123 e-Letters

  • Renal tumours in neonates are often misdiagnosed -A major concern.

    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...

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  • Additional evidence for the c.428del variant in KIAA0586 as hypomorphic allele that is only disease causing in compound heterozygosity with strong mutations.

    Matias Wagner1,2,3, Dominik S Westphal1,2, Iris Hannibal4, Johannes A. Mayr5, Tim M. Strom1,2, Thomas Meitinger1,2, Holger Prokisch1,2, Saskia B. Wortmann1,2,5
    1. Institute of Human Genetics, Technical University Munich, Munich, Germany;
    2. Institute of Human Genetics, Helmholtz Zentrum Munich, Neuherberg, Germany;
    3. Institute of Neurogenomics, Helmholtz Zentrum Munich, Neuherberg, Germany
    4. Dr. von Hauner Children’s Hospital, Ludwig-Maximilians University, Munich, Germany
    5. Department of Pediatrics, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), Salzburg, Austria

    Biallelic mutations in KIAA0586 have been related to Joubert syndrome (JBTS) 23 and as the most frequent disease causing variant c.428del (p.Arg143Lysfs*4) was identified.1 However, the allele frequency of 0.003117 and two homozygotes in the gnomAD dataset as well as additional reports of healthy carriers have questioned the variant’s pathogenicity.2, 3 Pauli et al. have recently hypothesized that c.428del is a hypomorphic allele which is only causing JBTS in compound heterozygosity with other mutations.

    In 15,000 in-house exome data sets, we have identified three individuals harboring c.428del in a homozygous state. In two, we identified other variants sufficiently explaining the phenotype: In a 6 year old girl with global developmental delay and progressive myoclonic astatic epilepsy, we identified a de novo variant c.2683del, p.Ser895Le...

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  • A mini review with an original Case report: Russell-Silver Syndrome (RSS)

    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.
    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...

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  • Reply to "Comment on: Kleinendorst et al. Genetic obesity: next-generation sequencing results of 1230 patients with obesity. J Med Genet 2018 Sep;55(9):578-586."

    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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  • Comment on: Kleinendorst et al. Genetic obesity: next-generation sequencing results of 1230 patients with obesity. J Med Genet 2018 Sep;55(9):578-586.

    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...

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  • Comment on Agalsidase alfa versus agalsidase beta for the treatment of Fabry disease: an international cohort study

    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...

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  • Novel biallelic truncating mutation in KLHL7 causing recessive Bohring-Opitz syndrome with central apnea

    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...

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  • Milder phenotype in a boy with Bainbridge Ropers Syndrome and ASXL3 mutation. Expanding the phenotypic spectrum

    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...

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  • Phenotypic non-penetrance in Milroy-like disease associated with a mutation in the vascular endothelial growth factor-C gene (VEGFC)

    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...

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  • Response

    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...

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