychosocial effects of whole-body MRI screening in adult high-risk pathogenic TP53 mutation carriers: a case-controlled study (SIGNIFY). J Med Genet 2020;57:226-236.

Evidence for a mitochondrial disease phenotype due to APOO deletion.
Kumarie Latchman1*, Antoni Barrientos 2*

1. Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, United States
2. Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, United States.
*Corresponding authors

The APOO (Apolipoprotein O) gene codes for MIC26, a subunit of the MICOS complex (mitochondrial contact site and cristae organizing system). APOO was recently reported as a novel mitochondrial disease locus upon identification of a loss-of-function missense variant, c. 350T>C , (p.I117T in MIC26 ) in a hemizygous male proband with mitochondrial myopathy, lactic acidosis, cognitive impairment, and autistic features. 1
Here, we present a six-year-old African American male with a history of epilepsy, developmental delay, hypotonia, coordination and balance difficulties, cognitive impairment, autism disorder, and microcytic anemia. Birth history was unremarkable, and he walked at 24 months despite coordination and balance deficits. His vocabulary is less than ten words at six years old, and he does not recognize body parts, letters, or numbers. Laboratory findings include normal lactic acid, 1.8 (0.4-1.8 mmol/L), and creatine kinase 126 U/L (<160 U/L). Brain magnetic resonance image was unremarkable. Family history is positive for schizophrenia and intellectual disability in his mother and psychiatric and seizure disorders in two previous maternal generations.
Whole-exome sequencing with copy number variant analysis revealed a ~275kb-deletion on Xp22.11, arr [GRCh37] Xp22.11(23731277_24006696)x0, which includes five annotated genes: exon 4 of KLHL15, ACOT9 (no associated conditions), and, in agreement with DNA microarray analysis, the entire genes APOO, SAT1 (associated with keratosis follicularis spinulosa decalvans), and CXorf58 (no associated conditions).
The phenotype of this patient is consistent with a mitochondrial disease due to a complete APOO gene deletion. Like the previously reported APOO case 1, our patient presented with muscle weakness -hypotonia and poor coordination-, cognitive impairment, and an autism spectrum disorder. Differently, our patient presents with epilepsy, which could result from the KLHL15 exon 4 deletion. 2-3 Functional studies are needed to determine how the absence of MIC26 impacts the MICOS complex integrity and function and overall mitochondrial physiology.

Acknowlegements
We thank the family for allowing us to report this case.
Research in the Barrientos laboratory is supported by National Institutes of Health grant R35-GM118141
Correspondence: Kumarie Latchman, kxl604@med.miami.edu, and Antoni Barrientos, ABarrientos@med.miami.edu

Conflict of interest: None declared.

REFERENCES
1. Benincá C, Zanette V, Brischigliaro M, Johnson M, Reyes A, Valle DAD, J Robinson A, Degiorgi A, Yeates A, Telles BA, Prudent J, Baruffini E, S F Santos ML, R de Souza RL, Fernandez-Vizarra E, J Whitworth A, Zeviani M. Mutation in the MICOS subunit gene APOO (MIC26) associated with an X-linked recessive mitochondrial myopathy, lactic acidosis, cognitive impairment and autistic features. J Med Genet 2021; 58:155-167.

2. Hu H, Haas SA, Chelly J, Van Esch H, Raynaud M, de Brouwer AP, Weinert S, Froyen G, Frints SG, Laumonnier F, Zemojtel T, Love MI, Richard H, Emde AK, Bienek M, Jensen C, Hambrock M, Fischer U, Langnick C, Feldkamp M, Wissink-Lindhout W, Lebrun N, Castelnau L, Rucci J, Montjean R, Dorseuil O, Billuart P, Stuhlmann T, Shaw M, Corbett MA, Gardner A, Willis-Owen S, Tan C, Friend KL, Belet S, van Roozendaal KE, Jimenez-Pocquet M, Moizard MP, Ronce N, Sun R, O'Keeffe S, Chenna R, van Bömmel A, Göke J, Hackett A, Field M, Christie L, Boyle J, Haan E, Nelson J, Turner G, Baynam G, Gillessen-Kaesbach G, Müller U, Steinberger D, Budny B, Badura-Stronka M, Latos-Bieleńska A, Ousager LB, Wieacker P, Rodríguez Criado G, Bondeson ML, Annerén G, Dufke A, Cohen M, Van Maldergem L, Vincent-Delorme C, Echenne B, Simon-Bouy B, Kleefstra T, Willemsen M, Fryns JP, Devriendt K, Ullmann R, Vingron M, Wrogemann K, Wienker TF, Tzschach A, van Bokhoven H, Gecz J, Jentsch TJ, Chen W, Ropers HH, Kalscheuer VM. X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes. Mol Psychiatry 2016; 21:133-48.

3. Mignon-Ravix C, Cacciagli P, Choucair N, Popovici C, Missirian C, Milh M, Mégarbané A, Busa T, Julia S, Girard N, Badens C, Sigaudy S, Philip N, Villard L. Intragenic rearrangements in X-linked intellectual deficiency: results of a-CGH in a series of 54 patients and identification of TRPC5 and KLHL15 as potential XLID genes. Am J Med Genet A 2014; 164A:1991-7.

Science has been defined as a process of progressive approximation to the truth, so-called “increasing verisimilitude” [1]. The letter of Professor Fischer is illustrative in this regard.

We previously described genetic analyses of a consanguineous Pakistani family diagnosed with “recessive progressive symmetric erythrokeratoderma” by multiple dermatologists. By autozygosity mapping and sequencing, we identified potentially pathogenic frameshift mutations in two genes located within a region of autozygosity on chr12q12-q14.1, SDR9C7 and KRT83, in perfect linkage disequilibrium in this family [2]. At that time we did not consider SDR9C7 a good candidate, and we concluded that the KRT83 frameshift was more likely to be causal.

Our study was carried out in the early autumn of 2015, we wrote our paper in the spring of 2016, a revised version was accepted for publication in autumn, 2016, and our paper was published online in late 2016. Presumably at the same time, Shigehara et al. [3] carried out parallel studies, unambiguously identifying SDR9C7 as the gene for recessive congenital lamellar ichthyosis based on three families with different mutations. Their findings were published at nearly the same time as ours, and were subsequently confirmed by other investigators [4-6]. Obviously, none of this was known at the time of our study.

With the 20:20 clarity of hindsight, it now seems clear that many of the clinical features in our study family are consistent with the diagnosis of congenital ichthyosis, resulting from the homozygous frameshift of SDR9C7. That places the true role of the KRT83 frameshift in this family into question. It is noteworthy that affected members of this family exhibit the additional clinical feature of striking erythrokeratoderma, not evident in affected members of the Pakistani family reported by Karim et al. [4] who carry the same SDR9C7 frameshift but not the frameshift in KRT83. Whether prominent erythrokeratoderma might be an atypical feature of congenital ichthyosis in this family, an epistatic effect of an unknown common unlinked variant in this population, whether that might reflect a specific effect of the additional homozygous KRT83 frameshift, or whether that might be a summary effect of the SDR9C7 and KRT83 frameshifts in perfect linkage disequilibrium in this family remains to be determined. Increasing verisimilitude indeed!

1. Niiniluoto I. Verisimilitude: the third period. Br J Phil Sci 1998;49:1–29.
2. Shah K, Ansar M, Mughal Z, Khan F, Ahmad W, Ferrara T, Spritz R. Recessive progressive symmetric erythrokeratoderma results from a homozygous loss-of-function mutation of KRT83 and is allelic with dominant monilethrix. J Med Genet 2017;54:186-9.
3. Shigehara Y, Okuda S, Nemer G, Chedraoui A, Hayashi R, Bitar F, Nakai H, Abbas O, Daou L, Abe R, Sleiman MB, Kibbi AG, Kurban M, Shimomura Y. Mutations in SDR9C7 gene encoding an enzyme for vitamin A metabolism underlie autosomal recessive congenital ichthyosis. Hum Mol Genet 2016;25:4484–93.
4. Karim N, Murtaza G, Naeem M. Whole‐exome sequencing identified a novel frameshift mutation in SDR9C7 underlying autosomal recessive congenital ichthyosis in a Pakistani family. Br J Dermatol 2017; 177: e191–2.
5. Takeichi T, Nomura T, Takama H, Kono M, Sugiura K, Watanabe D, Shimizu H, Simpson MA, McGrath JA, Akiyama M. Deficient stratum corneum intercellular lipid in a Japanese patient with lamellar ichthyosis by a homozygous deletion mutation in SDR9C7. Br J Dermatol 2017;177: e62–4.
6. Hotz A, Fagerberg C, Vahlquist A, Bygum A, Törmä H, Rauschendorf MA, Zhang H, Heinz L, Bourrat E, Hausser I, Vestergaard V, Dragomir A, Zimmer AD, Fischer J. Identification of mutations in SDR9C7 in six families with autosomal recessive congenital ichthyosis. Br J Dermatol 2018;178:e207-e209.