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.
Dr. Charles Allison,Dr. Taranika Sarkar,
and Prof.Dr.Jogenananda Pramanik
Careers Abroad Institute School of Medicine, Mandeville, Manchester, JM, WI.
We read and applauded the insightful article on clinical presentation of Russell-Silver syndrome with detail molecular diagnostic criteria as presented by Price S M., et al.[1] The low birth weight child who is non-dysmorphic with a prominent forehead and triangular face is more likely to be diagnosed as SRS if they have fifth finger clinodactyly, which in itself is not uncommon.[1] The genetic syndromes which affects growth and intellectual disability have been studied extensively. It has been proved by numerous large scale studies that IUGR is associated with significant neurodevelopmental impairment.
Show MoreFrom a meta analysis conducted by AAP it was concluded that IUGR is associated with lower cognitive scores for school age children. Furthermore children with IUGR born SGA reared in poorer environment demonstrate significant lower professional attainment and income than those reared in more stimulating environment. Here I present a case of
Russell-Silver Syndrome (RSS or SRS) which is a rare, clinically and genetically heterogeneous entity, caused by (epi)genetic alterations. It is characterized by prenatal and postnatal growth retardation, relative macrocephaly, the triangular face and body asymmetry.[ 6] Its incidence varies from 1 in 30,000 to 1 in 1,00,000 people. Individuals with RSS...
In “Genetic obesity: next-generation sequencing results of 1230 patients with obesity'', we presented our obesity gene panel data [1]. In their e-letter, Chèvre et al. question our panel selection because certain genes were omitted. Our gene panel was designed in 2012 after an extensive search in OMIM and other databases. Diagnostic genetic laboratories have to accept that custom diagnostic gene panels have a delay in inclusion of the newest research findings: development and implementation take time and changes require extensive validation against set quality parameters. We acknowledge this limitation in our paper: “Since research in obesity genetics is rapidly progressing, recently identified obesity-associated genes, such as CPE were not included in this panel” [1]. Furthermore, the authors say that we omitted the MRAP2 gene. It is, however, clearly listed as part of the gene panel. We even describe six identified MRAP2 variants in Table S1. Chèvre et al. also criticize the inclusion of insulin receptor genes, since they are not robustly associated with obesity. They were not included as 'obesity causing genes', but as 'comorbidity genes' (Table S2 Sequence variants identified in comorbidity genes) [1]. Diabetes is a serious comorbidity of obesity and knowledge of these mutations is important, especially when aiming for future personalized treatment.
The authors question the validity of how we determine the pathogenicity of identifi...
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...
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