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.
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
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 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.
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.
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.
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
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
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.
Careers Abroad Institute School of Medicine, Mandeville, Manchester, JM, WI.
We read and applauded the insightful article on clinical presentation of Russell-Silver syndrome with detail molecular diagnostic criteria as presented by Price S M., et al.[1] The low birth weight child who is non-dysmorphic with a prominent forehead and triangular face is more likely to be diagnosed as SRS if they have fifth finger clinodactyly, which in itself is not uncommon.[1] The genetic syndromes which affects growth and intellectual disability have been studied extensively. It has been proved by numerous large scale studies that IUGR is associated with significant neurodevelopmental impairment.
From a meta analysis conducted by AAP it was concluded that IUGR is associated with lower cognitive scores for school age children. Furthermore children with IUGR born SGA reared in poorer environment demonstrate significant lower professional attainment and income than those reared in more stimulating environment. Here I present a case of
Russell-Silver Syndrome (RSS or SRS) which is a rare, clinically and genetically heterogeneous entity, caused by (epi)genetic alterations. It is characterized by prenatal and postnatal growth retardation, relative macrocephaly, the triangular face and body asymmetry.[ 6] Its incidence varies from 1 in 30,000 to 1 in 1,00,000 people. Individuals with RSS...
Careers Abroad Institute School of Medicine, Mandeville, Manchester, JM, WI.
We read and applauded the insightful article on clinical presentation of Russell-Silver syndrome with detail molecular diagnostic criteria as presented by Price S M., et al.[1] The low birth weight child who is non-dysmorphic with a prominent forehead and triangular face is more likely to be diagnosed as SRS if they have fifth finger clinodactyly, which in itself is not uncommon.[1] The genetic syndromes which affects growth and intellectual disability have been studied extensively. It has been proved by numerous large scale studies that IUGR is associated with significant neurodevelopmental impairment.
From a meta analysis conducted by AAP it was concluded that IUGR is associated with lower cognitive scores for school age children. Furthermore children with IUGR born SGA reared in poorer environment demonstrate significant lower professional attainment and income than those reared in more stimulating environment. Here I present a case of
Russell-Silver Syndrome (RSS or SRS) which is a rare, clinically and genetically heterogeneous entity, caused by (epi)genetic alterations. It is characterized by prenatal and postnatal growth retardation, relative macrocephaly, the triangular face and body asymmetry.[ 6] Its incidence varies from 1 in 30,000 to 1 in 1,00,000 people. Individuals with RSS have mutations in the imprinted region of chromosome and are diagnosed with Intrauterine growth retardation (IUGR). The purpose of reporting of this syndrome is to increase awareness among general practitioners so that this rare condition is properly diagnosed and referred to specialty department for further evaluation and management. The RSS diagnosis is challenging because it is confused with other causes of IUGR and short stature like,
1. Fetal Alcohol Syndrome
2. Bloom syndrome
3. Nijmegen breakage syndrome
4. IGF1R mutation or deletion
5. IMAGe syndrome
6. Fanconi Syndrome
.
IUGR may also occur in a number of congenital disorders, including Mulibrey nanism and 3M syndrome. Chromosome abnormalities to consider in the differential diagnosis of RSS include:
1. mosaic Turner syndrome
2. diploid/triploid mixoploidy (because of limb asymmetry)
3. Yq deletions [7]
other chromosome deletions (involving 12p14 , 15q26.3, and a distal deletion of 22q11.2)
rearrangements of chromosome 17q25 [8]
Three M syndrome is an extremely rare genetic disorder with features that include low birth weight,short stature, characteristic head and facial features, and distinctive bone abnormalities. [7]
Disorders of DNA repair (chromosome breakage disorders), including Fanconi anemia, Bloom syndrome and Nijmegen breakage syndrome, are often associated small head size (microcephaly), limb abnormalities, and abnormal sensitivity to sunlight (photosensitivity).
Fetal alcohol spectrum disorders (FASDs) may be characterized by mental and physical birth defects from maternal use of alcohol during pregnancy.[9 ] The range and severity of symptoms vary greatly. In some cases, learning delays or intellectual disability occurs without any obvious physical abnormalities. [10] IMAGe syndrome is characterized by IUGR, metaphyseal dysplasia, adrenal hypoplasia congenital and genital abnormalities. One condition that has been confused with RSS is an X-linked disorder of short stature with skin hyperpigmentation. It has sometimes been referred to as X-linked RSS.[6] This condition may be difficult to distinguish from classic RSS in the absence of a positive family history.
Because RSS is generally sporadic (not inherited),a family history of growth failure and/or consanguinity might suggest a different diagnosis.[ 11]
Molecular genetic testing can confirm the diagnosis in around 60% of patients, and may be useful in guiding management.[12] However, genetic testing results are negative in a notable proportion of patients with the characteristic features of RSS. Therefore, a negative genetic test result does not exclude the diagnosis of RSS [7]
Case Report
A 22 year old woman presented to our clinic with amenorrhea since last six months. Before this episode her menarche was achieved at 19 years of age after giving hormonal therapy, with estrogen-progesterone (YAZ). She had menstrual cycles every 4 months and she noticed amenorrhea after stopping hormone therapy last month for severe anxiety. Her pregnancy test was found to be negative. She had no weight gain, no hirsutism, galactorrhea, headaches. The patient indicated that she exercises but not to degree of causing amenorrhea. She had normal secondary sexual characteristics.
The patient also complained of bloating and pain in her abdomen since last three months. She developed these episodes particularly after consuming fatty and carbohydrate rich food. The pain was felt all over the abdomen with no change in intensity with bowel movements. The intensity of the pain increased with activity. Severe constipation (with hard stools once a week) was noticed after she changed her diet to gluten-free high fibre diet. She used laxatives but that resulted in diarrhea and thus stopped consuming them. The patient had no weight loss, dyschezia, hematochezia, and vomiting.
Physical examination revealed a lean female with triangular face and prominent forehead without an asymmetry or clinodactyly. Arching of feet was noticed. No lymphadenopathy, thyromegaly, or pigmentation was noticed. Lungs were clear to auscultation and no murmurs heard on cardiovascular examination. Pelvic examination revealed a normal size uterus. No distension found on abdominal examination. Auscultation resulted in normal IBS. Mild diffuse tenderness without guarding rigidity or rebound was felt on deep palpation. Murphy's test came out to be negative. No CVAT, organomegaly was noticed. The patient appeared to have a flat affect and was prescribed antidepressant , counselled to continue laxatives and change of diet back high fibre gluten rich. Hormonal therapy was also resumed. TSH, Testosterone, FSH, LH, Estradiol and Prolactin levels were found to be within normal range. Pap smear finding was negative.
The patient was diagnosed with failure to thrive after birth. She had IUGR with episodes of hypoglycemia and had feeding difficulties. She was followed up by pediatric gasterenterologists for feeding therapy to obtain catch up growth. She continued her growth percentile in the lower percentile range which led to genetic testing and diagnosis of RSS. She also had delayed puberty and height achievement. Menarche was waited to see spontaneous catch up-growth and height achievement ruling out constitutional delay. Mid parental height was higher than she had and bone age testing was not done. Since spontaneous height achievement did not happen, she was given growth hormone injection at 16 years of age. She was given hormonal therapy for proper secondary sexual characteristics and bone health. Cognitive development was normal in her case and she completed her graduation studies recently.
Discussion
The purpose of this reporting is to identify and find the cause of irregular menstruation in RSS. This will prevent infertility, osteoporosis and cardiovascular morbidity. In this patient’s case , oligomenorrhea also placed her in the risk of endometrial cancer. She was having mood issues with anxiety and depression, which may not be correlated to these cases. But a correlation between IUGR ad ADHD symptoms are being studied in clinical studies. However cognition is usually affected with speech and needs early diagnosis and treatment with multiple specialists top provide early developmental intervention programs. Whether mood changes are due to underlying RSS or not, early diagnosis can prevent morbidity in patients. RSS patients with normal menstrual cycles should receive genetic counseling if they want to have kids.
References:
[1] Price S M. et al. (Dec 2018) The spectrum of Silver-Russell syndrome: a clinical and molecular genetic study and new diagnostic criteria Volume 36, Issue 11. https://jmg.bmj.com/content/36/11/837
In “Genetic obesity: next-generation sequencing results of 1230 patients with obesity'', we presented our obesity gene panel data [1]. In their e-letter, Chèvre et al. question our panel selection because certain genes were omitted. Our gene panel was designed in 2012 after an extensive search in OMIM and other databases. Diagnostic genetic laboratories have to accept that custom diagnostic gene panels have a delay in inclusion of the newest research findings: development and implementation take time and changes require extensive validation against set quality parameters. We acknowledge this limitation in our paper: “Since research in obesity genetics is rapidly progressing, recently identified obesity-associated genes, such as CPE were not included in this panel” [1]. Furthermore, the authors say that we omitted the MRAP2 gene. It is, however, clearly listed as part of the gene panel. We even describe six identified MRAP2 variants in Table S1. Chèvre et al. also criticize the inclusion of insulin receptor genes, since they are not robustly associated with obesity. They were not included as 'obesity causing genes', but as 'comorbidity genes' (Table S2 Sequence variants identified in comorbidity genes) [1]. Diabetes is a serious comorbidity of obesity and knowledge of these mutations is important, especially when aiming for future personalized treatment.
The authors question the validity of how we determine the pathogenicity of identifi...
In “Genetic obesity: next-generation sequencing results of 1230 patients with obesity'', we presented our obesity gene panel data [1]. In their e-letter, Chèvre et al. question our panel selection because certain genes were omitted. Our gene panel was designed in 2012 after an extensive search in OMIM and other databases. Diagnostic genetic laboratories have to accept that custom diagnostic gene panels have a delay in inclusion of the newest research findings: development and implementation take time and changes require extensive validation against set quality parameters. We acknowledge this limitation in our paper: “Since research in obesity genetics is rapidly progressing, recently identified obesity-associated genes, such as CPE were not included in this panel” [1]. Furthermore, the authors say that we omitted the MRAP2 gene. It is, however, clearly listed as part of the gene panel. We even describe six identified MRAP2 variants in Table S1. Chèvre et al. also criticize the inclusion of insulin receptor genes, since they are not robustly associated with obesity. They were not included as 'obesity causing genes', but as 'comorbidity genes' (Table S2 Sequence variants identified in comorbidity genes) [1]. Diabetes is a serious comorbidity of obesity and knowledge of these mutations is important, especially when aiming for future personalized treatment.
The authors question the validity of how we determine the pathogenicity of identified variants. Our diagnostics lab is ISO15189 accredited and, as a member of the Dutch Society of Clinical Genetic Laboratory Diagnostics, adheres to the ACMG guidelines for the interpretation of sequence variants [2]. As such, our variant interpretation is in line with the guideline.
Thirdly the authors suggest to use ‘severe/morbid early-onset obesity’ rather than ‘obesity’ to describe our cohort. We deliberately used the term ‘obesity’, since pathogenic mutations were also identified in patients who did not have severe obesity or only became obese in adulthood.
References
1. Kleinendorst L, Massink MPG, Cooiman MI, Savas M, van der Baan-Slootweg OH, Roelants RJ, Janssen ICM, Meijers-Heijboer HJ, Knoers N, Ploos van Amstel HK, van Rossum EFC, van den Akker ELT, van Haaften G, van der Zwaag B, van Haelst MM. Genetic obesity: next-generation sequencing results of 1230 patients with obesity. J Med Genet 2018;55:578-86.
2. Richards S , Aziz N , Bale S , Bick D , Das S , Gastier-Foster J , Grody WW , Hegde M , Lyon E , Spector E , Voelkerding K , Rehm HL , ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17:405–23.doi:10.1038/gim.2015.30
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 MoreEvidence 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...
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 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....
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...
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
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
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...
Dr. Charles Allison,Dr. Taranika Sarkar,
and Prof.Dr.Jogenananda Pramanik
Careers Abroad Institute School of Medicine, Mandeville, Manchester, JM, WI.
We read and applauded the insightful article on clinical presentation of Russell-Silver syndrome with detail molecular diagnostic criteria as presented by Price S M., et al.[1] The low birth weight child who is non-dysmorphic with a prominent forehead and triangular face is more likely to be diagnosed as SRS if they have fifth finger clinodactyly, which in itself is not uncommon.[1] The genetic syndromes which affects growth and intellectual disability have been studied extensively. It has been proved by numerous large scale studies that IUGR is associated with significant neurodevelopmental impairment.
Show MoreFrom a meta analysis conducted by AAP it was concluded that IUGR is associated with lower cognitive scores for school age children. Furthermore children with IUGR born SGA reared in poorer environment demonstrate significant lower professional attainment and income than those reared in more stimulating environment. Here I present a case of
Russell-Silver Syndrome (RSS or SRS) which is a rare, clinically and genetically heterogeneous entity, caused by (epi)genetic alterations. It is characterized by prenatal and postnatal growth retardation, relative macrocephaly, the triangular face and body asymmetry.[ 6] Its incidence varies from 1 in 30,000 to 1 in 1,00,000 people. Individuals with RSS...
In “Genetic obesity: next-generation sequencing results of 1230 patients with obesity'', we presented our obesity gene panel data [1]. In their e-letter, Chèvre et al. question our panel selection because certain genes were omitted. Our gene panel was designed in 2012 after an extensive search in OMIM and other databases. Diagnostic genetic laboratories have to accept that custom diagnostic gene panels have a delay in inclusion of the newest research findings: development and implementation take time and changes require extensive validation against set quality parameters. We acknowledge this limitation in our paper: “Since research in obesity genetics is rapidly progressing, recently identified obesity-associated genes, such as CPE were not included in this panel” [1]. Furthermore, the authors say that we omitted the MRAP2 gene. It is, however, clearly listed as part of the gene panel. We even describe six identified MRAP2 variants in Table S1. Chèvre et al. also criticize the inclusion of insulin receptor genes, since they are not robustly associated with obesity. They were not included as 'obesity causing genes', but as 'comorbidity genes' (Table S2 Sequence variants identified in comorbidity genes) [1]. Diabetes is a serious comorbidity of obesity and knowledge of these mutations is important, especially when aiming for future personalized treatment.
The authors question the validity of how we determine the pathogenicity of identifi...
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