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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK410087/ | 0KKmyzg | Primary Coenzyme Q10 Deficiency | C5244017 | 19 | primary coenzyme q10 deficiency. the CoQ10 deficiency.Children with severe multisystem CoQ10 deficiency generally die within the neonatal period or in the first year of life.The only child reported with COQ9-related coenzyme Q10 deficiency died before age two years of a progressive multisystem disorder .Of note, supplementation with high-dose oral CoQ10 can change the natural history of the disease by blocking progression of the renal disease and preventing the onset of neurologic manifestations in persons with biallelic pathogenic variants in COQ2, COQ6, COQ8B, and PDSS2 .Phenotypes of COQ2-, COQ8A-, and COQ8B-Related Coenzyme Q10 DeficiencyCOQ2. The findings in affected individuals from the ten families described to date differ in severity and age of onset .The main clinical features include SRNS, which can be:Isolated ;Associated with encephalomyopathy or severe multiple-system disease ;Associated with late-onset multiple-system atrophy with retinitis pigmentosa | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK410087/ | 0KKmyzg | Primary Coenzyme Q10 Deficiency | C5244017 | 19 | primary coenzyme q10 deficiency. variants in COQ2, COQ6, COQ8B, and PDSS2 .Phenotypes of COQ2-, COQ8A-, and COQ8B-Related Coenzyme Q10 DeficiencyCOQ2. The findings in affected individuals from the ten families described to date differ in severity and age of onset .The main clinical features include SRNS, which can be:Isolated ;Associated with encephalomyopathy or severe multiple-system disease ;Associated with late-onset multiple-system atrophy with retinitis pigmentosa .COQ8A. Affected individuals experience onset of muscle weakness and reduced exercise tolerance between ages 18 months and three years, followed by cerebellar ataxia (the predominant clinical feature) with severe cerebellar atrophy on MRI. The disease course varies, including both progressive and apparently self-limited ataxia. The ataxia may be:Isolated ;Progressive with cerebellar atrophy in addition to intellectual disability, epilepsy, stroke-like episodes, and/or exercise intolerance .COQ8B. Affected individuals | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK410087/ | 0KKmyzg | Primary Coenzyme Q10 Deficiency | C5244017 | 19 | primary coenzyme q10 deficiency. multiple-system atrophy with retinitis pigmentosa .COQ8A. Affected individuals experience onset of muscle weakness and reduced exercise tolerance between ages 18 months and three years, followed by cerebellar ataxia (the predominant clinical feature) with severe cerebellar atrophy on MRI. The disease course varies, including both progressive and apparently self-limited ataxia. The ataxia may be:Isolated ;Progressive with cerebellar atrophy in addition to intellectual disability, epilepsy, stroke-like episodes, and/or exercise intolerance .COQ8B. Affected individuals generally manifest SRNS in the second decade, and frequently evolve to end-stage renal disease . In addition, four affected individuals were reported with mild intellectual disability, two with occasional seizures, and one with retinitis pigmentosa.Genotype-Phenotype CorrelationsTo date the limited number of affected individuals reported for each related gene complicates the delineation of genotype-phenotype correlations.The factors that determine the clinical variability observed in primary CoQ10 deficiency are unknown. One possibility is that the | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK410087/ | 0KKmyzg | Primary Coenzyme Q10 Deficiency | C5244017 | 19 | primary coenzyme q10 deficiency. intolerance .COQ8B. Affected individuals generally manifest SRNS in the second decade, and frequently evolve to end-stage renal disease . In addition, four affected individuals were reported with mild intellectual disability, two with occasional seizures, and one with retinitis pigmentosa.Genotype-Phenotype CorrelationsTo date the limited number of affected individuals reported for each related gene complicates the delineation of genotype-phenotype correlations.The factors that determine the clinical variability observed in primary CoQ10 deficiency are unknown. One possibility is that the residual activity of the mutated protein modulates the phenotype; however, experimental data to evaluate this hypothesis are lacking.PrevalenceThe estimated overall incidence of primary coenzyme Q10 deficiency is less than 1:100,000; no precise epidemiologic data are available .Differential DiagnosisNote: It is important to consider primary CoQ10 deficiency in individuals with the following diverse presentations because primary CoQ10 deficiency is potentially treatable:Mitochondrial encephalomyopathies. See Mitochondrial Disorders Overview. The clinical manifestations of | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK410087/ | 0KKmyzg | Primary Coenzyme Q10 Deficiency | C5244017 | 19 | primary coenzyme q10 deficiency. are unknown. One possibility is that the residual activity of the mutated protein modulates the phenotype; however, experimental data to evaluate this hypothesis are lacking.PrevalenceThe estimated overall incidence of primary coenzyme Q10 deficiency is less than 1:100,000; no precise epidemiologic data are available .Differential DiagnosisNote: It is important to consider primary CoQ10 deficiency in individuals with the following diverse presentations because primary CoQ10 deficiency is potentially treatable:Mitochondrial encephalomyopathies. See Mitochondrial Disorders Overview. The clinical manifestations of mitochondrial encephalomyopathies and primary coenzyme Q10 deficiency can often be indistinguishable, especially in the severe phenotypes.Steroid-resistant nephrotic syndrome (SRNS) that results from mutation of other genes important for podocyte function (including DGKE, LAMB2, NPHS1, NPHS2, PLCE1, PTPRO, and WT1); clinically indistinguishable from the SRNS resulting from primary CoQ10 deficiency (See WT1 Disorder.)Early onset ataxia. See Hereditary Ataxia Overview. | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK410087/ | 0KKmyzg | Primary Coenzyme Q10 Deficiency | C5244017 | 19 | primary coenzyme q10 deficiency. Mitochondrial Disorders Overview. The clinical manifestations of mitochondrial encephalomyopathies and primary coenzyme Q10 deficiency can often be indistinguishable, especially in the severe phenotypes.Steroid-resistant nephrotic syndrome (SRNS) that results from mutation of other genes important for podocyte function (including DGKE, LAMB2, NPHS1, NPHS2, PLCE1, PTPRO, and WT1); clinically indistinguishable from the SRNS resulting from primary CoQ10 deficiency (See WT1 Disorder.)Early onset ataxia. See Hereditary Ataxia Overview.Muscle disease/myopathySecondary coenzymeQ10 deficiencies. Disorders in which reduction in CoQ10 levels is caused by mutation of genes not directly related to coenzyme Q10 biosynthesis . Molecular genetic testing is the only way to distinguish primary coenzyme Q10 deficiency from secondary coenzyme Q10 deficiencies.ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease and needs in an individual diagnosed with primary coenzyme Q10 deficiency, the following evaluations are recommended:Neurologic evaluation including brain | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK410087/ | 0KKmyzg | Primary Coenzyme Q10 Deficiency | C5244017 | 19 | primary coenzyme q10 deficiency. onset ataxia. See Hereditary Ataxia Overview.Muscle disease/myopathySecondary coenzymeQ10 deficiencies. Disorders in which reduction in CoQ10 levels is caused by mutation of genes not directly related to coenzyme Q10 biosynthesis . Molecular genetic testing is the only way to distinguish primary coenzyme Q10 deficiency from secondary coenzyme Q10 deficiencies.ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease and needs in an individual diagnosed with primary coenzyme Q10 deficiency, the following evaluations are recommended:Neurologic evaluation including brain MRIRenal evaluation with particular attention to the presence of proteinuriaCardiac evaluation including echocardiography with particular attention to possible hypertrophic cardiomyopathyOphthalmologic evaluation with particular attention to possible retinopathy and optic atrophyAudiometry with particular attention to possible sensorineural hearing lossConsultation with a clinical geneticist and/or genetic counselorTreatment of ManifestationsPharmacologic TreatmentCoenzyme Q10 supplementation. Individuals with primary CoQ10 deficiency may respond well to high-dose oral CoQ | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK410087/ | 0KKmyzg | Primary Coenzyme Q10 Deficiency | C5244017 | 19 | primary coenzyme q10 deficiency. evaluations are recommended:Neurologic evaluation including brain MRIRenal evaluation with particular attention to the presence of proteinuriaCardiac evaluation including echocardiography with particular attention to possible hypertrophic cardiomyopathyOphthalmologic evaluation with particular attention to possible retinopathy and optic atrophyAudiometry with particular attention to possible sensorineural hearing lossConsultation with a clinical geneticist and/or genetic counselorTreatment of ManifestationsPharmacologic TreatmentCoenzyme Q10 supplementation. Individuals with primary CoQ10 deficiency may respond well to high-dose oral CoQ10 supplementation (ranging from 5 to 50 mg/kg/day). Soluble formulations are apparently more bioavailable .Treatment should be instituted as early as possible because it can limit disease progression and reverse some manifestations; however, established severe neurologic and/or renal damage cannot be reversed.Individuals with the following genetic causes of primary CoQ10 deficiency apparently respond well to CoQ10 supplementation:COQ4-related coenzyme Q10 deficiency. Neurologic signs responded to CoQ10 supplementation in | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK410087/ | 0KKmyzg | Primary Coenzyme Q10 Deficiency | C5244017 | 19 | primary coenzyme q10 deficiency. respond well to high-dose oral CoQ10 supplementation (ranging from 5 to 50 mg/kg/day). Soluble formulations are apparently more bioavailable .Treatment should be instituted as early as possible because it can limit disease progression and reverse some manifestations; however, established severe neurologic and/or renal damage cannot be reversed.Individuals with the following genetic causes of primary CoQ10 deficiency apparently respond well to CoQ10 supplementation:COQ4-related coenzyme Q10 deficiency. Neurologic signs responded to CoQ10 supplementation in a single individual reported to date with a heterozygous deletion encompassing COQ4 ; no response was observed in patients reported by Chung et al .COQ6-related coenzyme Q10 deficiency. Homozygotes for the pathogenic variants p.Gly255Arg or p.Ala353Asp responded .COQ8B-related coenzyme Q10 deficiency. In a patient homozygous for a truncating pathogenic variant, edema resolved and proteinuria was significantly improved.PDSS2-related coenzyme Q | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK410087/ | 0KKmyzg | Primary Coenzyme Q10 Deficiency | C5244017 | 19 | primary coenzyme q10 deficiency. Neurologic signs responded to CoQ10 supplementation in a single individual reported to date with a heterozygous deletion encompassing COQ4 ; no response was observed in patients reported by Chung et al .COQ6-related coenzyme Q10 deficiency. Homozygotes for the pathogenic variants p.Gly255Arg or p.Ala353Asp responded .COQ8B-related coenzyme Q10 deficiency. In a patient homozygous for a truncating pathogenic variant, edema resolved and proteinuria was significantly improved.PDSS2-related coenzyme Q10 deficiency. The only kindred reported responded .Data for response to CoQ10 supplementation in individuals with mutation of other genes causing primary coenzyme Q10 deficiency are limited or lacking:COQ8A-related coenzyme Q10 deficiency. While most affected individuals respond poorly to CoQ10 supplementation, three individuals had a favorable response: one had objective stabilization of ataxia ; one had a dramatic and long-lasting improvement of dystonia and myoclonus after six months of treatment; and in one | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK410087/ | 0KKmyzg | Primary Coenzyme Q10 Deficiency | C5244017 | 19 | primary coenzyme q10 deficiency. improved.PDSS2-related coenzyme Q10 deficiency. The only kindred reported responded .Data for response to CoQ10 supplementation in individuals with mutation of other genes causing primary coenzyme Q10 deficiency are limited or lacking:COQ8A-related coenzyme Q10 deficiency. While most affected individuals respond poorly to CoQ10 supplementation, three individuals had a favorable response: one had objective stabilization of ataxia ; one had a dramatic and long-lasting improvement of dystonia and myoclonus after six months of treatment; and in one tremor and drawing ability improved .COQ9-related coenzyme Q10 deficiency. One patient with multiple-system disease characterized by intractable seizures, developmental delay, hypertrophic cardiomyopathy, and renal tubular dysfunction did not respond to CoQ10 supplementation; however, this may be due to late diagnosis .Ineffective treatments (or those without validated effects) for individuals with primary coenzyme Q10 deficiency include the following CoQ10 derivatives:Ubiquinol, the reduced form of CoQ10, has recently become | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK410087/ | 0KKmyzg | Primary Coenzyme Q10 Deficiency | C5244017 | 19 | primary coenzyme q10 deficiency. six months of treatment; and in one tremor and drawing ability improved .COQ9-related coenzyme Q10 deficiency. One patient with multiple-system disease characterized by intractable seizures, developmental delay, hypertrophic cardiomyopathy, and renal tubular dysfunction did not respond to CoQ10 supplementation; however, this may be due to late diagnosis .Ineffective treatments (or those without validated effects) for individuals with primary coenzyme Q10 deficiency include the following CoQ10 derivatives:Ubiquinol, the reduced form of CoQ10, has recently become commercially available; however, data on the therapeutic dosage and its efficacy are still lacking.Short chain quinone analogs such as idebenone have been reported to cause clinical deterioration in individuals with CoQ10 deficiency .Renal DiseaseACE inhibitors may be used in combination with CoQ10 supplementation in individuals with proteinuria .Renal transplantation is an option for those with end-stage renal disease .OtherTreatment of hypertrophic cardiomyopathy, retinopathy, and sensorineural hearing loss is routine (see Hypertrophic Cardiomyopathy and | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK410087/ | 0KKmyzg | Primary Coenzyme Q10 Deficiency | C5244017 | 19 | primary coenzyme q10 deficiency. form of CoQ10, has recently become commercially available; however, data on the therapeutic dosage and its efficacy are still lacking.Short chain quinone analogs such as idebenone have been reported to cause clinical deterioration in individuals with CoQ10 deficiency .Renal DiseaseACE inhibitors may be used in combination with CoQ10 supplementation in individuals with proteinuria .Renal transplantation is an option for those with end-stage renal disease .OtherTreatment of hypertrophic cardiomyopathy, retinopathy, and sensorineural hearing loss is routine (see Hypertrophic Cardiomyopathy and Hereditary Hearing Loss and Deafness).Prevention of Primary ManifestationsEarly CoQ10 supplementation may prevent the onset of manifestations of primary CoQ10 deficiency (see Treatment of Manifestations).SurveillanceWhile surveillance depends on the specific genetic defect and on the clinical manifestations (see Table 1), it should always include periodic evaluations of the following: neurologic findings, urine analysis (for proteinuria) and renal function, ophthalmologic findings, and hearing.Note: Because cardiomyopathy to date has been | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK410087/ | 0KKmyzg | Primary Coenzyme Q10 Deficiency | C5244017 | 19 | primary coenzyme q10 deficiency. loss is routine (see Hypertrophic Cardiomyopathy and Hereditary Hearing Loss and Deafness).Prevention of Primary ManifestationsEarly CoQ10 supplementation may prevent the onset of manifestations of primary CoQ10 deficiency (see Treatment of Manifestations).SurveillanceWhile surveillance depends on the specific genetic defect and on the clinical manifestations (see Table 1), it should always include periodic evaluations of the following: neurologic findings, urine analysis (for proteinuria) and renal function, ophthalmologic findings, and hearing.Note: Because cardiomyopathy to date has been found only in the most severe phenotype (i.e., neonatal onset), cardiac evaluation should be performed at the time of diagnosis, but not periodically unless cardiac involvement has been documented.Evaluation of Relatives at RiskGiven the importance of early CoQ10 supplementation, it is appropriate to evaluate the sibs of a proband who has primary coenzyme Q10 deficiency in order to identify as early as possible those sibs who would benefit from early initiation of treatment.If | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK410087/ | 0KKmyzg | Primary Coenzyme Q10 Deficiency | C5244017 | 19 | primary coenzyme q10 deficiency. Note: Because cardiomyopathy to date has been found only in the most severe phenotype (i.e., neonatal onset), cardiac evaluation should be performed at the time of diagnosis, but not periodically unless cardiac involvement has been documented.Evaluation of Relatives at RiskGiven the importance of early CoQ10 supplementation, it is appropriate to evaluate the sibs of a proband who has primary coenzyme Q10 deficiency in order to identify as early as possible those sibs who would benefit from early initiation of treatment.If the pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs.If the pathogenic variants in the family are not known and the diagnosis has been established by biochemical findings, one can consider measuring CoQ10 levels in skin fibroblasts of at-risk sibs .See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov in the US | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK410087/ | 0KKmyzg | Primary Coenzyme Q10 Deficiency | C5244017 | 19 | primary coenzyme q10 deficiency. benefit from early initiation of treatment.If the pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs.If the pathogenic variants in the family are not known and the diagnosis has been established by biochemical findings, one can consider measuring CoQ10 levels in skin fibroblasts of at-risk sibs .See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder. | [
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gard | https://rarediseases.info.nih.gov/diseases/5258/trichohepatoenteric-syndrome | 1LRq39g | Trichohepatoenteric syndrome | C1857276 | 20 | trichohepatoenteric syndrome. Trichohepatoenteric syndrome is a condition that affects the hair, liver, and intestines. The condition is characterized by chronic diarrhea that begins during the first six months after birth. Continued diarrhea can lead to an inability to gain weight (failure to thrive). Trichohepatoenteric syndrome also causes liver disease such as cirrhosis (chronic liver damage) or hepatomegaly (swollen liver). Affected individuals may have wooly or patchy hair. Tirchohepatoenteric syndrome is caused by mutations in TTC37or SKIV2L and is inherited in an autosomal recessive manner. The condition can be diagnosed by clinical examination and confirmed by genetic testing.Treatment options include nutrition through an IV (parenteral nutrition). | [
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orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=84064 | yxk4WDr | Syndromic diarrhea | C1857276 | 21 | syndromic diarrhea. A rare gastroenterologic disease manifesting as intractable diarrhea in the first month of life with failure to thrive and associated with facial dysmorphism, hair abnormalities, and, in some cases, immune disorders and intrauterine growth restriction.
Epidemiology
Syndromic diarrhea (SD/THE) prevalence is <1/1,000,000. More than 100 cases have been reported worldwide.
Clinical description
Severe, persistent and intractable diarrhea most often starts within the first month after birth (at latest 6 months) and is accompanied by severe malabsorption resulting in early and relentless protein-energy malnutrition and failure to thrive. SD children in most reported cases (>70%) were below the 10th percentile of birth weight and nearly half were born preterm suffering from intrauterine growth restriction. Patients present with facial dysmorphism including prominent forehead and cheeks, broad nasal root and hypertelorism. Hair is woolly, easily removable and in some cases sparse and poorly pigmented; further analysis reveals trichorrh | [
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orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=84064 | yxk4WDr | Syndromic diarrhea | C1857276 | 21 | syndromic diarrhea. ) and is accompanied by severe malabsorption resulting in early and relentless protein-energy malnutrition and failure to thrive. SD children in most reported cases (>70%) were below the 10th percentile of birth weight and nearly half were born preterm suffering from intrauterine growth restriction. Patients present with facial dysmorphism including prominent forehead and cheeks, broad nasal root and hypertelorism. Hair is woolly, easily removable and in some cases sparse and poorly pigmented; further analysis reveals trichorrhexis nodosa, pili torti, trichothiodystrophy and aniso- and poikilotrichosis. Liver disease, with extensive fibrosis or cirrhosis and siderosis, affects about half of the patients, and hepatomegaly may be observed. Patients are prone to frequent infections and may fail to produce antibodies upon vaccination or present low immunoglobulin levels. Skin abnormalities including café au lait spots, xerosis and rubbery skin are seen in half of the reported | [
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orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=84064 | yxk4WDr | Syndromic diarrhea | C1857276 | 21 | syndromic diarrhea. further analysis reveals trichorrhexis nodosa, pili torti, trichothiodystrophy and aniso- and poikilotrichosis. Liver disease, with extensive fibrosis or cirrhosis and siderosis, affects about half of the patients, and hepatomegaly may be observed. Patients are prone to frequent infections and may fail to produce antibodies upon vaccination or present low immunoglobulin levels. Skin abnormalities including café au lait spots, xerosis and rubbery skin are seen in half of the reported cases and are more prevalent with time. Cardiac abnormalities have been reported in a few cases and mild intellectual deficiency in half of patients.
Etiology
Autosomal recessive mutations in SKIV2L (40% of cases) and TTC37 (60% of cases) lead to SD/THE. These genes encode proteins that form the Ski complex, a group of proteins responsible for the 3'-5' degradation of aberrant mRNA. Many different mutations have been identified and are spread along | [
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orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=84064 | yxk4WDr | Syndromic diarrhea | C1857276 | 21 | syndromic diarrhea. in half of the reported cases and are more prevalent with time. Cardiac abnormalities have been reported in a few cases and mild intellectual deficiency in half of patients.
Etiology
Autosomal recessive mutations in SKIV2L (40% of cases) and TTC37 (60% of cases) lead to SD/THE. These genes encode proteins that form the Ski complex, a group of proteins responsible for the 3'-5' degradation of aberrant mRNA. Many different mutations have been identified and are spread along the genes. How Ski complex defects lead to the observed phenotype has yet to be elucidated and no genotype/phenotype correlation has been established to date.
Diagnostic methods
Diagnosis is suggested by clinical features. Small intestine biopsy shows non-specific villous atrophy with variable mononuclear cell infiltration of the lamina propria, but no specific histological abnormalities involving the epithelium. Genetic testing confirms these observations.
Differential diagnosis
Differential diagnoses include all causes of chronic diarrhea, copper and iron deficiencies due to malnutrition, intestinal epithelial dysplasia | [
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orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=84064 | yxk4WDr | Syndromic diarrhea | C1857276 | 21 | syndromic diarrhea. identified and are spread along the genes. How Ski complex defects lead to the observed phenotype has yet to be elucidated and no genotype/phenotype correlation has been established to date.
Diagnostic methods
Diagnosis is suggested by clinical features. Small intestine biopsy shows non-specific villous atrophy with variable mononuclear cell infiltration of the lamina propria, but no specific histological abnormalities involving the epithelium. Genetic testing confirms these observations.
Differential diagnosis
Differential diagnoses include all causes of chronic diarrhea, copper and iron deficiencies due to malnutrition, intestinal epithelial dysplasia, and microvillus inclusion disease.
Antenatal diagnosis
Antenatal diagnosis should be offered to the parents of an affected child once the molecular defect has been characterized.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Intractable diarrhea requires parenteral nutrition during a variable period of time ranging from a few months | [
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orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=84064 | yxk4WDr | Syndromic diarrhea | C1857276 | 21 | syndromic diarrhea. malnutrition, intestinal epithelial dysplasia, and microvillus inclusion disease.
Antenatal diagnosis
Antenatal diagnosis should be offered to the parents of an affected child once the molecular defect has been characterized.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Intractable diarrhea requires parenteral nutrition during a variable period of time ranging from a few months to over a decade. In some cases, the association of enteral with parenteral nutrition can be indicated. Immunoglobulin supplementation may be necessary and antibody production after vaccination should be monitored. Finally, some children can present with a severe liver disease, independent of parenteral nutrition, but which could be worsened by it. In cases of severe liver disease, the only therapeutic option is a liver graft.
Prognosis
Prognosis is poor with a mortality rate of up to 50%. The main complications are severe liver | [
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orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=84064 | yxk4WDr | Syndromic diarrhea | C1857276 | 21 | syndromic diarrhea. ranging from a few months to over a decade. In some cases, the association of enteral with parenteral nutrition can be indicated. Immunoglobulin supplementation may be necessary and antibody production after vaccination should be monitored. Finally, some children can present with a severe liver disease, independent of parenteral nutrition, but which could be worsened by it. In cases of severe liver disease, the only therapeutic option is a liver graft.
Prognosis
Prognosis is poor with a mortality rate of up to 50%. The main complications are severe liver disease and infections. Some patients are rapidly weaned off parenteral nutrition but others remain under parenteral dependence for more than 10 years. Most of the children achieve a small final stature and half manifest mild intellectual deficit. | [
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gard | https://rarediseases.info.nih.gov/diseases/9843/primary-familial-and-congenital-polycythemia | gA8kyk4 | Primary familial and congenital polycythemia | C0152264 | 22 | primary familial and congenital polycythemia. Primary familial and congenital polycythemia (PFCP) is an inherited blood disease that causes uncontrolled production of red blood cells (erythrocytes). This leads to an increased volume of red blood cells compared to the total blood volume (erythrocytosis). It may also lead to increased total blood volume or increased blood thickness (hyperviscosity), both of which can cause symptoms. The disease is present at birth, but symptoms (if they develop) may arise any time during childhood or adulthood. Possible symptoms may include headaches, dizziness, fatigue, nosebleeds, difficulty breathing after physical activity, muscle pain, a reddish complexion, and altered mental status. Some people develop blood clots that can block various blood vessels, preventing adequate blood flow (thromboembolic events). Most people have mild symptoms, but some people experience life-threatening complications such as heart attack or stroke. The risk of thrombosis and severe complications increases with age.
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gard | https://rarediseases.info.nih.gov/diseases/9843/primary-familial-and-congenital-polycythemia | gA8kyk4 | Primary familial and congenital polycythemia | C0152264 | 22 | primary familial and congenital polycythemia. ) may arise any time during childhood or adulthood. Possible symptoms may include headaches, dizziness, fatigue, nosebleeds, difficulty breathing after physical activity, muscle pain, a reddish complexion, and altered mental status. Some people develop blood clots that can block various blood vessels, preventing adequate blood flow (thromboembolic events). Most people have mild symptoms, but some people experience life-threatening complications such as heart attack or stroke. The risk of thrombosis and severe complications increases with age.
PFCP is diagnosed by blood tests detecting isolated erythrocytosis and low EPO levels, in the absence of spleen abnormalities and other underlying diseases that can cause erythrocytosis (such as certain blood diseases and blood cancers).
PFCP is inherited in an autosomal dominant manner, but some people with PFCP have no relatives with the disease. In about 12-15% of people with PFCP, it is caused by mutations in the EPOR gene. However | [
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gard | https://rarediseases.info.nih.gov/diseases/9843/primary-familial-and-congenital-polycythemia | gA8kyk4 | Primary familial and congenital polycythemia | C0152264 | 22 | primary familial and congenital polycythemia. of thrombosis and severe complications increases with age.
PFCP is diagnosed by blood tests detecting isolated erythrocytosis and low EPO levels, in the absence of spleen abnormalities and other underlying diseases that can cause erythrocytosis (such as certain blood diseases and blood cancers).
PFCP is inherited in an autosomal dominant manner, but some people with PFCP have no relatives with the disease. In about 12-15% of people with PFCP, it is caused by mutations in the EPOR gene. However in most people, the genetic cause is not yet known.
Most people with PFCP do not need ongoing treatment. Some people with high blood volume need to have blood drawn periodically (phlebotomy) to treat symptoms or to maintain close-to-normal hematocrit levels. Some people with PFCP need medicines to lower blood pressure (antihypertensive therapy). | [
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gard | https://rarediseases.info.nih.gov/diseases/9843/primary-familial-and-congenital-polycythemia | gA8kyk4 | Primary familial and congenital polycythemia | C0152264 | 22 | primary familial and congenital polycythemia. caused by mutations in the EPOR gene. However in most people, the genetic cause is not yet known.
Most people with PFCP do not need ongoing treatment. Some people with high blood volume need to have blood drawn periodically (phlebotomy) to treat symptoms or to maintain close-to-normal hematocrit levels. Some people with PFCP need medicines to lower blood pressure (antihypertensive therapy). | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1878/ | R9XGzLP | Donnai-Barrow Syndrome | C1857277 | 23 | donnai-barrow syndrome. SummaryClinical characteristics.Donnai-Barrow syndrome (DBS) is characterized by typical craniofacial features (large anterior fontanelle, wide metopic suture, widow's peak, markedly widely spaced eyes, enlarged globes, downslanted palpebral fissures, posteriorly rotated ears, depressed nasal bridge, and short nose. Ocular complications include high myopia, retinal detachment, retinal dystrophy, and progressive vision loss. Additional common features include agenesis of the corpus callosum, sensorineural hearing loss, intellectual disability, and congenital diaphragmatic hernia and/or omphalocele. Both inter- and intrafamilial phenotypic variability are observed.Diagnosis/testing.The diagnosis of DBS is established in a proband with: the characteristic clinical features and a distinctive pattern of low-molecular-weight proteinuria; and/or biallelic pathogenic variants in LRP2 identified by molecular genetic testing.Management.Treatment of manifestations: Surgical repair of diaphragmatic hernia and/or | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1878/ | R9XGzLP | Donnai-Barrow Syndrome | C1857277 | 23 | donnai-barrow syndrome. features include agenesis of the corpus callosum, sensorineural hearing loss, intellectual disability, and congenital diaphragmatic hernia and/or omphalocele. Both inter- and intrafamilial phenotypic variability are observed.Diagnosis/testing.The diagnosis of DBS is established in a proband with: the characteristic clinical features and a distinctive pattern of low-molecular-weight proteinuria; and/or biallelic pathogenic variants in LRP2 identified by molecular genetic testing.Management.Treatment of manifestations: Surgical repair of diaphragmatic hernia and/or omphalocele; corrective lenses for myopia; preventive treatments for retinal detachment; hearing aids and/or cochlear implants for hearing loss; antiepileptic drugs for seizures; supplementation as needed for low serum vitamins A and D; education tailored to degree of intellectual, visual, and hearing abilities.Surveillance: Ophthalmologic surveillance to monitor for retinal detachment; serial audiologic examinations; serial measurement of renal function including blood urea nitrogen and serum creatinine concentrations, urinalysis, | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1878/ | R9XGzLP | Donnai-Barrow Syndrome | C1857277 | 23 | donnai-barrow syndrome. manifestations: Surgical repair of diaphragmatic hernia and/or omphalocele; corrective lenses for myopia; preventive treatments for retinal detachment; hearing aids and/or cochlear implants for hearing loss; antiepileptic drugs for seizures; supplementation as needed for low serum vitamins A and D; education tailored to degree of intellectual, visual, and hearing abilities.Surveillance: Ophthalmologic surveillance to monitor for retinal detachment; serial audiologic examinations; serial measurement of renal function including blood urea nitrogen and serum creatinine concentrations, urinalysis, and serum vitamin A and D; monitor developmental progress and educational needs.Genetic counseling.DBS is inherited in an autosomal recessive manner. In general, the parents of an affected child are obligate heterozygotes with each carrying one pathogenic variant; one instance of uniparental disomy has been reported. When both parents are known to be carriers of a pathogenic variant, each sib of an affected individual has a 25% chance of being affected, a 50% chance | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1878/ | R9XGzLP | Donnai-Barrow Syndrome | C1857277 | 23 | donnai-barrow syndrome. nitrogen and serum creatinine concentrations, urinalysis, and serum vitamin A and D; monitor developmental progress and educational needs.Genetic counseling.DBS is inherited in an autosomal recessive manner. In general, the parents of an affected child are obligate heterozygotes with each carrying one pathogenic variant; one instance of uniparental disomy has been reported. When both parents are known to be carriers of a pathogenic variant, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. If the pathogenic variants in the family are known, carrier testing for at-risk relatives and prenatal testing of pregnancies at increased risk are possible.DiagnosisSuggestive FindingsDonnai-Barrow syndrome (DBS) should be suspected in individuals with the following clinical and radiographic features. No single clinical feature is pathognomonic for DBS, nor have diagnostic | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1878/ | R9XGzLP | Donnai-Barrow Syndrome | C1857277 | 23 | donnai-barrow syndrome. % chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. If the pathogenic variants in the family are known, carrier testing for at-risk relatives and prenatal testing of pregnancies at increased risk are possible.DiagnosisSuggestive FindingsDonnai-Barrow syndrome (DBS) should be suspected in individuals with the following clinical and radiographic features. No single clinical feature is pathognomonic for DBS, nor have diagnostic criteria been formalized.Clinical featuresCharacteristic facial features (see Figure 1):Large anterior fontanelle in infants and young childrenWide metopic suture in infants and young childrenWidow's peakWidely spaced eyes, typically markedEnlarged globes leading to the appearance of prominent eyesDownslanted palpebral fissuresPosteriorly rotated earsDepressed nasal bridgeShort nose with broad or | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1878/ | R9XGzLP | Donnai-Barrow Syndrome | C1857277 | 23 | donnai-barrow syndrome. pathognomonic for DBS, nor have diagnostic criteria been formalized.Clinical featuresCharacteristic facial features (see Figure 1):Large anterior fontanelle in infants and young childrenWide metopic suture in infants and young childrenWidow's peakWidely spaced eyes, typically markedEnlarged globes leading to the appearance of prominent eyesDownslanted palpebral fissuresPosteriorly rotated earsDepressed nasal bridgeShort nose with broad or bifid tipOphthalmologic abnormalities. High myopia (-6 diopters or worse), retinal detachment (30%), retinal dystrophy and optic nerve hypoplasia, progressive visual loss, iris coloboma or iris hypoplasia in some individualsSensorineural hearing loss. Onset in infancy or childhood (100%)Developmental delay. Almost always presentOmphalocele (or umbilical hernia) (~40%)Diaphragmatic hernia (or eventration) | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1878/ | R9XGzLP | Donnai-Barrow Syndrome | C1857277 | 23 | donnai-barrow syndrome. Depressed nasal bridgeShort nose with broad or bifid tipOphthalmologic abnormalities. High myopia (-6 diopters or worse), retinal detachment (30%), retinal dystrophy and optic nerve hypoplasia, progressive visual loss, iris coloboma or iris hypoplasia in some individualsSensorineural hearing loss. Onset in infancy or childhood (100%)Developmental delay. Almost always presentOmphalocele (or umbilical hernia) (~40%)Diaphragmatic hernia (or eventration) (~40%)Figure 1. Facial characteristics over time in the same male with Donnai-Barrow syndrome A. At age six months; broad forehead, markedly widely spaced eyes, left iris coloboma, and short noseRadiographic features. Agenesis of corpus callosum (complete or partial)Establishing the DiagnosisThe diagnosis of Donnai-Barrow syndrome (DBS) is established in a proband with the characteristic clinical features and a distinctive | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1878/ | R9XGzLP | Donnai-Barrow Syndrome | C1857277 | 23 | donnai-barrow syndrome. %)Diaphragmatic hernia (or eventration) (~40%)Figure 1. Facial characteristics over time in the same male with Donnai-Barrow syndrome A. At age six months; broad forehead, markedly widely spaced eyes, left iris coloboma, and short noseRadiographic features. Agenesis of corpus callosum (complete or partial)Establishing the DiagnosisThe diagnosis of Donnai-Barrow syndrome (DBS) is established in a proband with the characteristic clinical features and a distinctive pattern of low-molecular-weight proteinuria and/or biallelic pathogenic variants in LRP2 identified by molecular genetic testing (see Table 1).Biochemical TestingAbsent or abnormally functioning megalin, the protein encoded by LRP2, prevents normal renal proximal tubule reuptake of megalin ligands, resulting in excess spillage of proteins with low molecular weight in the urine in 100% of individuals with DBS. Among proteins identified by urinary protein electrophoresis* are: | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1878/ | R9XGzLP | Donnai-Barrow Syndrome | C1857277 | 23 | donnai-barrow syndrome. a proband with the characteristic clinical features and a distinctive pattern of low-molecular-weight proteinuria and/or biallelic pathogenic variants in LRP2 identified by molecular genetic testing (see Table 1).Biochemical TestingAbsent or abnormally functioning megalin, the protein encoded by LRP2, prevents normal renal proximal tubule reuptake of megalin ligands, resulting in excess spillage of proteins with low molecular weight in the urine in 100% of individuals with DBS. Among proteins identified by urinary protein electrophoresis* are:Retinol-binding protein (RBP)Vitamin D-binding protein (VDBP)*Note: The use of a "dipstick" is not an adequate substitute to protein electrophoresis to identify megalin ligands in the urine of individuals with DBS.Molecular Genetic TestingMolecular genetic testing approaches can include gene-targeted testing (single-gene testing, multigene panel) and comprehensive
genomic testing (exome sequencing, genome sequencing) depending on the phenotype | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1878/ | R9XGzLP | Donnai-Barrow Syndrome | C1857277 | 23 | donnai-barrow syndrome. Among proteins identified by urinary protein electrophoresis* are:Retinol-binding protein (RBP)Vitamin D-binding protein (VDBP)*Note: The use of a "dipstick" is not an adequate substitute to protein electrophoresis to identify megalin ligands in the urine of individuals with DBS.Molecular Genetic TestingMolecular genetic testing approaches can include gene-targeted testing (single-gene testing, multigene panel) and comprehensive
genomic testing (exome sequencing, genome sequencing) depending on the phenotype.Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of DBS has not been considered are more likely to be diagnosed using genomic testing (see Option 2).Option 1When the phenotypic and laboratory findings suggest the diagnosis of | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1878/ | R9XGzLP | Donnai-Barrow Syndrome | C1857277 | 23 | donnai-barrow syndrome. exome sequencing, genome sequencing) depending on the phenotype.Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of DBS has not been considered are more likely to be diagnosed using genomic testing (see Option 2).Option 1When the phenotypic and laboratory findings suggest the diagnosis of DBS, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:Single-gene testing. Sequence analysis of LRP2 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If only one or no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1878/ | R9XGzLP | Donnai-Barrow Syndrome | C1857277 | 23 | donnai-barrow syndrome. en the phenotypic and laboratory findings suggest the diagnosis of DBS, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:Single-gene testing. Sequence analysis of LRP2 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If only one or no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.Note: As LRP2 is among the longest genes in the human genome and contains several private benign variants, extreme caution must be used in interpreting sequence changes. The use of an interpretative framework (e.g., the published guidelines from the American College of Medical Genetics and Genomics and the Association for Molecular Pathology) is recommended .A multigene panel that includes LRP2 and other genes of interest (see Differential Diagnosis) may be considered. | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1878/ | R9XGzLP | Donnai-Barrow Syndrome | C1857277 | 23 | donnai-barrow syndrome. deletion/duplication analysis to detect intragenic deletions or duplications.Note: As LRP2 is among the longest genes in the human genome and contains several private benign variants, extreme caution must be used in interpreting sequence changes. The use of an interpretative framework (e.g., the published guidelines from the American College of Medical Genetics and Genomics and the Association for Molecular Pathology) is recommended .A multigene panel that includes LRP2 and other genes of interest (see Differential Diagnosis) may be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1878/ | R9XGzLP | Donnai-Barrow Syndrome | C1857277 | 23 | donnai-barrow syndrome. interest (see Differential Diagnosis) may be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.For an introduction to multigene panels click here. More detailed information for | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1878/ | R9XGzLP | Donnai-Barrow Syndrome | C1857277 | 23 | donnai-barrow syndrome. reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.Option 2When the diagnosis of DBS is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene are likely involved) is the best option. Exome sequencing is the most commonly used genomic testing method; genome sequencing is also possible.For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1878/ | R9XGzLP | Donnai-Barrow Syndrome | C1857277 | 23 | donnai-barrow syndrome. multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.Option 2When the diagnosis of DBS is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene are likely involved) is the best option. Exome sequencing is the most commonly used genomic testing method; genome sequencing is also possible.For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.Table 1. Molecular Genetic Testing Used in Donnai-Barrow SyndromeView in own windowGene 1MethodProportion of Pathogenic Variants 2 Detectable by MethodLRP2Sequence analysis 317/17 families 4, 5Gene-targeted deletion/duplication analysis 6None reported1. See Table A. Genes and Databases for chromosome locus and protein.2. See Molecular Genetics for information on allelic variants detected in this gene.3. | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1878/ | R9XGzLP | Donnai-Barrow Syndrome | C1857277 | 23 | donnai-barrow syndrome. information for clinicians ordering genomic testing can be found here.Table 1. Molecular Genetic Testing Used in Donnai-Barrow SyndromeView in own windowGene 1MethodProportion of Pathogenic Variants 2 Detectable by MethodLRP2Sequence analysis 317/17 families 4, 5Gene-targeted deletion/duplication analysis 6None reported1. See Table A. Genes and Databases for chromosome locus and protein.2. See Molecular Genetics for information on allelic variants detected in this gene.3. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.4. Kantarci et al , Kantarci et al , Stora et al , | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1878/ | R9XGzLP | Donnai-Barrow Syndrome | C1857277 | 23 | donnai-barrow syndrome. on allelic variants detected in this gene.3. Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.4. Kantarci et al , Kantarci et al , Stora et al , Shaheen et al , Storm et al , Schrauwen et al , Dachy et al , Khalifa et al , Anglani et al .5. One affected individual was homozygous for an LRP2 pathogenic variant resulting from paternal isodisomy of chromosome 2 (see Molecular Genetics) .6. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1878/ | R9XGzLP | Donnai-Barrow Syndrome | C1857277 | 23 | donnai-barrow syndrome. rci et al , Stora et al , Shaheen et al , Storm et al , Schrauwen et al , Dachy et al , Khalifa et al , Anglani et al .5. One affected individual was homozygous for an LRP2 pathogenic variant resulting from paternal isodisomy of chromosome 2 (see Molecular Genetics) .6. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.Clinical CharacteristicsClinical DescriptionThe following information is based on case reports reviewed in Patel et al , Pober et al , Shaheen et al , Roane et al , Storm et al , Dachy et al , Anglani et al , and Khan & Ghazi . | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1878/ | R9XGzLP | Donnai-Barrow Syndrome | C1857277 | 23 | donnai-barrow syndrome. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.Clinical CharacteristicsClinical DescriptionThe following information is based on case reports reviewed in Patel et al , Pober et al , Shaheen et al , Roane et al , Storm et al , Dachy et al , Anglani et al , and Khan & Ghazi .Craniofacial features.Widely spaced eyes, depressed nasal bridge, short nose with a broad and occasionally indented tip, broad forehead, and prominent parietal frontal bossing are characteristic findings and are consistently present in individuals with DBS and confirmed biallelic LRP2 pathogenic variants. Downslanted palpebral fissures and low-set posteriorly angulated ears are very frequent findings. While some of these features may change over time, the facial gest | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1878/ | R9XGzLP | Donnai-Barrow Syndrome | C1857277 | 23 | donnai-barrow syndrome. and Khan & Ghazi .Craniofacial features.Widely spaced eyes, depressed nasal bridge, short nose with a broad and occasionally indented tip, broad forehead, and prominent parietal frontal bossing are characteristic findings and are consistently present in individuals with DBS and confirmed biallelic LRP2 pathogenic variants. Downslanted palpebral fissures and low-set posteriorly angulated ears are very frequent findings. While some of these features may change over time, the facial gestalt remains characteristic in the few reported adults.Ophthalmologic abnormalities. Progressive visual loss resulting in legal blindness is common and seemingly the result of severe myopia and an attendant risk for retinal detachment, although prompt treatment can improve the chances of useful vision. Retinal detachment can be unilateral or bilateral, complete or partial, and can occur in young children. Prophylactic treatment with peripheral barrier photocoagulation to prevent retinal detachment has been successful in several individuals. Progressive retinal dystrophy has | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1878/ | R9XGzLP | Donnai-Barrow Syndrome | C1857277 | 23 | donnai-barrow syndrome. these features may change over time, the facial gestalt remains characteristic in the few reported adults.Ophthalmologic abnormalities. Progressive visual loss resulting in legal blindness is common and seemingly the result of severe myopia and an attendant risk for retinal detachment, although prompt treatment can improve the chances of useful vision. Retinal detachment can be unilateral or bilateral, complete or partial, and can occur in young children. Prophylactic treatment with peripheral barrier photocoagulation to prevent retinal detachment has been successful in several individuals. Progressive retinal dystrophy has been observed in a few individuals; the exact nature and rate of progression of the retinal dystrophy remain to be determined. Optic nerve hypoplasia has been reported in at least one individual. The combination of a small and recessed optic nerve head, surrounded by multiple rings of abnormal pigmentation masking the neuroretinal rim, and the presence of multiple thin vessels emanating from the optic disk was proposed as a characteristic finding on fundoscopy. Iris coloboma, frequently | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1878/ | R9XGzLP | Donnai-Barrow Syndrome | C1857277 | 23 | donnai-barrow syndrome. been successful in several individuals. Progressive retinal dystrophy has been observed in a few individuals; the exact nature and rate of progression of the retinal dystrophy remain to be determined. Optic nerve hypoplasia has been reported in at least one individual. The combination of a small and recessed optic nerve head, surrounded by multiple rings of abnormal pigmentation masking the neuroretinal rim, and the presence of multiple thin vessels emanating from the optic disk was proposed as a characteristic finding on fundoscopy. Iris coloboma, frequently bilateral or affecting the right eye, is common and often present alongside hypoplastic iris stroma. Glaucoma and cataracts have only rarely been reportedSensorineural hearing loss. Profound bilateral sensorineural hearing loss is frequently acquired and diagnosed in early childhood. Despite a relative paucity of data, it appears that hearing can deteriorate over time, but not every individual progresses to complete loss. Some individuals have useful hearing using hearing aids and seven reported individuals have successfully received cochlear implants | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1878/ | R9XGzLP | Donnai-Barrow Syndrome | C1857277 | 23 | donnai-barrow syndrome. on fundoscopy. Iris coloboma, frequently bilateral or affecting the right eye, is common and often present alongside hypoplastic iris stroma. Glaucoma and cataracts have only rarely been reportedSensorineural hearing loss. Profound bilateral sensorineural hearing loss is frequently acquired and diagnosed in early childhood. Despite a relative paucity of data, it appears that hearing can deteriorate over time, but not every individual progresses to complete loss. Some individuals have useful hearing using hearing aids and seven reported individuals have successfully received cochlear implants (see Deafness and Hereditary Hearing Loss Overview for definitions).Renal disease. The majority of individuals with DBS present with asymptomatic low-molecular weight proteinuria (LMWP). In the adult kidney, megalin is highly expressed in proximal tubules where it plays a key role in the reuptake of several proteins by receptor-mediated endocytosis. The characteristic urinary protein profile can be detected by Coomassie staining of a random urine sample. Increased excretion of vitamin D | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1878/ | R9XGzLP | Donnai-Barrow Syndrome | C1857277 | 23 | donnai-barrow syndrome. aids and seven reported individuals have successfully received cochlear implants (see Deafness and Hereditary Hearing Loss Overview for definitions).Renal disease. The majority of individuals with DBS present with asymptomatic low-molecular weight proteinuria (LMWP). In the adult kidney, megalin is highly expressed in proximal tubules where it plays a key role in the reuptake of several proteins by receptor-mediated endocytosis. The characteristic urinary protein profile can be detected by Coomassie staining of a random urine sample. Increased excretion of vitamin D-binding protein (VDBP) and retinol-binding protein (RBP) are consistent with the presence of DBS and may lead to hypovitaminoses in some individuals. Urinary loss of VDBP and RBP, however, are not specific to DBS and may be present in individuals with tubular dysfunction. Urinary cubilin and its ligands are detectable in urine samples of individuals with DBS. Hypercalciuria, nephrocalcinosis, nephrolithiasis, and focal segmental glomerulosclerosis | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1878/ | R9XGzLP | Donnai-Barrow Syndrome | C1857277 | 23 | donnai-barrow syndrome. a random urine sample. Increased excretion of vitamin D-binding protein (VDBP) and retinol-binding protein (RBP) are consistent with the presence of DBS and may lead to hypovitaminoses in some individuals. Urinary loss of VDBP and RBP, however, are not specific to DBS and may be present in individuals with tubular dysfunction. Urinary cubilin and its ligands are detectable in urine samples of individuals with DBS. Hypercalciuria, nephrocalcinosis, nephrolithiasis, and focal segmental glomerulosclerosis have been reported. Progression to nephropathy and end-stage renal disease is a rare but life-threatening complication, especially in adults, and urinary function should be monitored in individuals with DBS. One of the first reported individuals died of renal failure at age 30 years. No renal phenotype has been convincingly documented in individuals with a heterozygous LRP2 pathogenic variant.Developmental delay, intellectual disability, and behavioral features. Motor milestones are only slightly delayed and most children | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1878/ | R9XGzLP | Donnai-Barrow Syndrome | C1857277 | 23 | donnai-barrow syndrome. osis, nephrolithiasis, and focal segmental glomerulosclerosis have been reported. Progression to nephropathy and end-stage renal disease is a rare but life-threatening complication, especially in adults, and urinary function should be monitored in individuals with DBS. One of the first reported individuals died of renal failure at age 30 years. No renal phenotype has been convincingly documented in individuals with a heterozygous LRP2 pathogenic variant.Developmental delay, intellectual disability, and behavioral features. Motor milestones are only slightly delayed and most children become continent. No systematic studies of intellectual functioning exist, but available data suggest that all individuals with DBS have intellectual disabilities of varying degrees ranging from mild to moderate. Formal assessment is difficult because of the severe vision and hearing deficits. Roane at al described a child age five years engaging in self-injurious behavior that was responsive to behavioral therapy; however, self-injurious behavior is not typically observed in individuals with DBS. Teenagers and young adults attend | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1878/ | R9XGzLP | Donnai-Barrow Syndrome | C1857277 | 23 | donnai-barrow syndrome. Motor milestones are only slightly delayed and most children become continent. No systematic studies of intellectual functioning exist, but available data suggest that all individuals with DBS have intellectual disabilities of varying degrees ranging from mild to moderate. Formal assessment is difficult because of the severe vision and hearing deficits. Roane at al described a child age five years engaging in self-injurious behavior that was responsive to behavioral therapy; however, self-injurious behavior is not typically observed in individuals with DBS. Teenagers and young adults attend school with special provisions for hearing and vision problems. Some communicate using sign language, and can perform routine tasks and retain a variable degree of independence. An adult individual reportedly suffered from psychosis since childhood. Mood swings and depressive symptoms in this individual were compatible with her diagnosis of schizoaffective disorder. Overall, interactions with her were described as pleasant. She did not exhibit deterioration of cognitive or functional abilities beyond what was caused by her co- | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1878/ | R9XGzLP | Donnai-Barrow Syndrome | C1857277 | 23 | donnai-barrow syndrome. in individuals with DBS. Teenagers and young adults attend school with special provisions for hearing and vision problems. Some communicate using sign language, and can perform routine tasks and retain a variable degree of independence. An adult individual reportedly suffered from psychosis since childhood. Mood swings and depressive symptoms in this individual were compatible with her diagnosis of schizoaffective disorder. Overall, interactions with her were described as pleasant. She did not exhibit deterioration of cognitive or functional abilities beyond what was caused by her co-occurring psychiatric disorder but she did not live independently.Diaphragmatic hernia (or eventration) and/or omphalocele (or umbilical hernia) are each reported in approximately 40% of affected individuals. The two defects infrequently occur together . The absence of either or both does not exclude the diagnosis.Seizures. A few individuals have developed tonic-clonic seizures in childhood or adolescence. In one individual, the first episode of seizures developed into status epilepticus leading | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1878/ | R9XGzLP | Donnai-Barrow Syndrome | C1857277 | 23 | donnai-barrow syndrome. functional abilities beyond what was caused by her co-occurring psychiatric disorder but she did not live independently.Diaphragmatic hernia (or eventration) and/or omphalocele (or umbilical hernia) are each reported in approximately 40% of affected individuals. The two defects infrequently occur together . The absence of either or both does not exclude the diagnosis.Seizures. A few individuals have developed tonic-clonic seizures in childhood or adolescence. In one individual, the first episode of seizures developed into status epilepticus leading to her demise. No single antiepileptic drug has been demonstrated to be the treatment of choice specifically for this disorder, and therapy should follow standard guidelines.Growth. Relatively high birth weight (~4 kg) has been recorded in several infants. Macrocephaly is present in many individuals with DBS and it is often apparent at birth. Height and weight eventually appear to be within the normal range but a few of the older children are tall, with heights on | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1878/ | R9XGzLP | Donnai-Barrow Syndrome | C1857277 | 23 | donnai-barrow syndrome. the first episode of seizures developed into status epilepticus leading to her demise. No single antiepileptic drug has been demonstrated to be the treatment of choice specifically for this disorder, and therapy should follow standard guidelines.Growth. Relatively high birth weight (~4 kg) has been recorded in several infants. Macrocephaly is present in many individuals with DBS and it is often apparent at birth. Height and weight eventually appear to be within the normal range but a few of the older children are tall, with heights on the 90th centile.Neuroimaging. Agenesis of corpus callosum, either complete or partial, is reported in most individuals with DBS (see Figure 2). The presence of additional brain anomalies, such as periventricular nodular heterotopia and abnormalities of gyral patterns, is increasingly appreciated.Figure 2. MRI in a female age three years demonstrates numerous abnormalities including hypogenesis of the corpus callosum (most notably involving the rostrum and splenium) ( | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1878/ | R9XGzLP | Donnai-Barrow Syndrome | C1857277 | 23 | donnai-barrow syndrome. of the older children are tall, with heights on the 90th centile.Neuroimaging. Agenesis of corpus callosum, either complete or partial, is reported in most individuals with DBS (see Figure 2). The presence of additional brain anomalies, such as periventricular nodular heterotopia and abnormalities of gyral patterns, is increasingly appreciated.Figure 2. MRI in a female age three years demonstrates numerous abnormalities including hypogenesis of the corpus callosum (most notably involving the rostrum and splenium) (long white arrow), partially empty sella turcica (S), and small pons (P). Other. Involvement of other organ systems (e.g., ventriculoseptal defect, bicornuate uterus) has been reported but is rare. Pubertal development occurs at the appropriate times.Prognosis. Information on long-term follow up and natural history of DBS is limited to a few individuals because many affected pregnancies are interrupted or | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1878/ | R9XGzLP | Donnai-Barrow Syndrome | C1857277 | 23 | donnai-barrow syndrome. notably involving the rostrum and splenium) (long white arrow), partially empty sella turcica (S), and small pons (P). Other. Involvement of other organ systems (e.g., ventriculoseptal defect, bicornuate uterus) has been reported but is rare. Pubertal development occurs at the appropriate times.Prognosis. Information on long-term follow up and natural history of DBS is limited to a few individuals because many affected pregnancies are interrupted or result in perinatal death secondary to congenital malformations. Major risks are due to complications of retinal detachment leading to visual loss in individuals already compromised by hearing defects, and progression of renal dysfunction. Only two adults older than age 50 years with molecularly confirmed LRP2 pathogenic variants have been reported .The most notable health concern is deteriorating renal function, resulting in renal transplantation in one individual and renal rickets in the other.Genotype-Phenotype CorrelationsNo genotype-phenotype correlations | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1878/ | R9XGzLP | Donnai-Barrow Syndrome | C1857277 | 23 | donnai-barrow syndrome. a few individuals because many affected pregnancies are interrupted or result in perinatal death secondary to congenital malformations. Major risks are due to complications of retinal detachment leading to visual loss in individuals already compromised by hearing defects, and progression of renal dysfunction. Only two adults older than age 50 years with molecularly confirmed LRP2 pathogenic variants have been reported .The most notable health concern is deteriorating renal function, resulting in renal transplantation in one individual and renal rickets in the other.Genotype-Phenotype CorrelationsNo genotype-phenotype correlations are known.NomenclatureDonnai-Barrow syndrome (DBS) and faciooculoacousticorenal (FOAR) syndrome were reported as two distinct entities, although overlapping clinical features were appreciated . It is now known that these syndromes represent the same clinical entity and are caused by pathogenic variants in LRP2 .The following terms should no longer be used when referring to DBS:Syndrome of ocular and facial anomalies, telecanthus, and deafnessHolmes | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1878/ | R9XGzLP | Donnai-Barrow Syndrome | C1857277 | 23 | donnai-barrow syndrome. .Genotype-Phenotype CorrelationsNo genotype-phenotype correlations are known.NomenclatureDonnai-Barrow syndrome (DBS) and faciooculoacousticorenal (FOAR) syndrome were reported as two distinct entities, although overlapping clinical features were appreciated . It is now known that these syndromes represent the same clinical entity and are caused by pathogenic variants in LRP2 .The following terms should no longer be used when referring to DBS:Syndrome of ocular and facial anomalies, telecanthus, and deafnessHolmes-Schepens syndromeDiaphragmatic hernia-exomphalos-hypertelorism syndromeDiaphragmatic hernia-hypertelorism-myopia-deafness syndromePrevalenceNo population-based incidence or prevalence data are available. Only 49 individuals with sufficient clinical and/or molecular data to establish the diagnosis of DBS have been reported in the medical literature. Many of these individuals are members of a few large consanguineous families. | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1878/ | R9XGzLP | Donnai-Barrow Syndrome | C1857277 | 23 | donnai-barrow syndrome. facial anomalies, telecanthus, and deafnessHolmes-Schepens syndromeDiaphragmatic hernia-exomphalos-hypertelorism syndromeDiaphragmatic hernia-hypertelorism-myopia-deafness syndromePrevalenceNo population-based incidence or prevalence data are available. Only 49 individuals with sufficient clinical and/or molecular data to establish the diagnosis of DBS have been reported in the medical literature. Many of these individuals are members of a few large consanguineous families.DBS has been reported in different ethnic groups, including northern and central European, Middle Eastern, American of European origin, and African American. No one ethnic group predominates.Differential DiagnosisDonnai-Barrow syndrome (DBS) is associated with congenital diaphragmatic hernia (CDH) (see Congenital Diaphragmatic Hernia Overview).Table 2. Disorders to Consider in the Differential Diagnosis of Donnai-Barrow SyndromeView in own windowDifferential Diagnosis Disorder | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1878/ | R9XGzLP | Donnai-Barrow Syndrome | C1857277 | 23 | donnai-barrow syndrome. members of a few large consanguineous families.DBS has been reported in different ethnic groups, including northern and central European, Middle Eastern, American of European origin, and African American. No one ethnic group predominates.Differential DiagnosisDonnai-Barrow syndrome (DBS) is associated with congenital diaphragmatic hernia (CDH) (see Congenital Diaphragmatic Hernia Overview).Table 2. Disorders to Consider in the Differential Diagnosis of Donnai-Barrow SyndromeView in own windowDifferential Diagnosis DisorderGene(s)MOIClinical Features of This DisorderOverlapping w/DBSDistinguishing from DBSPallister-Killian syndrome (12p tetrasomy mosaicism) (OMIM 601803)N/ASporadicDiaphragmatic herniaRelatively high birth weightWidely spaced eyes
Marked hypotoniaMore severe DD in someSkin w/hypo- & hyperpigmented streaksCoarse facial featuresSparse | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1878/ | R9XGzLP | Donnai-Barrow Syndrome | C1857277 | 23 | donnai-barrow syndrome. SyndromeView in own windowDifferential Diagnosis DisorderGene(s)MOIClinical Features of This DisorderOverlapping w/DBSDistinguishing from DBSPallister-Killian syndrome (12p tetrasomy mosaicism) (OMIM 601803)N/ASporadicDiaphragmatic herniaRelatively high birth weightWidely spaced eyes
Marked hypotoniaMore severe DD in someSkin w/hypo- & hyperpigmented streaksCoarse facial featuresSparse hair
Fryns syndromeUnknownARDiaphragmatic defectsOccasionally agenesis of corpus callosumWidely spaced eyes
Abnormal fingers & toes: brachytelephalangy &/or underdeveloped nailsCharacteristic craniofacial dysmorphismsOrofacial cleftingPolyhydramnios
Chudley-McCullough syndrome (OMIM 604213)GPSM2ARSensorineural hearing loss | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1878/ | R9XGzLP | Donnai-Barrow Syndrome | C1857277 | 23 | donnai-barrow syndrome. igmented streaksCoarse facial featuresSparse hair
Fryns syndromeUnknownARDiaphragmatic defectsOccasionally agenesis of corpus callosumWidely spaced eyes
Abnormal fingers & toes: brachytelephalangy &/or underdeveloped nailsCharacteristic craniofacial dysmorphismsOrofacial cleftingPolyhydramnios
Chudley-McCullough syndrome (OMIM 604213)GPSM2ARSensorineural hearing lossPartial agenesis of corpus callosum
Hydrocephalus &/or ventriculomegalyCortical dysplasia &/or subcortical gray matter heterotopiaUsually normal psychomotor development
Acrocallosal syndrome (OMIM 200990)KIF7ARWidely spaced eyesAbsence of corpus callosumMacrocephalyLarge anterior fontanelle
Preaxial or postaxial polydactyly, occasionally syndactylyDent disease 1, Dent disease 2 1, Low | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1878/ | R9XGzLP | Donnai-Barrow Syndrome | C1857277 | 23 | donnai-barrow syndrome. )GPSM2ARSensorineural hearing lossPartial agenesis of corpus callosum
Hydrocephalus &/or ventriculomegalyCortical dysplasia &/or subcortical gray matter heterotopiaUsually normal psychomotor development
Acrocallosal syndrome (OMIM 200990)KIF7ARWidely spaced eyesAbsence of corpus callosumMacrocephalyLarge anterior fontanelle
Preaxial or postaxial polydactyly, occasionally syndactylyDent disease 1, Dent disease 2 1, Lowe syndromeCLCN5OCRLXLLow molecular-weight proteinuriaHypercalciuria, nephrocalcinosis, & nephrolithiasisRicketsCongenital or acquired cataracts, & glaucoma
Craniofrontonasal syndrome (OMIM 304110)EFNB1XLCongenital diaphragmatic herniaWidely spaced eyesAgenesis of corpus callosum
Craniofacial asymmetry, craniosynostosis, brachycephaly (more severe in females) | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1878/ | R9XGzLP | Donnai-Barrow Syndrome | C1857277 | 23 | donnai-barrow syndrome. t disease 1, Dent disease 2 1, Lowe syndromeCLCN5OCRLXLLow molecular-weight proteinuriaHypercalciuria, nephrocalcinosis, & nephrolithiasisRicketsCongenital or acquired cataracts, & glaucoma
Craniofrontonasal syndrome (OMIM 304110)EFNB1XLCongenital diaphragmatic herniaWidely spaced eyesAgenesis of corpus callosum
Craniofacial asymmetry, craniosynostosis, brachycephaly (more severe in females)Clefting of nasal tipAnomalies of joints & digits (e.g., grooved nails)
Stickler syndromeCOL2ACOL9A1COL9A2COL9A3COL11A1COL11A2 2ADARHigh myopia & occasional retinal detachmentHearing loss
Pierre Robin sequenceMidface hypoplasiaJoint problems (hypermobility, arthritis)
AD = autosomal dominant; AR = autosomal | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1878/ | R9XGzLP | Donnai-Barrow Syndrome | C1857277 | 23 | donnai-barrow syndrome. ostosis, brachycephaly (more severe in females)Clefting of nasal tipAnomalies of joints & digits (e.g., grooved nails)
Stickler syndromeCOL2ACOL9A1COL9A2COL9A3COL11A1COL11A2 2ADARHigh myopia & occasional retinal detachmentHearing loss
Pierre Robin sequenceMidface hypoplasiaJoint problems (hypermobility, arthritis)
AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; MOI = mode of inheritance; N/A = not applicable; XL = X-linked1. Clinical and biochemical overlap has been proposed between these conditions and DBS2. Heterozygous pathogenic variants in COL11A2 are associated with Stickler syndrome without ocular features.ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease and needs in an individual diagnosed with Donnai-Barrow syndrome (DBS), the | [
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] |
gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1878/ | R9XGzLP | Donnai-Barrow Syndrome | C1857277 | 23 | donnai-barrow syndrome. arthritis)
AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; MOI = mode of inheritance; N/A = not applicable; XL = X-linked1. Clinical and biochemical overlap has been proposed between these conditions and DBS2. Heterozygous pathogenic variants in COL11A2 are associated with Stickler syndrome without ocular features.ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease and needs in an individual diagnosed with Donnai-Barrow syndrome (DBS), the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.Table 3. Recommended Evaluations Following Initial Diagnosis in Individuals with Donnai-Barrow SyndromeView in own windowSystem/ConcernEvaluationCommentEyesOphthalmologic evaluationFrequent, detailed ophthalmologic exams to assess visual acuity & retinal integrityENTAudiologic evaluationSerial evaluation to monitor progression/degree of hearing lossNe | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1878/ | R9XGzLP | Donnai-Barrow Syndrome | C1857277 | 23 | donnai-barrow syndrome. i-Barrow syndrome (DBS), the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.Table 3. Recommended Evaluations Following Initial Diagnosis in Individuals with Donnai-Barrow SyndromeView in own windowSystem/ConcernEvaluationCommentEyesOphthalmologic evaluationFrequent, detailed ophthalmologic exams to assess visual acuity & retinal integrityENTAudiologic evaluationSerial evaluation to monitor progression/degree of hearing lossNeurologicNeuroimagingPreferably MRIEEGIf symptoms of seizure disorder are presentRenalSerum blood urea nitrogen (BUN), serum creatinine, & urinalysisTo assess renal functionSerum vitamin A & vitamin D (25-hydroxyvitamin D)Hypovitaminosis D & osteomalacia have been reported. Both 25-hydroxyvitamin D3 & 1,25-dihydroxyvitamin D3 are megalin ligands. Megalin | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1878/ | R9XGzLP | Donnai-Barrow Syndrome | C1857277 | 23 | donnai-barrow syndrome. evaluation to monitor progression/degree of hearing lossNeurologicNeuroimagingPreferably MRIEEGIf symptoms of seizure disorder are presentRenalSerum blood urea nitrogen (BUN), serum creatinine, & urinalysisTo assess renal functionSerum vitamin A & vitamin D (25-hydroxyvitamin D)Hypovitaminosis D & osteomalacia have been reported. Both 25-hydroxyvitamin D3 & 1,25-dihydroxyvitamin D3 are megalin ligands. Megalin is necessary for activation of 25-hydroxyvitamin D3 to 1,25-dihydroxyvitamin D3 in the renal proximal tubule.Miscellaneous/OtherDevelopmental evaluationDevelopmental testing appropriate for degree of vision & hearing impairmentsConsultation w/clinical geneticist &/or genetic counselorTreatment of ManifestationsTable 4. Treatment of Manifestations in Individuals with Donnai-Barrow SyndromeView in own windowManifestation/ | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1878/ | R9XGzLP | Donnai-Barrow Syndrome | C1857277 | 23 | donnai-barrow syndrome. -dihydroxyvitamin D3 are megalin ligands. Megalin is necessary for activation of 25-hydroxyvitamin D3 to 1,25-dihydroxyvitamin D3 in the renal proximal tubule.Miscellaneous/OtherDevelopmental evaluationDevelopmental testing appropriate for degree of vision & hearing impairmentsConsultation w/clinical geneticist &/or genetic counselorTreatment of ManifestationsTable 4. Treatment of Manifestations in Individuals with Donnai-Barrow SyndromeView in own windowManifestation/ConcernTreatmentConsiderations/OtherDiaphragmatic herniaSurgical repair 1Postoperative assessment of respiratory function to determine if there is ↑ risk for long-term respiratory problemsOmphaloceleSurgical repair 1MyopiaCorrective lensesPeripheral laser photocoagulation may minimize the risk of retinal detachment resulting from high myopia.RetinaldetachmentTreatment as per ophthalmologistHearing lossHearing aid &/or cochlear implant per ENT | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1878/ | R9XGzLP | Donnai-Barrow Syndrome | C1857277 | 23 | donnai-barrow syndrome. SyndromeView in own windowManifestation/ConcernTreatmentConsiderations/OtherDiaphragmatic herniaSurgical repair 1Postoperative assessment of respiratory function to determine if there is ↑ risk for long-term respiratory problemsOmphaloceleSurgical repair 1MyopiaCorrective lensesPeripheral laser photocoagulation may minimize the risk of retinal detachment resulting from high myopia.RetinaldetachmentTreatment as per ophthalmologistHearing lossHearing aid &/or cochlear implant per ENTSeizuresStandardized treatment w/AEDs by experienced neurologistMany different AEDs may be effective; no one AED has been shown effective specifically for this disorder.HypovitaminosesSupplementation as neededMonitoring of serum vitamins A & D (25-hydroxyvitamin D)AEDs = antiepileptic drugs; ENT = ear, nose, and throat (specialist)1. Surgical repair of omphalocele and/or diaphragmatic hernia appears | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1878/ | R9XGzLP | Donnai-Barrow Syndrome | C1857277 | 23 | donnai-barrow syndrome. aid &/or cochlear implant per ENTSeizuresStandardized treatment w/AEDs by experienced neurologistMany different AEDs may be effective; no one AED has been shown effective specifically for this disorder.HypovitaminosesSupplementation as neededMonitoring of serum vitamins A & D (25-hydroxyvitamin D)AEDs = antiepileptic drugs; ENT = ear, nose, and throat (specialist)1. Surgical repair of omphalocele and/or diaphragmatic hernia appears to pose no greater risk than repair of these defects in children with other genetic syndromes.The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.Developmental Disability / Intellectual Disability Management IssuesAges 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy. In the United States, early intervention is a federal | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1878/ | R9XGzLP | Donnai-Barrow Syndrome | C1857277 | 23 | donnai-barrow syndrome. of omphalocele and/or diaphragmatic hernia appears to pose no greater risk than repair of these defects in children with other genetic syndromes.The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.Developmental Disability / Intellectual Disability Management IssuesAges 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy. In the United States, early intervention is a federally funded program available in all states.Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed.Ages 5-21 yearsIn the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1878/ | R9XGzLP | Donnai-Barrow Syndrome | C1857277 | 23 | donnai-barrow syndrome. In the United States, early intervention is a federally funded program available in all states.Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed.Ages 5-21 yearsIn the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies and to support parents in maximizing quality of life.Consideration of private supportive therapies based on the affected individual's needs is | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1878/ | R9XGzLP | Donnai-Barrow Syndrome | C1857277 | 23 | donnai-barrow syndrome. local public school district. Affected children are permitted to remain in the public school district until age 21.Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies and to support parents in maximizing quality of life.Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.In the US:Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1878/ | R9XGzLP | Donnai-Barrow Syndrome | C1857277 | 23 | donnai-barrow syndrome. therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.In the US:Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.Communication issues. Consider evaluation for alternative means of communication (e.g., Augmentative and Alternative Communication ) for individuals who have expressive language difficulties.Social/Behavioral ConcernsConsultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavioral management strategies or providing prescription medications, such as medication used to treat attention deficit hyperactivity disorder, when necessary. Repetitive self-injurious behavior has been reported in a single individual and psychosis in another | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1878/ | R9XGzLP | Donnai-Barrow Syndrome | C1857277 | 23 | donnai-barrow syndrome. (SSI) for their child with a disability.Communication issues. Consider evaluation for alternative means of communication (e.g., Augmentative and Alternative Communication ) for individuals who have expressive language difficulties.Social/Behavioral ConcernsConsultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavioral management strategies or providing prescription medications, such as medication used to treat attention deficit hyperactivity disorder, when necessary. Repetitive self-injurious behavior has been reported in a single individual and psychosis in another (see Clinical Description).SurveillanceTable 5. Recommended Surveillance for Individuals with DBSView in own windowSystem/ConcernEvaluationFrequencyEyesOphthalmologic evaluationPer ophthalmologist & determined by findings presentENTAudiology examinationsData on natural history & possible progression of hearing loss are not currently available; thus, no frequency for monitoring has been established.RenalMeasurement of serum BUN, creatinine, & urinal | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1878/ | R9XGzLP | Donnai-Barrow Syndrome | C1857277 | 23 | donnai-barrow syndrome. been reported in a single individual and psychosis in another (see Clinical Description).SurveillanceTable 5. Recommended Surveillance for Individuals with DBSView in own windowSystem/ConcernEvaluationFrequencyEyesOphthalmologic evaluationPer ophthalmologist & determined by findings presentENTAudiology examinationsData on natural history & possible progression of hearing loss are not currently available; thus, no frequency for monitoring has been established.RenalMeasurement of serum BUN, creatinine, & urinalysis, serum vitamin A & DPer nephrologist & determined by findings presentMiscellaneous/OtherMonitoring of developmental progress & educational needsEvaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK1878/ | R9XGzLP | Donnai-Barrow Syndrome | C1857277 | 23 | donnai-barrow syndrome. serum BUN, creatinine, & urinalysis, serum vitamin A & DPer nephrologist & determined by findings presentMiscellaneous/OtherMonitoring of developmental progress & educational needsEvaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder. | [
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medlineplus | https://medlineplus.gov/genetics/condition/donnai-barrow-syndrome/ | XKjOOnQ | Donnai-Barrow syndrome | C1857277 | 24 | donnai-barrow syndrome. Donnai-Barrow syndrome is an inherited disorder that affects many parts of the body. This disorder is characterized by unusual facial features, including prominent, wide-set eyes with outer corners that point downward; a short bulbous nose with a flat nasal bridge; ears that are rotated backward; and a widow's peak hairline.Individuals with Donnai-Barrow syndrome have severe hearing loss caused by abnormalities of the inner ear (sensorineural hearing loss). In addition, they often experience vision problems, including extreme nearsightedness (high myopia), detachment or deterioration of the light-sensitive tissue in the back of the eye (the retina), and progressive vision loss. Some have a gap or split in the colored part of the eye (iris coloboma).In almost all people with Donnai-Barrow syndrome, the tissue connecting the left and right halves of the brain (corpus callosum) | [
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medlineplus | https://medlineplus.gov/genetics/condition/donnai-barrow-syndrome/ | XKjOOnQ | Donnai-Barrow syndrome | C1857277 | 24 | donnai-barrow syndrome. sensorineural hearing loss). In addition, they often experience vision problems, including extreme nearsightedness (high myopia), detachment or deterioration of the light-sensitive tissue in the back of the eye (the retina), and progressive vision loss. Some have a gap or split in the colored part of the eye (iris coloboma).In almost all people with Donnai-Barrow syndrome, the tissue connecting the left and right halves of the brain (corpus callosum) is underdeveloped or absent. Affected individuals may also have other structural abnormalities of the brain. They generally have mild to moderate intellectual disability and developmental delay.People with Donnai-Barrow syndrome may also have a hole in the muscle that separates the abdomen from the chest cavity (the diaphragm), which is called a congenital diaphragmatic hernia. This potentially serious birth defect allows the stomach and intestines to move into the chest and possibly crowd the | [
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medlineplus | https://medlineplus.gov/genetics/condition/donnai-barrow-syndrome/ | XKjOOnQ | Donnai-Barrow syndrome | C1857277 | 24 | donnai-barrow syndrome. right halves of the brain (corpus callosum) is underdeveloped or absent. Affected individuals may also have other structural abnormalities of the brain. They generally have mild to moderate intellectual disability and developmental delay.People with Donnai-Barrow syndrome may also have a hole in the muscle that separates the abdomen from the chest cavity (the diaphragm), which is called a congenital diaphragmatic hernia. This potentially serious birth defect allows the stomach and intestines to move into the chest and possibly crowd the developing heart and lungs. An opening in the wall of the abdomen (an omphalocele) that allows the abdominal organs to protrude through the navel may also occur in affected individuals. Occasionally people with Donnai-Barrow syndrome have abnormalities of the intestine, heart, or other organs.FrequencyAlthough its prevalence is unknown, Donnai-Barrow syndrome appears to be a rare disorder. A few dozen affected individuals | [
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medlineplus | https://medlineplus.gov/genetics/condition/donnai-barrow-syndrome/ | XKjOOnQ | Donnai-Barrow syndrome | C1857277 | 24 | donnai-barrow syndrome. to move into the chest and possibly crowd the developing heart and lungs. An opening in the wall of the abdomen (an omphalocele) that allows the abdominal organs to protrude through the navel may also occur in affected individuals. Occasionally people with Donnai-Barrow syndrome have abnormalities of the intestine, heart, or other organs.FrequencyAlthough its prevalence is unknown, Donnai-Barrow syndrome appears to be a rare disorder. A few dozen affected individuals have been reported in many regions of the world.CausesMutations in the LRP2 gene cause Donnai-Barrow syndrome. The LRP2 gene provides instructions for making a protein called megalin, which functions as a receptor. Receptor proteins have specific sites into which certain other proteins, called ligands, fit like keys into locks. Together, ligands and their receptors trigger signals that affect cell development and function. Megalin has many ligands involved | [
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medlineplus | https://medlineplus.gov/genetics/condition/donnai-barrow-syndrome/ | XKjOOnQ | Donnai-Barrow syndrome | C1857277 | 24 | donnai-barrow syndrome. rare disorder. A few dozen affected individuals have been reported in many regions of the world.CausesMutations in the LRP2 gene cause Donnai-Barrow syndrome. The LRP2 gene provides instructions for making a protein called megalin, which functions as a receptor. Receptor proteins have specific sites into which certain other proteins, called ligands, fit like keys into locks. Together, ligands and their receptors trigger signals that affect cell development and function. Megalin has many ligands involved in various body processes, including the absorption of vitamins A and D, immune functioning, stress response, and the transport of fats in the bloodstream.Megalin is embedded in the membrane of cells that line the surfaces and cavities of the body (epithelial cells). The receptor helps move its ligands from the cell surface into the cell (endocytosis). It is active in the development and function of many parts of the body, including the brain and spinal cord | [
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medlineplus | https://medlineplus.gov/genetics/condition/donnai-barrow-syndrome/ | XKjOOnQ | Donnai-Barrow syndrome | C1857277 | 24 | donnai-barrow syndrome. development and function. Megalin has many ligands involved in various body processes, including the absorption of vitamins A and D, immune functioning, stress response, and the transport of fats in the bloodstream.Megalin is embedded in the membrane of cells that line the surfaces and cavities of the body (epithelial cells). The receptor helps move its ligands from the cell surface into the cell (endocytosis). It is active in the development and function of many parts of the body, including the brain and spinal cord (central nervous system), eyes, ears, lungs, intestine, reproductive system, and the small tubes in the kidneys where urine is formed (renal tubules).LRP2 gene mutations that cause Donnai-Barrow syndrome are believed to result in the absence of functional megalin protein. The lack of functional megalin in the renal tubules causes megalin's various ligands to be excreted in the urine rather than being absorbed back into the bloodstream | [
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medlineplus | https://medlineplus.gov/genetics/condition/donnai-barrow-syndrome/ | XKjOOnQ | Donnai-Barrow syndrome | C1857277 | 24 | donnai-barrow syndrome. of the body, including the brain and spinal cord (central nervous system), eyes, ears, lungs, intestine, reproductive system, and the small tubes in the kidneys where urine is formed (renal tubules).LRP2 gene mutations that cause Donnai-Barrow syndrome are believed to result in the absence of functional megalin protein. The lack of functional megalin in the renal tubules causes megalin's various ligands to be excreted in the urine rather than being absorbed back into the bloodstream. The features of Donnai-Barrow syndrome are probably caused by the inability of megalin to help absorb these ligands, disruption of biochemical signaling pathways, or other effects of the nonfunctional megalin protein. However, it is unclear how these abnormalities result in the specific signs and symptoms of the disorder.A condition previously classified as a separate disorder called facio-oculo-acoustico-renal (FOAR) syndrome has also been found | [
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medlineplus | https://medlineplus.gov/genetics/condition/donnai-barrow-syndrome/ | XKjOOnQ | Donnai-Barrow syndrome | C1857277 | 24 | donnai-barrow syndrome. the urine rather than being absorbed back into the bloodstream. The features of Donnai-Barrow syndrome are probably caused by the inability of megalin to help absorb these ligands, disruption of biochemical signaling pathways, or other effects of the nonfunctional megalin protein. However, it is unclear how these abnormalities result in the specific signs and symptoms of the disorder.A condition previously classified as a separate disorder called facio-oculo-acoustico-renal (FOAR) syndrome has also been found to be caused by LRP2 mutations. FOAR syndrome is now considered to be the same disorder as Donnai-Barrow syndrome.Learn more about the gene associated with Donnai-Barrow syndrome
LRP2
Inheritance PatternThis condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. In almost all cases, the parents of an individual with an autosomal recessive condition each carry one copy of | [
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medlineplus | https://medlineplus.gov/genetics/condition/donnai-barrow-syndrome/ | XKjOOnQ | Donnai-Barrow syndrome | C1857277 | 24 | donnai-barrow syndrome. renal (FOAR) syndrome has also been found to be caused by LRP2 mutations. FOAR syndrome is now considered to be the same disorder as Donnai-Barrow syndrome.Learn more about the gene associated with Donnai-Barrow syndrome
LRP2
Inheritance PatternThis condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. In almost all cases, the parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene but typically do not show signs and symptoms of the condition.One individual with Donnai-Barrow syndrome was found to have inherited both copies of the mutated gene from his father as a result of a genetic change called uniparental disomy (UPD). UPD occurs when a person receives two copies of a chromosome, or part of a chromosome, from one parent and no copies from the other parent. UPD can occur as | [
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medlineplus | https://medlineplus.gov/genetics/condition/donnai-barrow-syndrome/ | XKjOOnQ | Donnai-Barrow syndrome | C1857277 | 24 | donnai-barrow syndrome. with an autosomal recessive condition each carry one copy of the mutated gene but typically do not show signs and symptoms of the condition.One individual with Donnai-Barrow syndrome was found to have inherited both copies of the mutated gene from his father as a result of a genetic change called uniparental disomy (UPD). UPD occurs when a person receives two copies of a chromosome, or part of a chromosome, from one parent and no copies from the other parent. UPD can occur as a random event during the formation of egg or sperm cells or may happen in early fetal development. | [
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] |
omim | https://www.omim.org/entry/222448 | gGN9NP8 | DONNAI-BARROW SYNDROME | C1857277 | 25 | donnai-barrow syndrome. A number sign (#) is used with this entry because Donnai-Barrow syndrome is caused by homozygous or compound heterozygous mutation in the LRP2 gene (600073) on chromosome 2q31.
Description
The faciooculoacousticorenal (FOAR) syndrome was first described as comprising facial anomalies, ocular anomalies, sensorineural hearing loss, and proteinuria. Facial features include prominent brow, short nose, and hypertelorism, and ocular anomalies include myopia, iris hypoplasia, and/or retinal detachment (Regenbogen and Coscas, 1985). Donnai-Barrow syndrome (DBS) was first described as a distinct disorder characterized by diaphragmatic hernia, exomphalos, absent corpus callosum, myopia, and sensorineural deafness. The classic distinguishing features between the 2 disorders were presence of proteinuria and absence of diaphragmatic hernia and corpus callosum anomalies in FOAR (Donnai and Barrow, 1993). However, early | [
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omim | https://www.omim.org/entry/222448 | gGN9NP8 | DONNAI-BARROW SYNDROME | C1857277 | 25 | donnai-barrow syndrome. ocular anomalies include myopia, iris hypoplasia, and/or retinal detachment (Regenbogen and Coscas, 1985). Donnai-Barrow syndrome (DBS) was first described as a distinct disorder characterized by diaphragmatic hernia, exomphalos, absent corpus callosum, myopia, and sensorineural deafness. The classic distinguishing features between the 2 disorders were presence of proteinuria and absence of diaphragmatic hernia and corpus callosum anomalies in FOAR (Donnai and Barrow, 1993). However, early reports noted that the 2 disorders shared many phenotypic features and may be identical (e.g., Devriendt et al., 1998). Although there is variability in the expression of some features (e.g., agenesis of the corpus callosum and proteinuria), the disorders are now considered to represent the same entity (Kantarci et al., 2007).
Clinical Features
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omim | https://www.omim.org/entry/222448 | gGN9NP8 | DONNAI-BARROW SYNDROME | C1857277 | 25 | donnai-barrow syndrome. and Barrow, 1993). However, early reports noted that the 2 disorders shared many phenotypic features and may be identical (e.g., Devriendt et al., 1998). Although there is variability in the expression of some features (e.g., agenesis of the corpus callosum and proteinuria), the disorders are now considered to represent the same entity (Kantarci et al., 2007).
Clinical Features
Murdoch and Mengel (1971), Holmes and Schepens (1972), and Ozer (1974) independently reported a brother and sister with a syndrome of ocular and facial anomalies, telecanthus, perceptive deafness, epiphyseal dysplasia of the femoral heads, and proteinuria. Myopia and both telecanthus and true hypertelorism were present. Fraser (1976) described a single case with proteinuria. Donnai and Barrow (1993) described 2 | [
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omim | https://www.omim.org/entry/222448 | gGN9NP8 | DONNAI-BARROW SYNDROME | C1857277 | 25 | donnai-barrow syndrome. Murdoch and Mengel (1971), Holmes and Schepens (1972), and Ozer (1974) independently reported a brother and sister with a syndrome of ocular and facial anomalies, telecanthus, perceptive deafness, epiphyseal dysplasia of the femoral heads, and proteinuria. Myopia and both telecanthus and true hypertelorism were present. Fraser (1976) described a single case with proteinuria. Donnai and Barrow (1993) described 2 unrelated patients, a male and a female, with a syndrome of diaphragmatic hernia, exomphalos, hypertelorism, agenesis of the corpus callosum, severe sensorineural deafness, and severe myopia. One child had iris coloboma and retinal detachment. Monitoring of subsequent pregnancies in both families revealed a further affected fetus in each. In a note added in proof, Donnai and Barrow (1993) indicated that a third affected child, a | [
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omim | https://www.omim.org/entry/222448 | gGN9NP8 | DONNAI-BARROW SYNDROME | C1857277 | 25 | donnai-barrow syndrome. nai and Barrow (1993) described 2 unrelated patients, a male and a female, with a syndrome of diaphragmatic hernia, exomphalos, hypertelorism, agenesis of the corpus callosum, severe sensorineural deafness, and severe myopia. One child had iris coloboma and retinal detachment. Monitoring of subsequent pregnancies in both families revealed a further affected fetus in each. In a note added in proof, Donnai and Barrow (1993) indicated that a third affected child, a female in a possibly related family, had been identified. The authors suggested autosomal recessive inheritance. Gripp et al. (1997) described a male infant, the offspring of first-cousin parents from Saudi Arabia, who had wide anterior fontanel and metopic suture with frontal bossing, hypertelorism, downslanting palpebral fissures, bilateral iris coloboma, omphalocele, and bilateral absence of the | [
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omim | https://www.omim.org/entry/222448 | gGN9NP8 | DONNAI-BARROW SYNDROME | C1857277 | 25 | donnai-barrow syndrome. 1993) indicated that a third affected child, a female in a possibly related family, had been identified. The authors suggested autosomal recessive inheritance. Gripp et al. (1997) described a male infant, the offspring of first-cousin parents from Saudi Arabia, who had wide anterior fontanel and metopic suture with frontal bossing, hypertelorism, downslanting palpebral fissures, bilateral iris coloboma, omphalocele, and bilateral absence of the diaphragm with herniation of internal organs causing pulmonary hypoplasia and death. Autopsy also showed intestinal malrotation. The findings were considered consistent with the syndrome described by Donnai and Barrow (1993). Schowalter et al. (1997) reported an 11-year-old boy with FOAR syndrome. He had iris coloboma, iris hypoplasia, macular hypoplasia, cataract, high myopia, retinal detachment, moderate sensorineural hearing loss, and | [
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omim | https://www.omim.org/entry/222448 | gGN9NP8 | DONNAI-BARROW SYNDROME | C1857277 | 25 | donnai-barrow syndrome. , omphalocele, and bilateral absence of the diaphragm with herniation of internal organs causing pulmonary hypoplasia and death. Autopsy also showed intestinal malrotation. The findings were considered consistent with the syndrome described by Donnai and Barrow (1993). Schowalter et al. (1997) reported an 11-year-old boy with FOAR syndrome. He had iris coloboma, iris hypoplasia, macular hypoplasia, cataract, high myopia, retinal detachment, moderate sensorineural hearing loss, and proteinuria without aminoaciduria. Facial features included prominent brow, flat nasal bridge, hypertelorism, and downslanting palpebral fissures. In contrast to the previously reported patients, he had normal intellect and was learning Braille. Devriendt et al. (1998) reported a male infant with hypertelorism, severe myopia, sensorineural deafness, diaphragmatic hernia, and proteinuria. Other features included large anterior fontanel | [
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