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 sur...
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.
We appreciate the article by Chirita-Emandi at al (1).
The authors showed the phenotype of nine patients with biallelic variants at BRCA1 gene associated with Fanconi anemia-like complementation group-S (MIM 617883). As it is a rare syndrome, the publication of articles describing the clinical characteristics and follow-up data are important to improve the knowledge and disseminate evidence-based information.
In Chirita-Emandi’s article, one patient is first reported and eight are from previous studies. All patients had prenatal and postnatal growth failure, microcephaly, skin pigmentation lesions, facial dysmorphism and cancer family history. Eight presented mild developmental delay, and six had cancer. None presented bone marrow failure or immunodeficiency (1).
In this letter, we would like to update the clinical case of one of these patients. In a previous article we reported a homozygous loss-of-function BRCA1 mutation in a 2.5-year-old girl with severe short stature, microcephaly, neurodevelopmental delay, congenital heart disease and dysmorphic features (2). At 6 years-old, she evaluated with neurological symptoms and her skull tomography detected an expansive and infiltrative lesion in the encephalic trunk, compressing and displacing the IV ventricle and obliterating the prepontine cistern and the cerebellar angles. The lesion characteristics were suggestive of diffuse astrocytoma. Soon after a decompressive neurological surgery, this child died....
We appreciate the article by Chirita-Emandi at al (1).
The authors showed the phenotype of nine patients with biallelic variants at BRCA1 gene associated with Fanconi anemia-like complementation group-S (MIM 617883). As it is a rare syndrome, the publication of articles describing the clinical characteristics and follow-up data are important to improve the knowledge and disseminate evidence-based information.
In Chirita-Emandi’s article, one patient is first reported and eight are from previous studies. All patients had prenatal and postnatal growth failure, microcephaly, skin pigmentation lesions, facial dysmorphism and cancer family history. Eight presented mild developmental delay, and six had cancer. None presented bone marrow failure or immunodeficiency (1).
In this letter, we would like to update the clinical case of one of these patients. In a previous article we reported a homozygous loss-of-function BRCA1 mutation in a 2.5-year-old girl with severe short stature, microcephaly, neurodevelopmental delay, congenital heart disease and dysmorphic features (2). At 6 years-old, she evaluated with neurological symptoms and her skull tomography detected an expansive and infiltrative lesion in the encephalic trunk, compressing and displacing the IV ventricle and obliterating the prepontine cistern and the cerebellar angles. The lesion characteristics were suggestive of diffuse astrocytoma. Soon after a decompressive neurological surgery, this child died.
Due to its rarity, we still do not have sufficient data to provide accurate medical management and guidelines protocols related to patients with biallelic BRCA1 variants. However, taking together, seven in eight patients had cancer up to 30 years-old and two of them had solid tumors other than breast or ovarian cancer, indicating the necessity of a closely follow-up and actively searching for malignancy. Nonetheless, further studies and international collaboration are fundamental to understanding the natural history of this disease and to propose appropriate medical recommendations.
References:
1. Chirita-Emandi A, Andreescu N, Popa C, Mihailescu A, Riza AL, Plesea R, et al. Biallelic variants in BRCA1 gene cause a recognizable phenotype within chromosomal instability syndromes reframed as BRCA1 deficiency. J Med Genet. 2020.
2. Freire BL, Homma TK, Funari MFA, Lerario AM, Leal AM, Velloso EDRP, et al. Homozygous loss of function BRCA1 variant causing a Fanconi-anemia-like phenotype, a clinical report and review of previous patients. Eur J Med Genet. 2018;61(3):130-3.
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 psychi...
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
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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.
I read with interest the article by Muroya et al. [1].
The authors mention that the inherited condition of
hypoparathyroidism, sensorineural deafness and renal dysplasia has been
recognized as a distinct clinical entity since the report by Bilous et al.
in 1992. In fact, this syndrome was described for the first time in 1977
by Barakat et al. [2]. The syndrome with presumed autosomal rec...
I read with interest the article by Muroya et al. [1].
The authors mention that the inherited condition of
hypoparathyroidism, sensorineural deafness and renal dysplasia has been
recognized as a distinct clinical entity since the report by Bilous et al.
in 1992. In fact, this syndrome was described for the first time in 1977
by Barakat et al. [2]. The syndrome with presumed autosomal recessive
inheritance was later named the “Barakat syndrome” [3-5]. In 1992 Bilous
et al. [6] described a phenotypically similar syndrome in one family with
autosomal dominant inheritance. The mode of inheritance may not be a
fundamental difference, and the disorder in the two families described by
Barakat and Bilous may be due to different mutations in the same
gene [7]. Inheritance in the family described by Barakat et al. could also be
autosomal dominant with reduced penetrance [7]. In 1997 Hasegawa et al. [8]
described a Japanese girl with this syndrome and a de novo deletion of
10p13. They suggested the name “HDR syndrome”. Subsequently, a few more
patients were reported.
Other synonyms for Barakat syndrome include
“Hypoparathyroidism, sensorineural deafness and renal dysplasia”, “HDR
syndrome”, and “Nephrosis, nerve deafness and hypoparathyroidism” [7]. The
syndrome should then consist of hypoparathyroidism, sensorineural deafness
and renal disease, since various renal abnormalities have been described
including nephrotic syndrome, renal dysplasia, hypoplasia and unilateral
renal agenesis, vesicoureteral reflux, pelvicalyceal deformity,
hydronephrosis, and chronic renal failure.
First described by Barakat et al. in 1977, Barakat syndrome is a rare
condition consisting of hypoparathyroidism, sensorineural deafness and
renal disease. The defect is on chromosome 10p15,10p15.1-p14, with
haploinsufficiency or mutation of the GATA3 gene being the underlying cause of the syndrome [7,9].
References
1. Muroya, K, Hasegawa,T, Ito,Y, Nagai,T. Isotani,H, Iwata,Y,
Yamamoto,K, Fujimoto,S, Seishu,S, Fukushima,Y, Hasegawa,Y, Ogata,T. GATA3
abnormalities and the phenotypic spectrum of HDR syndrome. J Med Genet
2001;38:374-80.
2. Barakat, AY, D'Albora, JB, Martin, MM, Jose, PA. Familial
nephrosis, nerve deafness, and hypoparathyroidism. J. Pediat 1977; 91: 61-
4.
3. McKusick V. Mendalian Inheritance in Man, 12th Edition, Volume 2,
Baltimore,The Johns Hopkins University Press, l998.
4. Magnalini SI, et al: Dictionary of Medical Syndromes, 4th
edition,Philadelphia, J.B. Lippencott-Raven, 1997, p 73.
5. Rimoin DL, Connor, JM, Pyeritz RE, Korf BR. Emery and Rimoin’s
Principles and Practice of Medical Genetics. Fourth Edition, Volume 2,
London, Churchill Livingstone, 2002, p2217.
6. Bilous, RW, Murty, G, Parkinson, DB, Thakker, RV, Coulthard, MG,
Burn, J, Mathias, D, Kendall-Taylor, P. Btief report: Autosomal dominant
familial hypoparathyroidism, sensorineural deafness, and renal dysplasia.
New Eng J Med 1992; 327: 1069-74.
7. Online Mendelian Inheritance in Man, Johns Hopkins University
#146255.
8. Hasegawa,T, Hasegawa, Y, Aso, T.; Koto, S, Nagai, T, Tsuchiya, Y,
Kim, K, Ohashi, H, Wakui, K, Fukushima, Y. HDR syndrome
(hypoparathyroidism, sensorineural deafness, renal dysplasia) associated
with del(10)(p13). Am J Med Genet 1997; 73: 416-8.
9. Van Esch, H, Groenen, P, Nesbit, MA, Schuffenhauer, S, Lichtner,
P, Vanderlinden, G, Harding, B, Beetz, R, Bilous, RW, Holdaway, I, Shaw,
NJ, Fryns, J.-P, Van de Ven, W, Thakker, RV, Devriendt, K. GATA3 haplo-
insufficiency causes human HDR syndrome. Nature 2000; 406: 419-22.
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 consisten...
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.
Fascinated to see the comments about irregular heartbeats as an x-linked ichthyosis suffer myself. If you are carrying out further studies I wonder if there is any trend for female carriers having the same. My mother an x-linked ichthyosis carrier has always had an extra hearth beat that causes problems for medical exams and operations. Could it be used as an additional test for expectant mums for potential x-linked babies. A great article and thanks - Jeremy Instone
Dear Mr Instone - Many thanks for your interest in our work and your comment! In our analyses we did look at ICD-10 diagnoses of atrial fibrillation/flutter, and self-reported heart problems in female carriers versus female non-carriers, but didn't see any difference in prevalence between the two groups (results in the Supplementary Data). However, as these are relatively crude measures, we cannot the exclude the possibility that there are actually higher rates of subtle cardiac dysfunction in female carriers relative to non-carriers, and further, more focussed studies might look at this. Regards, Dr William Davies
I recently came across this publication and was very surprised at some facts that seem inconsistent.
Shah et al. state that homozygous mutations in KRT83 are responsible for the skin phenotype of their patients, which they describe as an autosomal recessive form of progressive symmetric erythrokeratoderma (1). Ten individuals from a consanguineous Pakistani family were analyzed, including three patients with a skin phenotype. Shah et al. have successfully performed homozygosity mapping, followed by whole exome sequencing (WES), which are adequate methods to identify gene mutations in rare diseases.
First of all, I agree with the comment by Ramot et al from January 12, 2017, which states that it is very unlikely that KRT83, which is only expressed in hair cells, will lead to a skin phenotype.
In addition, the presented clinical pictures of the patients do not show typical signs of progressive symmetrical erythrokeratoderma; however the presented phenotype is compatible with lamellar ichthyosis (autosomal recessive congenital ichthyosis ARCI).
To my great astonishment, the authors themselves mention the correct solution in their publication, but unfortunately they have obviously drawn the wrong conclusion. It is described in the results section that within the homozygous interval on chromosome 12q12-q14, WES showed not only a homozygous KRT83 variant that was classified as pathogenic and causative for the present phenotype in this publication, but al...
I recently came across this publication and was very surprised at some facts that seem inconsistent.
Shah et al. state that homozygous mutations in KRT83 are responsible for the skin phenotype of their patients, which they describe as an autosomal recessive form of progressive symmetric erythrokeratoderma (1). Ten individuals from a consanguineous Pakistani family were analyzed, including three patients with a skin phenotype. Shah et al. have successfully performed homozygosity mapping, followed by whole exome sequencing (WES), which are adequate methods to identify gene mutations in rare diseases.
First of all, I agree with the comment by Ramot et al from January 12, 2017, which states that it is very unlikely that KRT83, which is only expressed in hair cells, will lead to a skin phenotype.
In addition, the presented clinical pictures of the patients do not show typical signs of progressive symmetrical erythrokeratoderma; however the presented phenotype is compatible with lamellar ichthyosis (autosomal recessive congenital ichthyosis ARCI).
To my great astonishment, the authors themselves mention the correct solution in their publication, but unfortunately they have obviously drawn the wrong conclusion. It is described in the results section that within the homozygous interval on chromosome 12q12-q14, WES showed not only a homozygous KRT83 variant that was classified as pathogenic and causative for the present phenotype in this publication, but also a homozygous frameshift mutation in the gene SDR9C7 (p.Thr122Asnfs).
The first publication that mutations in the SDR9C7 gene lead to autosomal recessive congenital ichthyosis (ARCI) was published in 2017 (2), followed by several others (3,4). Karim et al. then described the same frame shift mutation as Shah et al. (p.Thr122Asnfs) in SDR9C7 in Pakistani patients with autosomal recessive congenital ichthyosis (5).
May be it would be appropriate to write an erratum, or to correct the article under these new aspects.
1. Shah K, Ansar M, Mughal ZU et al. Recessive progressive symmetric erythrokeratoderma results from a homozygous loss-of-function mutation of KRT83 and is allelic with dominant monilethrix. J Med Genet. 2017 Mar;54(3):186-189
2. Shigehara Y, Okuda S, Nemer G et al . Mutations in SDR9C7 gene encoding an enzyme for vitamin A metabolism underlie autosomal recessive congenital ichthyosis. Hum Mol Genet 2016; 25: 4484– 93.
3. Takeichi T, Nomura T, Takama H et al . 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.
4. 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 Mar;178(3):e207-e209.
5. 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.
We read with interest the extensive retrospective study on von Hippel-Lindau disease as described by the authors (1) . This original article enlightened us about the age of onset, initial tumour size, concomitant tumours, mutation type and mutation location had an effect on growth rate in VHL-related RCC.It was very interesting to note that these renal tumours larger than 4 cm grew faster than those smaller than 4 cm.
Abdominal masses are frequent in newborn infants, two thirds being renal in origin and occasionally, a renal mass may be malignant and correspond to congenital mesoblastic nephroma, Wilms’ tumor, or fetal hamartoma(2).Birt-Hogg-Dubé (BHD) syndrome is another autosomal dominant genodermatosis characterized by increased risk of renal neoplasia and spontaneous pneumothorax (3) This syndrome is linked to mutations in the FLCN gene, which encodes folliculin and is preferentially expressed in the skin, kidney, and lung (4).In addition,renal epithelial and stromal tumors (REST) is a new concept gathering two benign mixed mesenchymal and epithelial tumors: cystic nephroma and mixed epithelial and stromal tumors [MEST] (5).Since 1998 new entities have surfaced in renal tumor classification and have been included in the WHO 2004 classification e.g new elements in the Bellini carcinoma definition.(6). Renal tumours of genetic origin may often confer diagnostic challenges. Whatever the nature of the renal mass, early intervention may save the kidney or the patient...
We read with interest the extensive retrospective study on von Hippel-Lindau disease as described by the authors (1) . This original article enlightened us about the age of onset, initial tumour size, concomitant tumours, mutation type and mutation location had an effect on growth rate in VHL-related RCC.It was very interesting to note that these renal tumours larger than 4 cm grew faster than those smaller than 4 cm.
Abdominal masses are frequent in newborn infants, two thirds being renal in origin and occasionally, a renal mass may be malignant and correspond to congenital mesoblastic nephroma, Wilms’ tumor, or fetal hamartoma(2).Birt-Hogg-Dubé (BHD) syndrome is another autosomal dominant genodermatosis characterized by increased risk of renal neoplasia and spontaneous pneumothorax (3) This syndrome is linked to mutations in the FLCN gene, which encodes folliculin and is preferentially expressed in the skin, kidney, and lung (4).In addition,renal epithelial and stromal tumors (REST) is a new concept gathering two benign mixed mesenchymal and epithelial tumors: cystic nephroma and mixed epithelial and stromal tumors [MEST] (5).Since 1998 new entities have surfaced in renal tumor classification and have been included in the WHO 2004 classification e.g new elements in the Bellini carcinoma definition.(6). Renal tumours of genetic origin may often confer diagnostic challenges. Whatever the nature of the renal mass, early intervention may save the kidney or the patient.
1.Peng X, Chen J, Wang J, et al Natural history of renal tumours in von Hippel-Lindau disease: a large retrospective study of Chinese patients Journal of Medical Genetics 2019;56:380-387.
2. Pinto E. · Guignard J.-P.Renal Masses in the Neonate.Biol Neonate 1995;68:175–184
(DOI:10.1159/000244235)
3. Pavlovich CP1, Walther MM, Eyler RA, et al.,Renal tumors in the Birt-Hogg-Dubé syndrome.Am J Surg Pathol. 2002 Dec;26(12):1542-52.
4.López V1, Jordá E, Monteagudo C.[Birt-Hogg-Dubé syndrome: an update].[Article in Spanish]Actas Dermosifiliogr. 2012 Apr;103(3):198-206. doi: 10.1016/j.ad.2011.07.009. Epub 2011 Sep 19.
5. Sibony M1, Vieillefond A.[Non clear cell renal cell carcinoma. 2008 update in renal tumor pathology].
[Article in French]Ann Pathol. 2008 Oct;28(5):381-401. doi: 10.1016/j.annpat.2008.07.009. Epub 2008 Oct 17.
6. Compérat EV1, Vasiliu V, Ferlicot S,et al.[Tumors of the kidneys: new entities].[Article in French] Ann Pathol. 2005 Apr;25(2):117-33.
Matias Wagner1,2,3, Dominik S Westphal1,2, Iris Hannibal4, Johannes A. Mayr5, Tim M. Strom1,2, Thomas Meitinger1,2, Holger Prokisch1,2, Saskia B. Wortmann1,2,5
1. Institute of Human Genetics, Technical University Munich, Munich, Germany;
2. Institute of Human Genetics, Helmholtz Zentrum Munich, Neuherberg, Germany;
3. Institute of Neurogenomics, Helmholtz Zentrum Munich, Neuherberg, Germany
4. Dr. von Hauner Children’s Hospital, Ludwig-Maximilians University, Munich, Germany
5. Department of Pediatrics, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), Salzburg, Austria
Biallelic mutations in KIAA0586 have been related to Joubert syndrome (JBTS) 23 and as the most frequent disease causing variant c.428del (p.Arg143Lysfs*4) was identified.1 However, the allele frequency of 0.003117 and two homozygotes in the gnomAD dataset as well as additional reports of healthy carriers have questioned the variant’s pathogenicity.2, 3 Pauli et al. have recently hypothesized that c.428del is a hypomorphic allele which is only causing JBTS in compound heterozygosity with other mutations.
In 15,000 in-house exome data sets, we have identified three individuals harboring c.428del in a homozygous state. In two, we identified other variants sufficiently explaining the phenotype: In a 6 year old girl with global developmental delay and progressive myoclonic astatic epilepsy, we identified a de novo variant c.2683del, p.Ser895Le...
Matias Wagner1,2,3, Dominik S Westphal1,2, Iris Hannibal4, Johannes A. Mayr5, Tim M. Strom1,2, Thomas Meitinger1,2, Holger Prokisch1,2, Saskia B. Wortmann1,2,5
1. Institute of Human Genetics, Technical University Munich, Munich, Germany;
2. Institute of Human Genetics, Helmholtz Zentrum Munich, Neuherberg, Germany;
3. Institute of Neurogenomics, Helmholtz Zentrum Munich, Neuherberg, Germany
4. Dr. von Hauner Children’s Hospital, Ludwig-Maximilians University, Munich, Germany
5. Department of Pediatrics, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), Salzburg, Austria
Biallelic mutations in KIAA0586 have been related to Joubert syndrome (JBTS) 23 and as the most frequent disease causing variant c.428del (p.Arg143Lysfs*4) was identified.1 However, the allele frequency of 0.003117 and two homozygotes in the gnomAD dataset as well as additional reports of healthy carriers have questioned the variant’s pathogenicity.2, 3 Pauli et al. have recently hypothesized that c.428del is a hypomorphic allele which is only causing JBTS in compound heterozygosity with other mutations.
In 15,000 in-house exome data sets, we have identified three individuals harboring c.428del in a homozygous state. In two, we identified other variants sufficiently explaining the phenotype: In a 6 year old girl with global developmental delay and progressive myoclonic astatic epilepsy, we identified a de novo variant c.2683del, p.Ser895Leufs*14 in KIAA2022 (NM_001008537.2, MIM#300912: mental retardation 98). In a 56 year old male patient from a large family with X-linked mental retardation, a hemizygous missense variant in FRMPD4 (NM_014728.3): c.41861G>T, p.Asp621Tyr was identified. In the third case, a 5 year old boy with medically unexplained isolated fatigue we did not identify other variants than c.428del in KIAA0586.
However, in a 3 year old male with global delays, truncal hypotonia, ataxia and eye movement disorders we identified the variant c.428del in compound heterozygosity with c.863_864del, p.Gln288Argfs*7 (NM_014749.3). As the clinical findings resemble the core phenotype of JBTS23, we consider the combination of these variants causal for the patient’s condition.4
Analysis of RNA sequencing data from two heterozygous carriers indicates that mutant transcripts escape nonsense mediated decay. Residual function of the c.428del KIAA0586 allele most likely originates from the use of an alternative start codon (Supplementary figure).
These findings further strengthen the hypothesis of Pauli et al. that c.428del is indeed a hypomorphic allele which is only disease causing in trans with a loss of function mutation.
References
1. Bachmann-Gagescu R, et al. KIAA0586 is Mutated in Joubert Syndrome. Human mutation 36, 831-835 (2015).
2. Pauli S, et al. Homozygosity for the c.428delG variant in KIAA0586 in a healthy individual: implications for molecular testing in patients with Joubert syndrome. Journal of medical genetics, (2018).
3. Sulem P, et al. Identification of a large set of rare complete human knockouts. Nature genetics 47, 448-452 (2015).
4. Bachmann-Gagescu R, et al. Joubert syndrome: a model for untangling recessive disorders with extreme genetic heterogeneity. Journal of medical genetics 52, 514-522 (2015).
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 sur...
Show MoreWe appreciate the article by Chirita-Emandi at al (1).
Show MoreThe authors showed the phenotype of nine patients with biallelic variants at BRCA1 gene associated with Fanconi anemia-like complementation group-S (MIM 617883). As it is a rare syndrome, the publication of articles describing the clinical characteristics and follow-up data are important to improve the knowledge and disseminate evidence-based information.
In Chirita-Emandi’s article, one patient is first reported and eight are from previous studies. All patients had prenatal and postnatal growth failure, microcephaly, skin pigmentation lesions, facial dysmorphism and cancer family history. Eight presented mild developmental delay, and six had cancer. None presented bone marrow failure or immunodeficiency (1).
In this letter, we would like to update the clinical case of one of these patients. In a previous article we reported a homozygous loss-of-function BRCA1 mutation in a 2.5-year-old girl with severe short stature, microcephaly, neurodevelopmental delay, congenital heart disease and dysmorphic features (2). At 6 years-old, she evaluated with neurological symptoms and her skull tomography detected an expansive and infiltrative lesion in the encephalic trunk, compressing and displacing the IV ventricle and obliterating the prepontine cistern and the cerebellar angles. The lesion characteristics were suggestive of diffuse astrocytoma. Soon after a decompressive neurological surgery, this child died....
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
Show MoreHere, 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 psychi...
Dear Editor,
I read with interest the article by Muroya et al. [1].
The authors mention that the inherited condition of hypoparathyroidism, sensorineural deafness and renal dysplasia has been recognized as a distinct clinical entity since the report by Bilous et al. in 1992. In fact, this syndrome was described for the first time in 1977 by Barakat et al. [2]. The syndrome with presumed autosomal rec...
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 consisten...
Show MoreFascinated to see the comments about irregular heartbeats as an x-linked ichthyosis suffer myself. If you are carrying out further studies I wonder if there is any trend for female carriers having the same. My mother an x-linked ichthyosis carrier has always had an extra hearth beat that causes problems for medical exams and operations. Could it be used as an additional test for expectant mums for potential x-linked babies. A great article and thanks - Jeremy Instone
Dear Mr Instone - Many thanks for your interest in our work and your comment! In our analyses we did look at ICD-10 diagnoses of atrial fibrillation/flutter, and self-reported heart problems in female carriers versus female non-carriers, but didn't see any difference in prevalence between the two groups (results in the Supplementary Data). However, as these are relatively crude measures, we cannot the exclude the possibility that there are actually higher rates of subtle cardiac dysfunction in female carriers relative to non-carriers, and further, more focussed studies might look at this. Regards, Dr William Davies
I recently came across this publication and was very surprised at some facts that seem inconsistent.
Show MoreShah et al. state that homozygous mutations in KRT83 are responsible for the skin phenotype of their patients, which they describe as an autosomal recessive form of progressive symmetric erythrokeratoderma (1). Ten individuals from a consanguineous Pakistani family were analyzed, including three patients with a skin phenotype. Shah et al. have successfully performed homozygosity mapping, followed by whole exome sequencing (WES), which are adequate methods to identify gene mutations in rare diseases.
First of all, I agree with the comment by Ramot et al from January 12, 2017, which states that it is very unlikely that KRT83, which is only expressed in hair cells, will lead to a skin phenotype.
In addition, the presented clinical pictures of the patients do not show typical signs of progressive symmetrical erythrokeratoderma; however the presented phenotype is compatible with lamellar ichthyosis (autosomal recessive congenital ichthyosis ARCI).
To my great astonishment, the authors themselves mention the correct solution in their publication, but unfortunately they have obviously drawn the wrong conclusion. It is described in the results section that within the homozygous interval on chromosome 12q12-q14, WES showed not only a homozygous KRT83 variant that was classified as pathogenic and causative for the present phenotype in this publication, but al...
We read with interest the extensive retrospective study on von Hippel-Lindau disease as described by the authors (1) . This original article enlightened us about the age of onset, initial tumour size, concomitant tumours, mutation type and mutation location had an effect on growth rate in VHL-related RCC.It was very interesting to note that these renal tumours larger than 4 cm grew faster than those smaller than 4 cm.
Show MoreAbdominal masses are frequent in newborn infants, two thirds being renal in origin and occasionally, a renal mass may be malignant and correspond to congenital mesoblastic nephroma, Wilms’ tumor, or fetal hamartoma(2).Birt-Hogg-Dubé (BHD) syndrome is another autosomal dominant genodermatosis characterized by increased risk of renal neoplasia and spontaneous pneumothorax (3) This syndrome is linked to mutations in the FLCN gene, which encodes folliculin and is preferentially expressed in the skin, kidney, and lung (4).In addition,renal epithelial and stromal tumors (REST) is a new concept gathering two benign mixed mesenchymal and epithelial tumors: cystic nephroma and mixed epithelial and stromal tumors [MEST] (5).Since 1998 new entities have surfaced in renal tumor classification and have been included in the WHO 2004 classification e.g new elements in the Bellini carcinoma definition.(6). Renal tumours of genetic origin may often confer diagnostic challenges. Whatever the nature of the renal mass, early intervention may save the kidney or the patient...
Matias Wagner1,2,3, Dominik S Westphal1,2, Iris Hannibal4, Johannes A. Mayr5, Tim M. Strom1,2, Thomas Meitinger1,2, Holger Prokisch1,2, Saskia B. Wortmann1,2,5
1. Institute of Human Genetics, Technical University Munich, Munich, Germany;
2. Institute of Human Genetics, Helmholtz Zentrum Munich, Neuherberg, Germany;
3. Institute of Neurogenomics, Helmholtz Zentrum Munich, Neuherberg, Germany
4. Dr. von Hauner Children’s Hospital, Ludwig-Maximilians University, Munich, Germany
5. Department of Pediatrics, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), Salzburg, Austria
Biallelic mutations in KIAA0586 have been related to Joubert syndrome (JBTS) 23 and as the most frequent disease causing variant c.428del (p.Arg143Lysfs*4) was identified.1 However, the allele frequency of 0.003117 and two homozygotes in the gnomAD dataset as well as additional reports of healthy carriers have questioned the variant’s pathogenicity.2, 3 Pauli et al. have recently hypothesized that c.428del is a hypomorphic allele which is only causing JBTS in compound heterozygosity with other mutations.
In 15,000 in-house exome data sets, we have identified three individuals harboring c.428del in a homozygous state. In two, we identified other variants sufficiently explaining the phenotype: In a 6 year old girl with global developmental delay and progressive myoclonic astatic epilepsy, we identified a de novo variant c.2683del, p.Ser895Le...
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