Science has been defined as a process of progressive approximation to the truth, so-called “increasing verisimilitude” [1]. The letter of Professor Fischer is illustrative in this regard.
We previously described genetic analyses of a consanguineous Pakistani family diagnosed with “recessive progressive symmetric erythrokeratoderma” by multiple dermatologists. By autozygosity mapping and sequencing, we identified potentially pathogenic frameshift mutations in two genes located within a region of autozygosity on chr12q12-q14.1, SDR9C7 and KRT83, in perfect linkage disequilibrium in this family [2]. At that time we did not consider SDR9C7 a good candidate, and we concluded that the KRT83 frameshift was more likely to be causal.
Our study was carried out in the early autumn of 2015, we wrote our paper in the spring of 2016, a revised version was accepted for publication in autumn, 2016, and our paper was published online in late 2016. Presumably at the same time, Shigehara et al. [3] carried out parallel studies, unambiguously identifying SDR9C7 as the gene for recessive congenital lamellar ichthyosis based on three families with different mutations. Their findings were published at nearly the same time as ours, and were subsequently confirmed by other investigators [4-6]. Obviously, none of this was known at the time of our study.
With the 20:20 clarity of hindsight, it now seems clear that many of the clinical features in our study family are consisten...
Science has been defined as a process of progressive approximation to the truth, so-called “increasing verisimilitude” [1]. The letter of Professor Fischer is illustrative in this regard.
We previously described genetic analyses of a consanguineous Pakistani family diagnosed with “recessive progressive symmetric erythrokeratoderma” by multiple dermatologists. By autozygosity mapping and sequencing, we identified potentially pathogenic frameshift mutations in two genes located within a region of autozygosity on chr12q12-q14.1, SDR9C7 and KRT83, in perfect linkage disequilibrium in this family [2]. At that time we did not consider SDR9C7 a good candidate, and we concluded that the KRT83 frameshift was more likely to be causal.
Our study was carried out in the early autumn of 2015, we wrote our paper in the spring of 2016, a revised version was accepted for publication in autumn, 2016, and our paper was published online in late 2016. Presumably at the same time, Shigehara et al. [3] carried out parallel studies, unambiguously identifying SDR9C7 as the gene for recessive congenital lamellar ichthyosis based on three families with different mutations. Their findings were published at nearly the same time as ours, and were subsequently confirmed by other investigators [4-6]. Obviously, none of this was known at the time of our study.
With the 20:20 clarity of hindsight, it now seems clear that many of the clinical features in our study family are consistent with the diagnosis of congenital ichthyosis, resulting from the homozygous frameshift of SDR9C7. That places the true role of the KRT83 frameshift in this family into question. It is noteworthy that affected members of this family exhibit the additional clinical feature of striking erythrokeratoderma, not evident in affected members of the Pakistani family reported by Karim et al. [4] who carry the same SDR9C7 frameshift but not the frameshift in KRT83. Whether prominent erythrokeratoderma might be an atypical feature of congenital ichthyosis in this family, an epistatic effect of an unknown common unlinked variant in this population, whether that might reflect a specific effect of the additional homozygous KRT83 frameshift, or whether that might be a summary effect of the SDR9C7 and KRT83 frameshifts in perfect linkage disequilibrium in this family remains to be determined. Increasing verisimilitude indeed!
1. Niiniluoto I. Verisimilitude: the third period. Br J Phil Sci 1998;49:1–29.
2. Shah K, Ansar M, Mughal Z, Khan F, Ahmad W, Ferrara T, Spritz R. Recessive progressive symmetric erythrokeratoderma results from a homozygous loss-of-function mutation of KRT83 and is allelic with dominant monilethrix. J Med Genet 2017;54:186-9.
3. Shigehara Y, Okuda S, Nemer G, Chedraoui A, Hayashi R, Bitar F, Nakai H, Abbas O, Daou L, Abe R, Sleiman MB, Kibbi AG, Kurban M, Shimomura Y. Mutations in SDR9C7 gene encoding an enzyme for vitamin A metabolism underlie autosomal recessive congenital ichthyosis. Hum Mol Genet 2016;25:4484–93.
4. Karim N, Murtaza G, Naeem M. Whole‐exome sequencing identified a novel frameshift mutation in SDR9C7 underlying autosomal recessive congenital ichthyosis in a Pakistani family. Br J Dermatol 2017; 177: e191–2.
5. Takeichi T, Nomura T, Takama H, Kono M, Sugiura K, Watanabe D, Shimizu H, Simpson MA, McGrath JA, Akiyama M. Deficient stratum corneum intercellular lipid in a Japanese patient with lamellar ichthyosis by a homozygous deletion mutation in SDR9C7. Br J Dermatol 2017;177: e62–4.
6. Hotz A, Fagerberg C, Vahlquist A, Bygum A, Törmä H, Rauschendorf MA, Zhang H, Heinz L, Bourrat E, Hausser I, Vestergaard V, Dragomir A, Zimmer AD, Fischer J. Identification of mutations in SDR9C7 in six families with autosomal recessive congenital ichthyosis. Br J Dermatol 2018;178:e207-e209.
Fascinated to see the comments about irregular heartbeats as an x-linked ichthyosis suffer myself. If you are carrying out further studies I wonder if there is any trend for female carriers having the same. My mother an x-linked ichthyosis carrier has always had an extra hearth beat that causes problems for medical exams and operations. Could it be used as an additional test for expectant mums for potential x-linked babies. A great article and thanks - Jeremy Instone
Dear Mr Instone - Many thanks for your interest in our work and your comment! In our analyses we did look at ICD-10 diagnoses of atrial fibrillation/flutter, and self-reported heart problems in female carriers versus female non-carriers, but didn't see any difference in prevalence between the two groups (results in the Supplementary Data). However, as these are relatively crude measures, we cannot the exclude the possibility that there are actually higher rates of subtle cardiac dysfunction in female carriers relative to non-carriers, and further, more focussed studies might look at this. Regards, Dr William Davies
I recently came across this publication and was very surprised at some facts that seem inconsistent.
Shah et al. state that homozygous mutations in KRT83 are responsible for the skin phenotype of their patients, which they describe as an autosomal recessive form of progressive symmetric erythrokeratoderma (1). Ten individuals from a consanguineous Pakistani family were analyzed, including three patients with a skin phenotype. Shah et al. have successfully performed homozygosity mapping, followed by whole exome sequencing (WES), which are adequate methods to identify gene mutations in rare diseases.
First of all, I agree with the comment by Ramot et al from January 12, 2017, which states that it is very unlikely that KRT83, which is only expressed in hair cells, will lead to a skin phenotype.
In addition, the presented clinical pictures of the patients do not show typical signs of progressive symmetrical erythrokeratoderma; however the presented phenotype is compatible with lamellar ichthyosis (autosomal recessive congenital ichthyosis ARCI).
To my great astonishment, the authors themselves mention the correct solution in their publication, but unfortunately they have obviously drawn the wrong conclusion. It is described in the results section that within the homozygous interval on chromosome 12q12-q14, WES showed not only a homozygous KRT83 variant that was classified as pathogenic and causative for the present phenotype in this publication, but al...
I recently came across this publication and was very surprised at some facts that seem inconsistent.
Shah et al. state that homozygous mutations in KRT83 are responsible for the skin phenotype of their patients, which they describe as an autosomal recessive form of progressive symmetric erythrokeratoderma (1). Ten individuals from a consanguineous Pakistani family were analyzed, including three patients with a skin phenotype. Shah et al. have successfully performed homozygosity mapping, followed by whole exome sequencing (WES), which are adequate methods to identify gene mutations in rare diseases.
First of all, I agree with the comment by Ramot et al from January 12, 2017, which states that it is very unlikely that KRT83, which is only expressed in hair cells, will lead to a skin phenotype.
In addition, the presented clinical pictures of the patients do not show typical signs of progressive symmetrical erythrokeratoderma; however the presented phenotype is compatible with lamellar ichthyosis (autosomal recessive congenital ichthyosis ARCI).
To my great astonishment, the authors themselves mention the correct solution in their publication, but unfortunately they have obviously drawn the wrong conclusion. It is described in the results section that within the homozygous interval on chromosome 12q12-q14, WES showed not only a homozygous KRT83 variant that was classified as pathogenic and causative for the present phenotype in this publication, but also a homozygous frameshift mutation in the gene SDR9C7 (p.Thr122Asnfs).
The first publication that mutations in the SDR9C7 gene lead to autosomal recessive congenital ichthyosis (ARCI) was published in 2017 (2), followed by several others (3,4). Karim et al. then described the same frame shift mutation as Shah et al. (p.Thr122Asnfs) in SDR9C7 in Pakistani patients with autosomal recessive congenital ichthyosis (5).
May be it would be appropriate to write an erratum, or to correct the article under these new aspects.
1. Shah K, Ansar M, Mughal ZU et al. Recessive progressive symmetric erythrokeratoderma results from a homozygous loss-of-function mutation of KRT83 and is allelic with dominant monilethrix. J Med Genet. 2017 Mar;54(3):186-189
2. Shigehara Y, Okuda S, Nemer G et al . Mutations in SDR9C7 gene encoding an enzyme for vitamin A metabolism underlie autosomal recessive congenital ichthyosis. Hum Mol Genet 2016; 25: 4484– 93.
3. Takeichi T, Nomura T, Takama H et al . Deficient stratum corneum intercellular lipid in a Japanese patient with lamellar ichthyosis by a homozygous deletion mutation in SDR9C7 . Br J Dermatol 2017; 177: e62– 4.
4. Hotz A, Fagerberg C, Vahlquist A, Bygum A, Törmä H, Rauschendorf MA, Zhang H, Heinz L, Bourrat E, Hausser I, Vestergaard V, Dragomir A, Zimmer AD, Fischer J. Identification of mutations in SDR9C7 in six families with autosomal recessive congenital ichthyosis. Br J Dermatol. 2018 Mar;178(3):e207-e209.
5. Karim N, Murtaza G, Naeem M. Whole‐exome sequencing identified a novel frameshift mutation in SDR9C7 underlying autosomal recessive congenital ichthyosis in a Pakistani family. Br J Dermatol 2017; 177: e191– 2.
We read with interest the extensive retrospective study on von Hippel-Lindau disease as described by the authors (1) . This original article enlightened us about the age of onset, initial tumour size, concomitant tumours, mutation type and mutation location had an effect on growth rate in VHL-related RCC.It was very interesting to note that these renal tumours larger than 4 cm grew faster than those smaller than 4 cm.
Abdominal masses are frequent in newborn infants, two thirds being renal in origin and occasionally, a renal mass may be malignant and correspond to congenital mesoblastic nephroma, Wilms’ tumor, or fetal hamartoma(2).Birt-Hogg-Dubé (BHD) syndrome is another autosomal dominant genodermatosis characterized by increased risk of renal neoplasia and spontaneous pneumothorax (3) This syndrome is linked to mutations in the FLCN gene, which encodes folliculin and is preferentially expressed in the skin, kidney, and lung (4).In addition,renal epithelial and stromal tumors (REST) is a new concept gathering two benign mixed mesenchymal and epithelial tumors: cystic nephroma and mixed epithelial and stromal tumors [MEST] (5).Since 1998 new entities have surfaced in renal tumor classification and have been included in the WHO 2004 classification e.g new elements in the Bellini carcinoma definition.(6). Renal tumours of genetic origin may often confer diagnostic challenges. Whatever the nature of the renal mass, early intervention may save the kidney or the patient...
We read with interest the extensive retrospective study on von Hippel-Lindau disease as described by the authors (1) . This original article enlightened us about the age of onset, initial tumour size, concomitant tumours, mutation type and mutation location had an effect on growth rate in VHL-related RCC.It was very interesting to note that these renal tumours larger than 4 cm grew faster than those smaller than 4 cm.
Abdominal masses are frequent in newborn infants, two thirds being renal in origin and occasionally, a renal mass may be malignant and correspond to congenital mesoblastic nephroma, Wilms’ tumor, or fetal hamartoma(2).Birt-Hogg-Dubé (BHD) syndrome is another autosomal dominant genodermatosis characterized by increased risk of renal neoplasia and spontaneous pneumothorax (3) This syndrome is linked to mutations in the FLCN gene, which encodes folliculin and is preferentially expressed in the skin, kidney, and lung (4).In addition,renal epithelial and stromal tumors (REST) is a new concept gathering two benign mixed mesenchymal and epithelial tumors: cystic nephroma and mixed epithelial and stromal tumors [MEST] (5).Since 1998 new entities have surfaced in renal tumor classification and have been included in the WHO 2004 classification e.g new elements in the Bellini carcinoma definition.(6). Renal tumours of genetic origin may often confer diagnostic challenges. Whatever the nature of the renal mass, early intervention may save the kidney or the patient.
1.Peng X, Chen J, Wang J, et al Natural history of renal tumours in von Hippel-Lindau disease: a large retrospective study of Chinese patients Journal of Medical Genetics 2019;56:380-387.
2. Pinto E. · Guignard J.-P.Renal Masses in the Neonate.Biol Neonate 1995;68:175–184
(DOI:10.1159/000244235)
3. Pavlovich CP1, Walther MM, Eyler RA, et al.,Renal tumors in the Birt-Hogg-Dubé syndrome.Am J Surg Pathol. 2002 Dec;26(12):1542-52.
4.López V1, Jordá E, Monteagudo C.[Birt-Hogg-Dubé syndrome: an update].[Article in Spanish]Actas Dermosifiliogr. 2012 Apr;103(3):198-206. doi: 10.1016/j.ad.2011.07.009. Epub 2011 Sep 19.
5. Sibony M1, Vieillefond A.[Non clear cell renal cell carcinoma. 2008 update in renal tumor pathology].
[Article in French]Ann Pathol. 2008 Oct;28(5):381-401. doi: 10.1016/j.annpat.2008.07.009. Epub 2008 Oct 17.
6. Compérat EV1, Vasiliu V, Ferlicot S,et al.[Tumors of the kidneys: new entities].[Article in French] Ann Pathol. 2005 Apr;25(2):117-33.
Matias Wagner1,2,3, Dominik S Westphal1,2, Iris Hannibal4, Johannes A. Mayr5, Tim M. Strom1,2, Thomas Meitinger1,2, Holger Prokisch1,2, Saskia B. Wortmann1,2,5
1. Institute of Human Genetics, Technical University Munich, Munich, Germany;
2. Institute of Human Genetics, Helmholtz Zentrum Munich, Neuherberg, Germany;
3. Institute of Neurogenomics, Helmholtz Zentrum Munich, Neuherberg, Germany
4. Dr. von Hauner Children’s Hospital, Ludwig-Maximilians University, Munich, Germany
5. Department of Pediatrics, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), Salzburg, Austria
Biallelic mutations in KIAA0586 have been related to Joubert syndrome (JBTS) 23 and as the most frequent disease causing variant c.428del (p.Arg143Lysfs*4) was identified.1 However, the allele frequency of 0.003117 and two homozygotes in the gnomAD dataset as well as additional reports of healthy carriers have questioned the variant’s pathogenicity.2, 3 Pauli et al. have recently hypothesized that c.428del is a hypomorphic allele which is only causing JBTS in compound heterozygosity with other mutations.
In 15,000 in-house exome data sets, we have identified three individuals harboring c.428del in a homozygous state. In two, we identified other variants sufficiently explaining the phenotype: In a 6 year old girl with global developmental delay and progressive myoclonic astatic epilepsy, we identified a de novo variant c.2683del, p.Ser895Le...
Matias Wagner1,2,3, Dominik S Westphal1,2, Iris Hannibal4, Johannes A. Mayr5, Tim M. Strom1,2, Thomas Meitinger1,2, Holger Prokisch1,2, Saskia B. Wortmann1,2,5
1. Institute of Human Genetics, Technical University Munich, Munich, Germany;
2. Institute of Human Genetics, Helmholtz Zentrum Munich, Neuherberg, Germany;
3. Institute of Neurogenomics, Helmholtz Zentrum Munich, Neuherberg, Germany
4. Dr. von Hauner Children’s Hospital, Ludwig-Maximilians University, Munich, Germany
5. Department of Pediatrics, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), Salzburg, Austria
Biallelic mutations in KIAA0586 have been related to Joubert syndrome (JBTS) 23 and as the most frequent disease causing variant c.428del (p.Arg143Lysfs*4) was identified.1 However, the allele frequency of 0.003117 and two homozygotes in the gnomAD dataset as well as additional reports of healthy carriers have questioned the variant’s pathogenicity.2, 3 Pauli et al. have recently hypothesized that c.428del is a hypomorphic allele which is only causing JBTS in compound heterozygosity with other mutations.
In 15,000 in-house exome data sets, we have identified three individuals harboring c.428del in a homozygous state. In two, we identified other variants sufficiently explaining the phenotype: In a 6 year old girl with global developmental delay and progressive myoclonic astatic epilepsy, we identified a de novo variant c.2683del, p.Ser895Leufs*14 in KIAA2022 (NM_001008537.2, MIM#300912: mental retardation 98). In a 56 year old male patient from a large family with X-linked mental retardation, a hemizygous missense variant in FRMPD4 (NM_014728.3): c.41861G>T, p.Asp621Tyr was identified. In the third case, a 5 year old boy with medically unexplained isolated fatigue we did not identify other variants than c.428del in KIAA0586.
However, in a 3 year old male with global delays, truncal hypotonia, ataxia and eye movement disorders we identified the variant c.428del in compound heterozygosity with c.863_864del, p.Gln288Argfs*7 (NM_014749.3). As the clinical findings resemble the core phenotype of JBTS23, we consider the combination of these variants causal for the patient’s condition.4
Analysis of RNA sequencing data from two heterozygous carriers indicates that mutant transcripts escape nonsense mediated decay. Residual function of the c.428del KIAA0586 allele most likely originates from the use of an alternative start codon (Supplementary figure).
These findings further strengthen the hypothesis of Pauli et al. that c.428del is indeed a hypomorphic allele which is only disease causing in trans with a loss of function mutation.
References
1. Bachmann-Gagescu R, et al. KIAA0586 is Mutated in Joubert Syndrome. Human mutation 36, 831-835 (2015).
2. Pauli S, et al. Homozygosity for the c.428delG variant in KIAA0586 in a healthy individual: implications for molecular testing in patients with Joubert syndrome. Journal of medical genetics, (2018).
3. Sulem P, et al. Identification of a large set of rare complete human knockouts. Nature genetics 47, 448-452 (2015).
4. Bachmann-Gagescu R, et al. Joubert syndrome: a model for untangling recessive disorders with extreme genetic heterogeneity. Journal of medical genetics 52, 514-522 (2015).
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]
Science has been defined as a process of progressive approximation to the truth, so-called “increasing verisimilitude” [1]. The letter of Professor Fischer is illustrative in this regard.
We previously described genetic analyses of a consanguineous Pakistani family diagnosed with “recessive progressive symmetric erythrokeratoderma” by multiple dermatologists. By autozygosity mapping and sequencing, we identified potentially pathogenic frameshift mutations in two genes located within a region of autozygosity on chr12q12-q14.1, SDR9C7 and KRT83, in perfect linkage disequilibrium in this family [2]. At that time we did not consider SDR9C7 a good candidate, and we concluded that the KRT83 frameshift was more likely to be causal.
Our study was carried out in the early autumn of 2015, we wrote our paper in the spring of 2016, a revised version was accepted for publication in autumn, 2016, and our paper was published online in late 2016. Presumably at the same time, Shigehara et al. [3] carried out parallel studies, unambiguously identifying SDR9C7 as the gene for recessive congenital lamellar ichthyosis based on three families with different mutations. Their findings were published at nearly the same time as ours, and were subsequently confirmed by other investigators [4-6]. Obviously, none of this was known at the time of our study.
With the 20:20 clarity of hindsight, it now seems clear that many of the clinical features in our study family are consisten...
Show MoreFascinated to see the comments about irregular heartbeats as an x-linked ichthyosis suffer myself. If you are carrying out further studies I wonder if there is any trend for female carriers having the same. My mother an x-linked ichthyosis carrier has always had an extra hearth beat that causes problems for medical exams and operations. Could it be used as an additional test for expectant mums for potential x-linked babies. A great article and thanks - Jeremy Instone
Dear Mr Instone - Many thanks for your interest in our work and your comment! In our analyses we did look at ICD-10 diagnoses of atrial fibrillation/flutter, and self-reported heart problems in female carriers versus female non-carriers, but didn't see any difference in prevalence between the two groups (results in the Supplementary Data). However, as these are relatively crude measures, we cannot the exclude the possibility that there are actually higher rates of subtle cardiac dysfunction in female carriers relative to non-carriers, and further, more focussed studies might look at this. Regards, Dr William Davies
I recently came across this publication and was very surprised at some facts that seem inconsistent.
Show MoreShah et al. state that homozygous mutations in KRT83 are responsible for the skin phenotype of their patients, which they describe as an autosomal recessive form of progressive symmetric erythrokeratoderma (1). Ten individuals from a consanguineous Pakistani family were analyzed, including three patients with a skin phenotype. Shah et al. have successfully performed homozygosity mapping, followed by whole exome sequencing (WES), which are adequate methods to identify gene mutations in rare diseases.
First of all, I agree with the comment by Ramot et al from January 12, 2017, which states that it is very unlikely that KRT83, which is only expressed in hair cells, will lead to a skin phenotype.
In addition, the presented clinical pictures of the patients do not show typical signs of progressive symmetrical erythrokeratoderma; however the presented phenotype is compatible with lamellar ichthyosis (autosomal recessive congenital ichthyosis ARCI).
To my great astonishment, the authors themselves mention the correct solution in their publication, but unfortunately they have obviously drawn the wrong conclusion. It is described in the results section that within the homozygous interval on chromosome 12q12-q14, WES showed not only a homozygous KRT83 variant that was classified as pathogenic and causative for the present phenotype in this publication, but al...
We read with interest the extensive retrospective study on von Hippel-Lindau disease as described by the authors (1) . This original article enlightened us about the age of onset, initial tumour size, concomitant tumours, mutation type and mutation location had an effect on growth rate in VHL-related RCC.It was very interesting to note that these renal tumours larger than 4 cm grew faster than those smaller than 4 cm.
Show MoreAbdominal masses are frequent in newborn infants, two thirds being renal in origin and occasionally, a renal mass may be malignant and correspond to congenital mesoblastic nephroma, Wilms’ tumor, or fetal hamartoma(2).Birt-Hogg-Dubé (BHD) syndrome is another autosomal dominant genodermatosis characterized by increased risk of renal neoplasia and spontaneous pneumothorax (3) This syndrome is linked to mutations in the FLCN gene, which encodes folliculin and is preferentially expressed in the skin, kidney, and lung (4).In addition,renal epithelial and stromal tumors (REST) is a new concept gathering two benign mixed mesenchymal and epithelial tumors: cystic nephroma and mixed epithelial and stromal tumors [MEST] (5).Since 1998 new entities have surfaced in renal tumor classification and have been included in the WHO 2004 classification e.g new elements in the Bellini carcinoma definition.(6). Renal tumours of genetic origin may often confer diagnostic challenges. Whatever the nature of the renal mass, early intervention may save the kidney or the patient...
Matias Wagner1,2,3, Dominik S Westphal1,2, Iris Hannibal4, Johannes A. Mayr5, Tim M. Strom1,2, Thomas Meitinger1,2, Holger Prokisch1,2, Saskia B. Wortmann1,2,5
1. Institute of Human Genetics, Technical University Munich, Munich, Germany;
2. Institute of Human Genetics, Helmholtz Zentrum Munich, Neuherberg, Germany;
3. Institute of Neurogenomics, Helmholtz Zentrum Munich, Neuherberg, Germany
4. Dr. von Hauner Children’s Hospital, Ludwig-Maximilians University, Munich, Germany
5. Department of Pediatrics, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), Salzburg, Austria
Biallelic mutations in KIAA0586 have been related to Joubert syndrome (JBTS) 23 and as the most frequent disease causing variant c.428del (p.Arg143Lysfs*4) was identified.1 However, the allele frequency of 0.003117 and two homozygotes in the gnomAD dataset as well as additional reports of healthy carriers have questioned the variant’s pathogenicity.2, 3 Pauli et al. have recently hypothesized that c.428del is a hypomorphic allele which is only causing JBTS in compound heterozygosity with other mutations.
In 15,000 in-house exome data sets, we have identified three individuals harboring c.428del in a homozygous state. In two, we identified other variants sufficiently explaining the phenotype: In a 6 year old girl with global developmental delay and progressive myoclonic astatic epilepsy, we identified a de novo variant c.2683del, p.Ser895Le...
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...
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