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).
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
To the Editor:
We read with interest the article by Kleinendorst et al. on a next-generation sequencing-based gene panel analysis of 52 obesity-related genes in 1,230 patients with obesity [1]. This study is among the first to screen an exhaustive list of causal genes to determine the prevalence of monogenic obesity in a large series of severely obese children and adults recruited from a medical setting [2]. Genetic testing for obesity should be routinely performed in carefully selected patients, especially given the possibility of effective personalized treatments for a subset of monogenic cases [3]. We wanted to express several important concerns.
First, the selection of these 52 genes is highly questionable. Several genes that have not been robustly associated with highly penetrant forms of obesity in the literature were included in the panel (e.g. IRS1, IRS2, IRS4, MCHR1), while 3 non-syndromic (MRAP2, KSR2, ADCY3) and 39 syndromic monogenic obesity genes were omitted [4,5].
Second, the authors claim a ‘definitive diagnosis of a genetic obesity disorder’ in 3.9% of obese probands. This is a highly dubious conclusion considering that the authors used proprietary bioinformatics tools and did not detail how they classified variants as being pathogenic/likely pathogenic, uncertain, or likely begnin/begnin. In vitro functional characterization experiments are needed to confirm the pathogenicity of genetic variants [2].
Third, the authors should have...
To the Editor:
We read with interest the article by Kleinendorst et al. on a next-generation sequencing-based gene panel analysis of 52 obesity-related genes in 1,230 patients with obesity [1]. This study is among the first to screen an exhaustive list of causal genes to determine the prevalence of monogenic obesity in a large series of severely obese children and adults recruited from a medical setting [2]. Genetic testing for obesity should be routinely performed in carefully selected patients, especially given the possibility of effective personalized treatments for a subset of monogenic cases [3]. We wanted to express several important concerns.
First, the selection of these 52 genes is highly questionable. Several genes that have not been robustly associated with highly penetrant forms of obesity in the literature were included in the panel (e.g. IRS1, IRS2, IRS4, MCHR1), while 3 non-syndromic (MRAP2, KSR2, ADCY3) and 39 syndromic monogenic obesity genes were omitted [4,5].
Second, the authors claim a ‘definitive diagnosis of a genetic obesity disorder’ in 3.9% of obese probands. This is a highly dubious conclusion considering that the authors used proprietary bioinformatics tools and did not detail how they classified variants as being pathogenic/likely pathogenic, uncertain, or likely begnin/begnin. In vitro functional characterization experiments are needed to confirm the pathogenicity of genetic variants [2].
Third, the authors should have used the term ‘severe/morbid early-onset obesity’ rather than ‘obesity’ to describe the study participants, given their extreme anthropometric characteristics (age of obesity onset <5 years, median adult body mass index (BMI) 43.6 kg/m2, median child BMI-standard deviation score (SDS) +3.4). Patients with early-onset/extreme forms of obesity are likely to be enriched for monogenic mutations, which may lead to biased prevalence estimates of monogenic mutations that are not transferable to common obesity (BMI ≥30 kg/m2, BMI-SDS ≥2).
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. Philippe J, Stijnen P, Meyre D, De Graeve F, Thuillier D, Delplanque J, Gyapay G, Sand O, Creemers JW, Froguel P, Bonnefond A. A nonsense loss-of-function mutation in PCSK1 contributes to dominantly inherited human obesity. Int J Obes (Lond) 2015;39:295-302.
3. Pigeyre M, Yazdi FT, Kaur Y, Meyre D. Recent progress in genetics, epigenetics and metagenomics unveils the pathophysiology of human obesity. Clin Sci (Lond) 2016;130:943-86.
4. Kaur Y, de Souza RJ, Gibson WT, Meyre D. A systematic review of genetic syndromes with obesity. Obes Rev 2017;18:603-34.
5. Pigeyre M, Meyre D. Monogenic obesity. In: Freemark MS, eds. Pediatric Obesity: Etiology, Pathogenesis and Treatment. Cham: Springer International Publishing AG 2018:135-52
in their recent study Arends and colleagues demonstrate a significant 2.8-fold increased risk for the formation of neutralizing anti-drug antibodies (ADA) in male patients with Fabry disease (FD) when treated with agalsidase-beta (1.0 mg/kg every other week) compared to agalsidase-alfa (0.2 mg/kg every other week).[1] Interestingly, Rombach and colleagues and later Smid and colleagues reported no significant differences in a humoral response, when using an identical dosage of 0.2 mg/kg for both drugs. [2,3] Hence, the 5-fold higher dosage of agalsidase-beta and not the compound itself seems to be an important trigger for antibody formation. However, none of the studies determined the cross reactive immunological status, which is crucial for the risk of a humoral response. The subgroup analysis of patients with ADAs by Arends and colleagues also revealed a better biochemical response to agalsidase-beta at 1.0 mg/kg in terms of decreasing lyso-Gb3 levels.[1] The authors propose that a saturation of antibody titers due to the 5-fold higher dosage might lead to the observed effect. In this respect, we recently demonstrated that antibodies can be supersaturated and that appropriate (i.e. individually optimized) enzyme dosages can overcome ADA titers already during infusions, which may result in improved patients’ outcome.[4] However, in the same study, we also demonstrated that even in patients treated with low-dose enzyme replacement therapy ADA titers can...
in their recent study Arends and colleagues demonstrate a significant 2.8-fold increased risk for the formation of neutralizing anti-drug antibodies (ADA) in male patients with Fabry disease (FD) when treated with agalsidase-beta (1.0 mg/kg every other week) compared to agalsidase-alfa (0.2 mg/kg every other week).[1] Interestingly, Rombach and colleagues and later Smid and colleagues reported no significant differences in a humoral response, when using an identical dosage of 0.2 mg/kg for both drugs. [2,3] Hence, the 5-fold higher dosage of agalsidase-beta and not the compound itself seems to be an important trigger for antibody formation. However, none of the studies determined the cross reactive immunological status, which is crucial for the risk of a humoral response. The subgroup analysis of patients with ADAs by Arends and colleagues also revealed a better biochemical response to agalsidase-beta at 1.0 mg/kg in terms of decreasing lyso-Gb3 levels.[1] The authors propose that a saturation of antibody titers due to the 5-fold higher dosage might lead to the observed effect. In this respect, we recently demonstrated that antibodies can be supersaturated and that appropriate (i.e. individually optimized) enzyme dosages can overcome ADA titers already during infusions, which may result in improved patients’ outcome.[4] However, in the same study, we also demonstrated that even in patients treated with low-dose enzyme replacement therapy ADA titers can be supersaturated.[4] Therefore, we conclude that assessments of individual antibody titers should be performed to determine optimal enzyme dosages for supersaturation of present antibodies and thus probably resulting in higher therapy efficiency and improved disease progression.
1. Arends M, Biegstraaten M, Wanner C, Sirrs S, Mehta A, Elliott PM, Oder D, Watkinson OT, Bichet DG, Khan A, Iwanochko M, Vaz FM, van Kuilenburg ABP, West ML, Hughes DA, Hollak CEM. Agalsidase alfa versus agalsidase beta for the treatment of Fabry disease: an international cohort study. J Med Genet. 2018 Feb 7. doi: 10.1136/jmedgenet-2017-104863. [Epub ahead of print]
2. Rombach SM, Aerts JM, Poorthuis BJ, Groener JE, Donker-Koopman W, Hendriks E, Mirzaian M, Kuiper S, Wijburg FA, Hollak CE, Linthorst GE. Long-term effect of antibodies against infused alpha-galactosidase A in Fabry disease on plasma and urinary (lyso)Gb3 reduction and treatment outcome. PLoS One. 2012;7:e47805.
3. Smid BE, Hoogendijk SL, Wijburg FA, et al. A revised home treatment algorithm for Fabry disease: influence of antibody formation. Mol Genet Metab 2013;108:132-7.
4. Lenders M, Schmitz B, Brand SM, Foell D, Brand E. Characterization of drug-neutralizing antibodies in patients with Fabry disease during infusion. J Allergy Clin Immunol. 2018 Feb 5. doi: 10.1016/j.jaci.2017.12.1001. [Epub ahead of print]
We read with interest the case series of 6 patients with Bohring-Opitz syndrome (BOS) phenotype who were found to have autosomal recessive truncating mutations in the KLHL7 gene[1]. The purpose of this letter is to report a novel truncating mutation in KLHL7, and to expand the phenotype of recessive KLHL7 variants.
Our patient is a now 32-month-old male of Guatemalan descent who was born at 37 weeks’ gestation after a pregnancy complicated by fetal hydronephrosis, IUGR, and maternal hypertension. Birthweight was 2.5 kg, and he failed the neonatal hearing screen bilaterally. He was admitted to the NICU for desaturation events and was treated with supplemental oxygen. Polysomnography was performed at 4 weeks of life and identified central sleep apnea, with a central apnea index of 11 events/hour and no significant obstructive component. PHOX2B testing ruled out congenital central hypoventilation syndrome. A brain MRI demonstrated hypoplasia of the corpus callosum, delayed myelination, pontine hypoplasia, and subependymal nodular heterotopia along the lateral ventricles. A chromosome microarray was negative for deletions and duplications, though it indicated multiple areas of homozygosity (combined total length ~24 Mb).
He demonstrated some neck control at 3 months of age, and at age 2 years was able to roll for mobility. He remains nonverbal, tracheosteomy- and gastrostomy tube-dependent. Kyphoscoliosis was noted at 11 months of age and is progressing. He is also...
We read with interest the case series of 6 patients with Bohring-Opitz syndrome (BOS) phenotype who were found to have autosomal recessive truncating mutations in the KLHL7 gene[1]. The purpose of this letter is to report a novel truncating mutation in KLHL7, and to expand the phenotype of recessive KLHL7 variants.
Our patient is a now 32-month-old male of Guatemalan descent who was born at 37 weeks’ gestation after a pregnancy complicated by fetal hydronephrosis, IUGR, and maternal hypertension. Birthweight was 2.5 kg, and he failed the neonatal hearing screen bilaterally. He was admitted to the NICU for desaturation events and was treated with supplemental oxygen. Polysomnography was performed at 4 weeks of life and identified central sleep apnea, with a central apnea index of 11 events/hour and no significant obstructive component. PHOX2B testing ruled out congenital central hypoventilation syndrome. A brain MRI demonstrated hypoplasia of the corpus callosum, delayed myelination, pontine hypoplasia, and subependymal nodular heterotopia along the lateral ventricles. A chromosome microarray was negative for deletions and duplications, though it indicated multiple areas of homozygosity (combined total length ~24 Mb).
He demonstrated some neck control at 3 months of age, and at age 2 years was able to roll for mobility. He remains nonverbal, tracheosteomy- and gastrostomy tube-dependent. Kyphoscoliosis was noted at 11 months of age and is progressing. He is also noted to have a secundum atrial septal defect, and right-sided grade 4 vesicoureteral reflux with reflux nephropathy and hydroureter. An ophthalmology evaluation at age 16 months revealed optic nerve pallor and enlarged optic nerve cups (cup-to-disc ratio 0.6), but no retinal findings. His physical exam is notable for microcephaly (-2 SD), a prominent forehead, low-set ears with uplifted lobes, micrognathia, high palate, bilateral knee and elbow contractures, wrist flexion with ulnar deviation of the wrists and fingers (“BOS posture”), long fingers with camptodactyly and middle finger in palm deformity, prominent heels, a right hydrocele and buried penis, central hypotonia with appendicular hypertonia, and bilateral ankle clonus.
Whole exome sequencing revealed a novel truncating homozygous mutation in the KLHL7 gene (NM_001031710.2:c.976C>T, p.Arg326*). Parents were each found to carry one copy of the variant.
We report our patient with many features of patients with KLHL7-related disorder, including IUGR, optic nerve abnormalities, brain abnormalities, central hypotonia, joint contractures,, scoliosis, feeding difficulty and genitourinary and cardiac differences, features overlapping the Crisponi/CISS1-like phenotype and BOS-like phenotype. Our patient was also found to have severe central sleep apnea, well documented by polysomnography. We thus expand the phenotypic and mutational spectrum of KLHL7-related disorders.
References:
1 Bruel A-L, Bigoni S, Kennedy J, et al. Expanding the clinical spectrum of recessive truncating mutations of KLHL7 to a Bohring-Opitz-like phenotype. J Med Genet 2017;54:830–5.
We read with interest the case series of 12 patients with loss-of-function denovo heterozygous mutations in ASXL3, reported by Balasubramanian et al in August 2017. We want to report on a further case of Bainbridge – Ropers Syndrome (BRS) seen in our department. The purpose of this letter is two-fold. The first is to report on the mild features of BRS and the second is to expand the spectrum of features in BRS reiterating that all cases may not have severe features.
The proband is now 7 years old who first presented to the genetic services at the age of 3 years with global developmental delay and epilepsy. He is the first child of non-consanguineous healthy parent of Indian heritage. There is no family history of learning difficulties, autism or developmental delay.
He was born after a normal pregnancy by LSCS for prolonged labour with a birth weight of 2.9kg at term. He started sitting independently at 16 months and walking at 22 months. He has speech and language delay. He initially presented with 2 episodes of febrile convulsions; the first lasting 1 minute and second 10 minutes, at 3 and a half years of age. He then went on to develop tonic- clonic seizures thereafter all requiring hospital admission. He was recruited to the deciphering development disorder project (DDD) and on whole exome sequencing detected two variants in ASXL3 and DMD gene respectively.
This variant is predicted to cause a frameshift mutation resulting in a premature terminat...
We read with interest the case series of 12 patients with loss-of-function denovo heterozygous mutations in ASXL3, reported by Balasubramanian et al in August 2017. We want to report on a further case of Bainbridge – Ropers Syndrome (BRS) seen in our department. The purpose of this letter is two-fold. The first is to report on the mild features of BRS and the second is to expand the spectrum of features in BRS reiterating that all cases may not have severe features.
The proband is now 7 years old who first presented to the genetic services at the age of 3 years with global developmental delay and epilepsy. He is the first child of non-consanguineous healthy parent of Indian heritage. There is no family history of learning difficulties, autism or developmental delay.
He was born after a normal pregnancy by LSCS for prolonged labour with a birth weight of 2.9kg at term. He started sitting independently at 16 months and walking at 22 months. He has speech and language delay. He initially presented with 2 episodes of febrile convulsions; the first lasting 1 minute and second 10 minutes, at 3 and a half years of age. He then went on to develop tonic- clonic seizures thereafter all requiring hospital admission. He was recruited to the deciphering development disorder project (DDD) and on whole exome sequencing detected two variants in ASXL3 and DMD gene respectively.
This variant is predicted to cause a frameshift mutation resulting in a premature termination codon in exon 12 of ASXL3. There are no other reports of this variant in any databases or in the published literature. Loss of function variant in ASXL3 have been reported in patients with Bainbridge – Ropers Syndrome (OMIM #615485)
Our patient was also found to have another variant – DMD C 726a>t p(Gln242His). This variant is predicted to replace the amino acid Glutamine with Histidine at position 242 in the dystrophin protein. There are no reports of this variant in any databases or in the published literature. The protein prediction algorithm within the Alamut variant analysis software package (v2.7.2) do not predict an effect on protein function and there is no evidence of an alteration to splicing. Loss of function variants in the DMD cause XP21 dystrophionopathy, however most pathogenic variants lead to a truncated protein and missense variants in DMD are usually well tolerated. Our proband has a normal creatinine kinase level and is showing no features of Xp21 dystrophionopathy therefore it is unlikely that this variant is pathogenic.
At 7 years of age he can talk in sentences, he walks independently and attends special school. He is still in nappies and there are no concerns regarding his feeding and sleeping. His height and weight are on the 91st centile and the head circumference on the 2nd centile. His facial features consist of long face, arched eyebrows, synophrys and prominent columella.
In conclusion we present a boy with milder features of BRS. He did not have the characteristic features of severe muscular hypotonia with feeding difficulties, significant speech and motor delay with epilepsy. He has mild developmental delay with some characteristic facial features with a denovo pathogenic frameshift mutation in exon 12 of ASXL3. Our case illustrates that the clinical features in BRS can show wide variation, which can present with milder features of developmental delay, facial dysmorphism and premature protein truncation.
References:
Balasubramanian M, Willoughby J, Fry AE, Weber A, Firth HV, Deshpande C, Berg JN, Chandler K, Metcalfe KA, Lam W, et al. Delineating the phenotypic spectrum of Bainbridge-Ropers syndrome: 12 new patients with de novo, heterozygous, loss-of-function mutations in ASXL3 and review of published literature. J Med Genet. 2017 Aug; 54(8):537-543.
Hori I, Miya F, Ohashi K, Negishi Y, Hattori A, Ando N, Okamoto N, Kato M, Tsunoda T, Yamasaki M, et al Novel splicing mutation in the ASXL3 gene causing Bainbridge-Ropers syndrome. Am J Med Genet A. 2016 Jul; 170(7):1863-7.
Kuechler A, Czeschik JC, Graf E, Grasshoff U, Hüffmeier U, Busa T, Beck-Woedl S, Faivre L, Rivière JB, Bader I, et al. Bainbridge-Ropers syndrome caused by loss-of-function variants in ASXL3: a recognizable condition. Eur J Hum Genet. 2017 Feb; 25(2):183-191.
Srivastava A, Ritesh KC, Tsan YC, Liao R, Su F, Cao X, Hannibal MC, Keegan CE, Chinnaiyan AM, Martin DM, Bielas SL. De novo dominant ASXL3 mutations alter H2A deubiquitination and transcription in Bainbridge-Ropers syndrome. Hum Mol Genet. 2016 Feb 1;25(3):597-608.
Phenotypic non-penetrance in Milroy-like disease associated with a mutation in the vascular endothelial growth factor-C gene (VEGFC)
Boersma, H.J.1, M.V. Heitink2, J.M. van de Kamp3, van Geel, M 1,4
1 Department of Dermatology, Maastricht University Medical Centre+, Maastricht, The Netherlands
2 Department of Dermatology, VieCuri, Venlo, The Netherlands
3 Department of Clinical Genetics, VU Medical Centre, Amsterdam, The Netherlands
4 Department of Clinical Genetics, Maastricht University Medical Centre+, Maastricht, The Netherlands
With great interest, we read the article by Balboa-Beltran et al [1], where they presented a three-generation family with a phenotype of typical Milroy disease without mutations in FLT4 but instead in VEGFC. Milroy disease is an autosomal dominant, congenital form of primary lymphoedema with reduced penetrance. In approximately 70% of Milroy disease patients, mutations in FLT4 are identified [2]. Connell et al. presented research wherein FLT4 pathogenic variants were detected in 75% of clearly affected patients having a positive family history and in 68% of typical Milroy patients but without a family history [3], suggesting that other genes may be involved. Balboa-Beltran et al [1], detected a novel nonsense mutation (p.(Arg210*)) in VEGFC by exome sequencing causing Milroy-like disease. They found that all carriers of this VEGFC mutation exhibited the clinical diagnostic criteria of Milroy disease, inclu...
Phenotypic non-penetrance in Milroy-like disease associated with a mutation in the vascular endothelial growth factor-C gene (VEGFC)
Boersma, H.J.1, M.V. Heitink2, J.M. van de Kamp3, van Geel, M 1,4
1 Department of Dermatology, Maastricht University Medical Centre+, Maastricht, The Netherlands
2 Department of Dermatology, VieCuri, Venlo, The Netherlands
3 Department of Clinical Genetics, VU Medical Centre, Amsterdam, The Netherlands
4 Department of Clinical Genetics, Maastricht University Medical Centre+, Maastricht, The Netherlands
With great interest, we read the article by Balboa-Beltran et al [1], where they presented a three-generation family with a phenotype of typical Milroy disease without mutations in FLT4 but instead in VEGFC. Milroy disease is an autosomal dominant, congenital form of primary lymphoedema with reduced penetrance. In approximately 70% of Milroy disease patients, mutations in FLT4 are identified [2]. Connell et al. presented research wherein FLT4 pathogenic variants were detected in 75% of clearly affected patients having a positive family history and in 68% of typical Milroy patients but without a family history [3], suggesting that other genes may be involved. Balboa-Beltran et al [1], detected a novel nonsense mutation (p.(Arg210*)) in VEGFC by exome sequencing causing Milroy-like disease. They found that all carriers of this VEGFC mutation exhibited the clinical diagnostic criteria of Milroy disease, including lower-limb swelling at birth or soon thereafter and upslanting toenails. In their article, the mutation segregated with the phenotype in the family according to a dominant inheritance model with full penetrance. In an article by Gordon et al [4] it was already demonstrated that mutations in VEGFC can cause a Milroy disease-like phenotype similar to that found in patients with mutations in the FLT4 gene. We would like to add to this knowledge by presenting a new case, seen in our Dutch academic hospital.
In 2013, a young, male patient (1 year) exhibited lymphoedema in his right foot without a dilated vena saphena magna. At birth he presented with bilateral foot and lower leg lymphoedema, diminishing on the left after 3 months. The symptoms were suggestive of Milroy’s disease. To determine whether these symptoms were caused by a mutation, we performed Sanger sequence analysis for FLT4 and VEGFC and found the same heterozygous nonsense VEGFC mutation as described by Balboa-Beltran et al [1]. To determine if the mutation occurred de novo or segregated in the family, both parents were tested. The mutation was also found in his asymptomatic 28-year-old father. The patient’s paternal grandmother, also having the mutation, mentioned that she exhibited heavy peripheral oedema when she was pregnant. The paternal great-grandmother (not tested) supposedly developed extreme peripheral oedema after a uterus-extirpation in the past and we were informed that the paternal grandmother’s sister had large ankles at adult age. However, no conclusions may be drawn from the latter family members, since mutation analysis was not performed. This family suggests, in contrast to the article of Balboa-Beltran et al [1], that non-penetrance of this nonsense mutation in VEGFC is evident, in line with the patient’s initial absence of disease history within the family. Similar variable penetrance, is reported in Milroy disease associated with mutations in FLT4, where 10%-15% of individuals with an FLT4 pathogenic variant were shown to be clinically unaffected [2].
References:
1 Balboa-Beltran E, Fernandez-Seara MJ, Perez-Munuzuri A, et al. A novel stop mutation in the vascular endothelial growth factor-C gene (VEGFC) results in Milroy-like disease. J Med Genet 2014;51(7):475-8.
2 Brice G, Child A, Evans A, et al. Milroy disease and the VEGFR-3 mutation phenotype. J Med Genet 2005;42(2):98-102.
3 Connell FC, Ostergaard P, Carver C, et al. Analysis of the coding regions of VEGFR3 and VEGFC in Milroy disease and other primary lymphoedemas. Human Genet, 2009; 124(6), 625–631.
4 Gordon K, Schulte D, Brice G, et al. Mutation in vascular endothelial growth factor-C, a ligand for vascular endothelial growth factor receptor-3, is associated with autosomal dominant milroy-like primary lymphedema. Circ Res 2013;112(6):956-60.
We thank our colleagues for their interest in our study recently published in the Journal of Medical Genetics entitled ‘Risk assessment of maternally inherited SDHD paraganglioma and pheochromocytoma’.
In response, we would like to underline that our study is a prospective study (see 'Methods' section) and not a case study.
Today, the French national registry for hereditary paraganglioma (PGL.R) contains 193 SDHD different families carrying more than 60 different mutations, which is different from the Dutch situation where 87.1% of the SDHD-mutation carriers have the same founder Dutch mutation p.Asp92Tyr [1]. As explained in our paper, we have launched this prospective study because of the few cases of SDHD-tumors inherited via the maternal line reported in the literature, but also because we were aware of three other putative cases among patients suffering from paraganglioma or pheochromocytoma (PPGL) registered in PGL.R. Unfortunately, for those three cases we were not able to collect tumor tissues to definitely prove the role of the maternally inherited SDHD mutation in the tumorigenesis. The identification of a new case, a young asymptomatic woman, by our prospective study was nevertheless a surprise for us. So we strongly suggest our colleagues to take advantage from their large cohort of 600 at-risk subjects to perform the same prospective study in asymptomatic subjects, although most of them would carry the same SDHD founder mutation, to confi...
We thank our colleagues for their interest in our study recently published in the Journal of Medical Genetics entitled ‘Risk assessment of maternally inherited SDHD paraganglioma and pheochromocytoma’.
In response, we would like to underline that our study is a prospective study (see 'Methods' section) and not a case study.
Today, the French national registry for hereditary paraganglioma (PGL.R) contains 193 SDHD different families carrying more than 60 different mutations, which is different from the Dutch situation where 87.1% of the SDHD-mutation carriers have the same founder Dutch mutation p.Asp92Tyr [1]. As explained in our paper, we have launched this prospective study because of the few cases of SDHD-tumors inherited via the maternal line reported in the literature, but also because we were aware of three other putative cases among patients suffering from paraganglioma or pheochromocytoma (PPGL) registered in PGL.R. Unfortunately, for those three cases we were not able to collect tumor tissues to definitely prove the role of the maternally inherited SDHD mutation in the tumorigenesis. The identification of a new case, a young asymptomatic woman, by our prospective study was nevertheless a surprise for us. So we strongly suggest our colleagues to take advantage from their large cohort of 600 at-risk subjects to perform the same prospective study in asymptomatic subjects, although most of them would carry the same SDHD founder mutation, to confirm or not our data.
Based on the results of our prospective study, we suggest to inform adult patients of the potential risk and to propose them a first screening that would include imaging. Our clinical experience of 18 years of genetic counselling and management of subjects with genetically determined forms of PPGL within a specialized multidisciplinary team is different from those of our colleagues. In the PGL.EVA study [2,3], we observed a significant decrease of depression and anxiety after initial screening. In the subgroup with tumor diagnosis, we observed a tendency for decrease of depression and no increase of anxiety. In the present study, evaluation of the feeling of patients at the reception of our letter revealed their satisfaction to the interest given by an expert center and to the possibility to take advantage of science progress.
Moreover, they clearly expressed being comforted by the possibility to communicate with an expert center of the disease in case of symptoms.
We think that in 2017 a large PPGL revealed by a complication, such as deafness or cardiac complications, in SDHD mutation carrier relatives would be unacceptable. Beyond the mortality rate, which cannot be definitely assessed with a mean duration of follow-up of 7.6 years only as in the paper published by van Hulsteijn [4], the quality of life should also be considered. Interestingly, the same Dutch team reported in 2013 that the quality of life is decreased in patients with paraganglioma (significantly impaired scores on physical, psychological and social subscales) after questioning 174 patients versus 100 controls [5].
So we do believe that after several reports of clinical cases, our study is a new step forward evidencebased guidelines for SDHD families. Our current recommendations might be further re-evaluated with new data from prospective or randomized studies as well as with the assessment of the natural history of the SDHD-related disease following a prospective long term follow-up of the patients enrolled in hereditary paraganglioma registries equivalent to the French PGL.R.
Anne-Paule Gimenez-Roqueplo
Khadija Lahlou-Laforêt
Nelly Burnichon
References
[1]. Hensen EF et al. High prevalence of founder mutations of the succinate dehydrogenase genes in the Netherlands. Clin Genet 2012; 81:284-288
[2]. Lahlou-Laforêt K. Consoli SM, Caumont-Prim A., Rohmer V., Gimenez-Roqueplo AP, on behalf of the PGL.EVA investigators. Psychological impact of tumor screening in SDHx mutation carriers recruited in a 3 year national protocol. IMPAHC 2015, 5-7 May 2015, Manchester
[3]. Gimenez-Roqueplo et al. Imaging Work-Up for Screening of Paraganglioma and Pheochromocytoma in SDHx Mutation Carriers: A Multicenter Prospective Study from the PGL.EVA Investigators. J Clin Endocrinol Metab 2014; 98: E162-E173
[4]. Van Hulsteijn LT et al. No evidence for increased mortality in SDHD variant carriers compared with the general population. Eur J Hum Genet 2015; :23:1713-1716
[5]. van Hulsteijn LT et al. Quality of life is decreased in patients with paragangliomas. Eur J Endocrinol 2013;168:689-97.
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...
Show MoreDr. 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...
Show MoreTo the Editor:
Show MoreWe read with interest the article by Kleinendorst et al. on a next-generation sequencing-based gene panel analysis of 52 obesity-related genes in 1,230 patients with obesity [1]. This study is among the first to screen an exhaustive list of causal genes to determine the prevalence of monogenic obesity in a large series of severely obese children and adults recruited from a medical setting [2]. Genetic testing for obesity should be routinely performed in carefully selected patients, especially given the possibility of effective personalized treatments for a subset of monogenic cases [3]. We wanted to express several important concerns.
First, the selection of these 52 genes is highly questionable. Several genes that have not been robustly associated with highly penetrant forms of obesity in the literature were included in the panel (e.g. IRS1, IRS2, IRS4, MCHR1), while 3 non-syndromic (MRAP2, KSR2, ADCY3) and 39 syndromic monogenic obesity genes were omitted [4,5].
Second, the authors claim a ‘definitive diagnosis of a genetic obesity disorder’ in 3.9% of obese probands. This is a highly dubious conclusion considering that the authors used proprietary bioinformatics tools and did not detail how they classified variants as being pathogenic/likely pathogenic, uncertain, or likely begnin/begnin. In vitro functional characterization experiments are needed to confirm the pathogenicity of genetic variants [2].
Third, the authors should have...
Dear Editor,
in their recent study Arends and colleagues demonstrate a significant 2.8-fold increased risk for the formation of neutralizing anti-drug antibodies (ADA) in male patients with Fabry disease (FD) when treated with agalsidase-beta (1.0 mg/kg every other week) compared to agalsidase-alfa (0.2 mg/kg every other week).[1] Interestingly, Rombach and colleagues and later Smid and colleagues reported no significant differences in a humoral response, when using an identical dosage of 0.2 mg/kg for both drugs. [2,3] Hence, the 5-fold higher dosage of agalsidase-beta and not the compound itself seems to be an important trigger for antibody formation. However, none of the studies determined the cross reactive immunological status, which is crucial for the risk of a humoral response. The subgroup analysis of patients with ADAs by Arends and colleagues also revealed a better biochemical response to agalsidase-beta at 1.0 mg/kg in terms of decreasing lyso-Gb3 levels.[1] The authors propose that a saturation of antibody titers due to the 5-fold higher dosage might lead to the observed effect. In this respect, we recently demonstrated that antibodies can be supersaturated and that appropriate (i.e. individually optimized) enzyme dosages can overcome ADA titers already during infusions, which may result in improved patients’ outcome.[4] However, in the same study, we also demonstrated that even in patients treated with low-dose enzyme replacement therapy ADA titers can...
Show MoreWe read with interest the case series of 6 patients with Bohring-Opitz syndrome (BOS) phenotype who were found to have autosomal recessive truncating mutations in the KLHL7 gene[1]. The purpose of this letter is to report a novel truncating mutation in KLHL7, and to expand the phenotype of recessive KLHL7 variants.
Show MoreOur patient is a now 32-month-old male of Guatemalan descent who was born at 37 weeks’ gestation after a pregnancy complicated by fetal hydronephrosis, IUGR, and maternal hypertension. Birthweight was 2.5 kg, and he failed the neonatal hearing screen bilaterally. He was admitted to the NICU for desaturation events and was treated with supplemental oxygen. Polysomnography was performed at 4 weeks of life and identified central sleep apnea, with a central apnea index of 11 events/hour and no significant obstructive component. PHOX2B testing ruled out congenital central hypoventilation syndrome. A brain MRI demonstrated hypoplasia of the corpus callosum, delayed myelination, pontine hypoplasia, and subependymal nodular heterotopia along the lateral ventricles. A chromosome microarray was negative for deletions and duplications, though it indicated multiple areas of homozygosity (combined total length ~24 Mb).
He demonstrated some neck control at 3 months of age, and at age 2 years was able to roll for mobility. He remains nonverbal, tracheosteomy- and gastrostomy tube-dependent. Kyphoscoliosis was noted at 11 months of age and is progressing. He is also...
We read with interest the case series of 12 patients with loss-of-function denovo heterozygous mutations in ASXL3, reported by Balasubramanian et al in August 2017. We want to report on a further case of Bainbridge – Ropers Syndrome (BRS) seen in our department. The purpose of this letter is two-fold. The first is to report on the mild features of BRS and the second is to expand the spectrum of features in BRS reiterating that all cases may not have severe features.
The proband is now 7 years old who first presented to the genetic services at the age of 3 years with global developmental delay and epilepsy. He is the first child of non-consanguineous healthy parent of Indian heritage. There is no family history of learning difficulties, autism or developmental delay.
He was born after a normal pregnancy by LSCS for prolonged labour with a birth weight of 2.9kg at term. He started sitting independently at 16 months and walking at 22 months. He has speech and language delay. He initially presented with 2 episodes of febrile convulsions; the first lasting 1 minute and second 10 minutes, at 3 and a half years of age. He then went on to develop tonic- clonic seizures thereafter all requiring hospital admission. He was recruited to the deciphering development disorder project (DDD) and on whole exome sequencing detected two variants in ASXL3 and DMD gene respectively.
This variant is predicted to cause a frameshift mutation resulting in a premature terminat...
Show MorePhenotypic non-penetrance in Milroy-like disease associated with a mutation in the vascular endothelial growth factor-C gene (VEGFC)
Boersma, H.J.1, M.V. Heitink2, J.M. van de Kamp3, van Geel, M 1,4
1 Department of Dermatology, Maastricht University Medical Centre+, Maastricht, The Netherlands
2 Department of Dermatology, VieCuri, Venlo, The Netherlands
3 Department of Clinical Genetics, VU Medical Centre, Amsterdam, The Netherlands
4 Department of Clinical Genetics, Maastricht University Medical Centre+, Maastricht, The Netherlands
With great interest, we read the article by Balboa-Beltran et al [1], where they presented a three-generation family with a phenotype of typical Milroy disease without mutations in FLT4 but instead in VEGFC. Milroy disease is an autosomal dominant, congenital form of primary lymphoedema with reduced penetrance. In approximately 70% of Milroy disease patients, mutations in FLT4 are identified [2]. Connell et al. presented research wherein FLT4 pathogenic variants were detected in 75% of clearly affected patients having a positive family history and in 68% of typical Milroy patients but without a family history [3], suggesting that other genes may be involved. Balboa-Beltran et al [1], detected a novel nonsense mutation (p.(Arg210*)) in VEGFC by exome sequencing causing Milroy-like disease. They found that all carriers of this VEGFC mutation exhibited the clinical diagnostic criteria of Milroy disease, inclu...
Show MoreWe thank our colleagues for their interest in our study recently published in the Journal of Medical Genetics entitled ‘Risk assessment of maternally inherited SDHD paraganglioma and pheochromocytoma’.
Show MoreIn response, we would like to underline that our study is a prospective study (see 'Methods' section) and not a case study.
Today, the French national registry for hereditary paraganglioma (PGL.R) contains 193 SDHD different families carrying more than 60 different mutations, which is different from the Dutch situation where 87.1% of the SDHD-mutation carriers have the same founder Dutch mutation p.Asp92Tyr [1]. As explained in our paper, we have launched this prospective study because of the few cases of SDHD-tumors inherited via the maternal line reported in the literature, but also because we were aware of three other putative cases among patients suffering from paraganglioma or pheochromocytoma (PPGL) registered in PGL.R. Unfortunately, for those three cases we were not able to collect tumor tissues to definitely prove the role of the maternally inherited SDHD mutation in the tumorigenesis. The identification of a new case, a young asymptomatic woman, by our prospective study was nevertheless a surprise for us. So we strongly suggest our colleagues to take advantage from their large cohort of 600 at-risk subjects to perform the same prospective study in asymptomatic subjects, although most of them would carry the same SDHD founder mutation, to confi...
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