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omim | https://www.omim.org/entry/252011 | rowjg6v | MITOCHONDRIAL COMPLEX II DEFICIENCY | C1855008 | 31,757 | mitochondrial complex ii deficiency. mutation was unable to rescue the oxidative growth defect, consistent with a loss of function.
Clinical Management
Bugiani et al. (2006) reported favorable results with oral riboflavin treatment in 2 Italian patients with complex II deficiency. The patients showed acute psychomotor regression in the first year of life, followed by rapidly progressive neurologic deterioration, spastic quadriparesis with dystonic posturing, and mental impairment. One patient was blind. Complex II deficiency was demonstrated in muscle and fibroblasts. Treatment with oral riboflavin resulted in stabilization of the clinical condition and moderate improvement in cognitive and communicative abilities. Riboflavin supplementation to the growth medium of cultured fibroblasts resulted in a 2-fold increase of complex II activity in patient cells but not control cells.
Molecular Genetics
In 2 sibs with complex II deficiency presenting as Leigh syndrome reported by Bourgeois et al. (1992), Bourgeron et al. (1995) identified a homozygous mutation in the SDHA gene (600857.0001) | [
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] |
omim | https://www.omim.org/entry/252011 | rowjg6v | MITOCHONDRIAL COMPLEX II DEFICIENCY | C1855008 | 31,757 | mitochondrial complex ii deficiency. Treatment with oral riboflavin resulted in stabilization of the clinical condition and moderate improvement in cognitive and communicative abilities. Riboflavin supplementation to the growth medium of cultured fibroblasts resulted in a 2-fold increase of complex II activity in patient cells but not control cells.
Molecular Genetics
In 2 sibs with complex II deficiency presenting as Leigh syndrome reported by Bourgeois et al. (1992), Bourgeron et al. (1995) identified a homozygous mutation in the SDHA gene (600857.0001). Bourgeron et al. (1995) claimed that this was the first report of a nuclear gene mutation causing a mitochondrial respiratory chain deficiency in humans. In affected members of an Italian and Turkish family with mitochondrial complex II deficiency, Ghezzi et al. (2009) identified 2 different homozygous mutations in the SDHAF1 gene (612848.0001 and 612848.0002, respectively). Some of patients had been reported by Brockmann et | [
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omim | https://www.omim.org/entry/252011 | rowjg6v | MITOCHONDRIAL COMPLEX II DEFICIENCY | C1855008 | 31,757 | mitochondrial complex ii deficiency. (600857.0001). Bourgeron et al. (1995) claimed that this was the first report of a nuclear gene mutation causing a mitochondrial respiratory chain deficiency in humans. In affected members of an Italian and Turkish family with mitochondrial complex II deficiency, Ghezzi et al. (2009) identified 2 different homozygous mutations in the SDHAF1 gene (612848.0001 and 612848.0002, respectively). Some of patients had been reported by Brockmann et al. (2002) and Bugiani et al. (2006). Associations Pending Confirmation
For discussion of a possible association between mitochondrial complex II deficiency and variation in the SDHB gene, see 185470.0020; for discussion of a possible association with variation in the SDHD gene, see 602690.0029.
INHERITANCE
- Autosomal recessive
GROWTH
Height
- Short stature
Other
- Poor growth
HEAD & NECK
Eyes
- Ptosis
- Ophthalmoplegia
- Pigment | [
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omim | https://www.omim.org/entry/252011 | rowjg6v | MITOCHONDRIAL COMPLEX II DEFICIENCY | C1855008 | 31,757 | mitochondrial complex ii deficiency. been reported by Brockmann et al. (2002) and Bugiani et al. (2006). Associations Pending Confirmation
For discussion of a possible association between mitochondrial complex II deficiency and variation in the SDHB gene, see 185470.0020; for discussion of a possible association with variation in the SDHD gene, see 602690.0029.
INHERITANCE
- Autosomal recessive
GROWTH
Height
- Short stature
Other
- Poor growth
HEAD & NECK
Eyes
- Ptosis
- Ophthalmoplegia
- Pigmentary retinopathy
- Optic atrophy
- Nystagmus
- Impaired vision
CARDIOVASCULAR
Heart
- Hypertrophic cardiomyopathy
- Dilated cardiomyopathy
- Left ventricular noncompaction
SKELETAL
- Joint contractures
MUSCLE, SOFT TISSUES
- Hypotonia, neonatal
- Muscle weakness
- Exercise intolerance
- Ragged red fibers seen on muscle biopsy
- Abnormal mitochondria with paracrystalline inclusions seen on muscle biopsy
- Accumulated lipid droplets seen on muscle biopsy
NEUROLOGIC
Central Nervous System
- Psychomotor regression in infants
- Spasticity
- Hyperreflexia
- Extensor plantar responses
- Ataxia | [
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omim | https://www.omim.org/entry/252011 | rowjg6v | MITOCHONDRIAL COMPLEX II DEFICIENCY | C1855008 | 31,757 | mitochondrial complex ii deficiency. - Ptosis
- Ophthalmoplegia
- Pigmentary retinopathy
- Optic atrophy
- Nystagmus
- Impaired vision
CARDIOVASCULAR
Heart
- Hypertrophic cardiomyopathy
- Dilated cardiomyopathy
- Left ventricular noncompaction
SKELETAL
- Joint contractures
MUSCLE, SOFT TISSUES
- Hypotonia, neonatal
- Muscle weakness
- Exercise intolerance
- Ragged red fibers seen on muscle biopsy
- Abnormal mitochondria with paracrystalline inclusions seen on muscle biopsy
- Accumulated lipid droplets seen on muscle biopsy
NEUROLOGIC
Central Nervous System
- Psychomotor regression in infants
- Spasticity
- Hyperreflexia
- Extensor plantar responses
- Ataxia
- Cognitive impairment
- Dystonia
- Myoclonus
- Seizures
- Leukoencephalopathy, progressive
- Spongiform encephalomyelopathy
- Leigh syndrome (
245000
), in a subset of patients
- Kearns-Sayre syndrome (
530000
), in a subset of patients
METABOLIC FEATURES
- Lactic acidosis may occur with stress or infection
LABORATORY ABNORMALITIES
- Decreased activity of mitochondrial complex II (succinate dehydrogenase)
- Mildly increased serum lactate
MISCELLANEOUS
- Onset in first year of life | [
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] |
omim | https://www.omim.org/entry/252011 | rowjg6v | MITOCHONDRIAL COMPLEX II DEFICIENCY | C1855008 | 31,757 | mitochondrial complex ii deficiency. ia
- Extensor plantar responses
- Ataxia
- Cognitive impairment
- Dystonia
- Myoclonus
- Seizures
- Leukoencephalopathy, progressive
- Spongiform encephalomyelopathy
- Leigh syndrome (
245000
), in a subset of patients
- Kearns-Sayre syndrome (
530000
), in a subset of patients
METABOLIC FEATURES
- Lactic acidosis may occur with stress or infection
LABORATORY ABNORMALITIES
- Decreased activity of mitochondrial complex II (succinate dehydrogenase)
- Mildly increased serum lactate
MISCELLANEOUS
- Onset in first year of life
- Highly variable phenotype
MOLECULAR BASIS
- Caused by mutation in the flavoprotein subunit of succinate dehydrogenase complex gene (SDHA,
600857.0001
)
- Caused by mutation in the succinate dehydrogenase complex assembly factor 1 gene (SDHAF1,
612848.0001
)
- Caused by mutation in the succinate dehydrogenase complex, subunit D, integral membrane protein gene (SDHD,
602690.0029
)
▲ Close | [
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] |
omim | https://www.omim.org/entry/252011 | rowjg6v | MITOCHONDRIAL COMPLEX II DEFICIENCY | C1855008 | 31,757 | mitochondrial complex ii deficiency. - Onset in first year of life
- Highly variable phenotype
MOLECULAR BASIS
- Caused by mutation in the flavoprotein subunit of succinate dehydrogenase complex gene (SDHA,
600857.0001
)
- Caused by mutation in the succinate dehydrogenase complex assembly factor 1 gene (SDHAF1,
612848.0001
)
- Caused by mutation in the succinate dehydrogenase complex, subunit D, integral membrane protein gene (SDHD,
602690.0029
)
▲ Close | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. SummaryClinical characteristics.Prolidase deficiency is characterized by skin lesions (typically severe, chronic, recalcitrant, and painful skin ulcers of the lower extremities and telangiectasias of the face and hands), recurrent infections (particularly of the skin and respiratory tract), dysmorphic facial features, variable intellectual disability, and hepatomegaly with elevated liver enzymes and splenomegaly. Anemia, thrombocytopenia, hypergammaglobulinemia, and hypocomplementemia are common. An association between systemic lupus erythematosus (SLE) and prolidase deficiency has been described.Diagnosis/testing.The diagnosis of prolidase deficiency is established by detection of either biallelic PEPD pathogenic variants or reduced prolidase enzyme activity in a proband who has characteristic clinical findings and imidodipeptiduria.Management.Treatment of manifestations: No curative treatment is available. Supportive treatment of skin, lung, and immunologic manifestations has been efficacious in some (but not in all) patients. Caution is warranted in the treatment of infections, which | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. SLE) and prolidase deficiency has been described.Diagnosis/testing.The diagnosis of prolidase deficiency is established by detection of either biallelic PEPD pathogenic variants or reduced prolidase enzyme activity in a proband who has characteristic clinical findings and imidodipeptiduria.Management.Treatment of manifestations: No curative treatment is available. Supportive treatment of skin, lung, and immunologic manifestations has been efficacious in some (but not in all) patients. Caution is warranted in the treatment of infections, which can be fulminant and fatal. Developmental and educational interventions as needed to address motor and cognitive delays.Prevention of secondary complications: Those who have undergone splenectomy should be appropriately immunized and treated promptly with antibiotics at the first sign of infection. Antibiotic prophylaxis should also be considered in the appropriate setting.Surveillance: In the absence of formal surveillance guidelines, the authors recommend annual: skin examination for evidence of malignant transformation in persons with chronic recalcitrant skin ulcers, complete blood count, liver function tests, | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. the treatment of infections, which can be fulminant and fatal. Developmental and educational interventions as needed to address motor and cognitive delays.Prevention of secondary complications: Those who have undergone splenectomy should be appropriately immunized and treated promptly with antibiotics at the first sign of infection. Antibiotic prophylaxis should also be considered in the appropriate setting.Surveillance: In the absence of formal surveillance guidelines, the authors recommend annual: skin examination for evidence of malignant transformation in persons with chronic recalcitrant skin ulcers, complete blood count, liver function tests, and abdominal ultrasound examination to assess the size of the liver and spleen. Follow up as recommended by a pulmonologist and immunologist. Follow-up assessments of motor and cognitive development as recommended for educational planning.Agents/circumstances to avoid: In those with splenomegaly: avoid contact sports given the increased risk for splenic rupture.Genetic counseling.Prolidase deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. count, liver function tests, and abdominal ultrasound examination to assess the size of the liver and spleen. Follow up as recommended by a pulmonologist and immunologist. Follow-up assessments of motor and cognitive development as recommended for educational planning.Agents/circumstances to avoid: In those with splenomegaly: avoid contact sports given the increased risk for splenic rupture.Genetic counseling.Prolidase deficiency is inherited in an autosomal recessive manner. At conception, 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. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the PEPD pathogenic variants in the family have been identified.DiagnosisNo formal diagnostic criteria or testing algorithms for prolidase deficiency have been published.Suggestive FindingsProlidase deficiency should be suspected in individuals with the following clinical, laboratory, and biochemical findings. | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. 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. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the PEPD pathogenic variants in the family have been identified.DiagnosisNo formal diagnostic criteria or testing algorithms for prolidase deficiency have been published.Suggestive FindingsProlidase deficiency should be suspected in individuals with the following clinical, laboratory, and biochemical findings.ClinicalSkin lesions, typically lower extremity ulcers. Other lesions such as telangiectasias of the face and hands are also common .Recurrent infections, particularly of the skin and respiratory tract Chronic lung disease with digital clubbing and a cystic fibrosis-like phenotype Dysmorphic facial features, including widely spaced eyes, proptosis, depressed nasal bridge, prognathism, thin vermilion of the upper lip, and low anterior and posterior hairline Developmental delay of variable degree Splenomegaly Systemic | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. laboratory, and biochemical findings.ClinicalSkin lesions, typically lower extremity ulcers. Other lesions such as telangiectasias of the face and hands are also common .Recurrent infections, particularly of the skin and respiratory tract Chronic lung disease with digital clubbing and a cystic fibrosis-like phenotype Dysmorphic facial features, including widely spaced eyes, proptosis, depressed nasal bridge, prognathism, thin vermilion of the upper lip, and low anterior and posterior hairline Developmental delay of variable degree Splenomegaly Systemic lupus erythematosus-like phenotype Laboratory. Frequent, although not universal, laboratory findings include the following:Anemia, usually mild (hemoglobin >10 g/dL), but occasionally below that value Thrombocytopenia, usually mild (>100,000 platelets per μL), although rarely it can be lower Elevated liver enzymes, with elevation of aspartate aminotransferase in the 100s Hypergammaglobulinemia, mainly elevation of IgG and IgA, although occasionally also elevation of IgM. Reference | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. delay of variable degree Splenomegaly Systemic lupus erythematosus-like phenotype Laboratory. Frequent, although not universal, laboratory findings include the following:Anemia, usually mild (hemoglobin >10 g/dL), but occasionally below that value Thrombocytopenia, usually mild (>100,000 platelets per μL), although rarely it can be lower Elevated liver enzymes, with elevation of aspartate aminotransferase in the 100s Hypergammaglobulinemia, mainly elevation of IgG and IgA, although occasionally also elevation of IgM. Reference ranges for immunoglobulins are age dependent, but upper limits of normal at any age are: IgG ~1600 mg/dL, IgA 350 mg/dL, and IgM 280 mg/dL.IgG levels >2,000 mg/dL have been reported numerous times and as high as 3,680 mg/dL .IgA levels >500 mg/dL have been reported on several occasions and as high as 850 mg/dL .IgM concentrations as high as | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. also elevation of IgM. Reference ranges for immunoglobulins are age dependent, but upper limits of normal at any age are: IgG ~1600 mg/dL, IgA 350 mg/dL, and IgM 280 mg/dL.IgG levels >2,000 mg/dL have been reported numerous times and as high as 3,680 mg/dL .IgA levels >500 mg/dL have been reported on several occasions and as high as 850 mg/dL .IgM concentrations as high as 568 mg/dL have been described .Hypocomplementemia. Levels of C3 ranging from 30 to 74 mg/dL (normal: 75-175 mg/dL) have been published , with C4 as low as 9 mg/dL (normal: 20-40 mg/dL) .Biochemical. Prolidase deficiency is characterized by massive imidodipeptiduria* (10-30 mmol/day) on urine amino acid analysis .In individuals with prolidase | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. .IgM concentrations as high as 568 mg/dL have been described .Hypocomplementemia. Levels of C3 ranging from 30 to 74 mg/dL (normal: 75-175 mg/dL) have been published , with C4 as low as 9 mg/dL (normal: 20-40 mg/dL) .Biochemical. Prolidase deficiency is characterized by massive imidodipeptiduria* (10-30 mmol/day) on urine amino acid analysis .In individuals with prolidase deficiency imidodipeptiduria has been detected as early as in the newborn period, even in the absence of signs or symptoms of the disease. (This finding has been used as the basis for urinary newborn screening in Quebec .)Under normal circumstances the urinary excretion of glycylproline is negligible ; thus, the absence of detectable imidodipeptiduria in properly processed samples is sufficient evidence to rule out a diagnosis of prolidase deficiency .Click here (pdf | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. .In individuals with prolidase deficiency imidodipeptiduria has been detected as early as in the newborn period, even in the absence of signs or symptoms of the disease. (This finding has been used as the basis for urinary newborn screening in Quebec .)Under normal circumstances the urinary excretion of glycylproline is negligible ; thus, the absence of detectable imidodipeptiduria in properly processed samples is sufficient evidence to rule out a diagnosis of prolidase deficiency .Click here (pdf) for information on laboratory methods used to detect imidodipeptiduria.Other biochemical findings:The concentration of imidodipeptides is much lower in serum than urine .Gly-Pro has been reported in the plasma by some investigators , but not others .CSF amino acid analysis was normal in the first report of probable prolidase deficiency .*Note: A number of published reports mistakenly refer to imidodipeptiduria as "iminodipe | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. deficiency .Click here (pdf) for information on laboratory methods used to detect imidodipeptiduria.Other biochemical findings:The concentration of imidodipeptides is much lower in serum than urine .Gly-Pro has been reported in the plasma by some investigators , but not others .CSF amino acid analysis was normal in the first report of probable prolidase deficiency .*Note: A number of published reports mistakenly refer to imidodipeptiduria as "iminodipeptiduria." Iminodipeptides are dipeptides in which proline or hydroxyproline is the N-terminal amino acid (i.e., Pro/Hyp-X, for example prolylglycine), whereas imidodipeptides are dipeptides in which proline or hydroxyproline is the C-terminal amino acid (i.e., X-Pro/Hyp, for example glycylproline).Establishing the DiagnosisThe diagnosis of prolidase deficiency | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. as "iminodipeptiduria." Iminodipeptides are dipeptides in which proline or hydroxyproline is the N-terminal amino acid (i.e., Pro/Hyp-X, for example prolylglycine), whereas imidodipeptides are dipeptides in which proline or hydroxyproline is the C-terminal amino acid (i.e., X-Pro/Hyp, for example glycylproline).Establishing the DiagnosisThe diagnosis of prolidase deficiency is established in a proband (who has the characteristic clinical findings and imidodipeptiduria) by detection of either biallelic PEPD pathogenic variants (see Table 2) or reduced prolidase enzyme activity.Molecular genetic testing approaches include single gene testing and targeted analysis for pathogenic variants.Single-gene testing. For most individuals, sequence analysis of PEPD is performed first, followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. The diagnosis of prolidase deficiency is established in a proband (who has the characteristic clinical findings and imidodipeptiduria) by detection of either biallelic PEPD pathogenic variants (see Table 2) or reduced prolidase enzyme activity.Molecular genetic testing approaches include single gene testing and targeted analysis for pathogenic variants.Single-gene testing. For most individuals, sequence analysis of PEPD is performed first, followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.Targeted analysis for pathogenic variants. For Amish from Geauga County, Ohio and Druze and Arab Muslims from northern Israel, testing for the founder variants p.Arg265Ter and p.Ser202Phe, respectively, may be performed first followed by sequence analysis and gene-targeted deletion/duplication analysis if one or no pathogenic variant is identified.Table 2. Summary of Molecular Genetic Testing Used in Prolidase DeficiencyView in own window | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. or no pathogenic variant is found.Targeted analysis for pathogenic variants. For Amish from Geauga County, Ohio and Druze and Arab Muslims from northern Israel, testing for the founder variants p.Arg265Ter and p.Ser202Phe, respectively, may be performed first followed by sequence analysis and gene-targeted deletion/duplication analysis if one or no pathogenic variant is identified.Table 2. Summary of Molecular Genetic Testing Used in Prolidase DeficiencyView in own windowGene 1Test MethodPathogenic Variants DetectedProportion of Probands with Pathogenic Variants 2 Detectable by This MethodPEPDSequence analysis 3Sequence variants28/30 4Gene-targeted deletion/duplication analysis 5Exon or whole-gene deletions2/30 4Targeted analysis for pathogenic variantsp.Arg265Ter4/4 6p.Ser202Phe17/20 71. See Table A. Genes and Databases for chromosome locus and | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. idase DeficiencyView in own windowGene 1Test MethodPathogenic Variants DetectedProportion of Probands with Pathogenic Variants 2 Detectable by This MethodPEPDSequence analysis 3Sequence variants28/30 4Gene-targeted deletion/duplication analysis 5Exon or whole-gene deletions2/30 4Targeted analysis for pathogenic variantsp.Arg265Ter4/4 6p.Ser202Phe17/20 71. 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. Lupi et al | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. 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. Lupi et al 5. 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 gene-targeted microarray designed to detect single-exon deletions or duplications.6. Amish from Geauga County, Ohio 7. Druze and Arab Muslims from northern Israel Measurement of prolidase enzyme activity. In affected individuals, prolidase enzyme | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. 4. Lupi et al 5. 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 gene-targeted microarray designed to detect single-exon deletions or duplications.6. Amish from Geauga County, Ohio 7. Druze and Arab Muslims from northern Israel Measurement of prolidase enzyme activity. In affected individuals, prolidase enzyme activity in erythrocytes, leukocytes, or cultured fibroblasts ranges from none to <10% .Click here (pdf) for a short review of laboratory techniques used in the diagnosis of prolidase deficiency; see also Kurien et al and Viglio et al .Clinical CharacteristicsClinical DescriptionSkin. The hallmark of prolidase deficiency is severe, chronic, recalcitrant, and painful skin ulcers. The ulcers are located mainly on the lower extremities, particularly the feet. However | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. affected individuals, prolidase enzyme activity in erythrocytes, leukocytes, or cultured fibroblasts ranges from none to <10% .Click here (pdf) for a short review of laboratory techniques used in the diagnosis of prolidase deficiency; see also Kurien et al and Viglio et al .Clinical CharacteristicsClinical DescriptionSkin. The hallmark of prolidase deficiency is severe, chronic, recalcitrant, and painful skin ulcers. The ulcers are located mainly on the lower extremities, particularly the feet. However, individuals are reported with upper extremity involvement, including one with recurrent upper extremity ulceration beginning at age nine years , one with active ulcers on the hands , and one with a healed scar from prior ulcers in the dorsum of the hand . One had scarring from healed ulcers over most of her body; however, at the time of publication active ulcers were mainly on the legs .Skin ulcers can begin as early as age six months or as late as age 30 years .Ulceration is | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. , particularly the feet. However, individuals are reported with upper extremity involvement, including one with recurrent upper extremity ulceration beginning at age nine years , one with active ulcers on the hands , and one with a healed scar from prior ulcers in the dorsum of the hand . One had scarring from healed ulcers over most of her body; however, at the time of publication active ulcers were mainly on the legs .Skin ulcers can begin as early as age six months or as late as age 30 years .Ulceration is recurrent, and individual ulcers can take months to heal.Typically, no precipitating factors are identified with the appearance of an ulcer, although trauma has been reported as a triggering factor in at least two individuals . See Figure 1.Figure 1. Typical skin ulcerations in individuals with prolidase deficiency. A variety of skin findings can precede the appearance of ulcers by many years . In the first 20 patients reported , eight had telangiectasias of the face, shoulders, and hands; five | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. age 30 years .Ulceration is recurrent, and individual ulcers can take months to heal.Typically, no precipitating factors are identified with the appearance of an ulcer, although trauma has been reported as a triggering factor in at least two individuals . See Figure 1.Figure 1. Typical skin ulcerations in individuals with prolidase deficiency. A variety of skin findings can precede the appearance of ulcers by many years . In the first 20 patients reported , eight had telangiectasias of the face, shoulders, and hands; five had scaly, erythematous, maculopapular lesions; and two had purpuric lesions in the absence of hematologic abnormalities. In addition, five had premature graying of the hair.Occasional findings:Lymphedema Hyperkeratosis of the elbows and knees Hirsutism Perioral pitted scars or radial scars As prolidase deficiency is associated with chronic recalcitrant lower extremity ulcers, an increased risk of squamous cell carcinoma of the skin could be expected, and indeed has been reported | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. shoulders, and hands; five had scaly, erythematous, maculopapular lesions; and two had purpuric lesions in the absence of hematologic abnormalities. In addition, five had premature graying of the hair.Occasional findings:Lymphedema Hyperkeratosis of the elbows and knees Hirsutism Perioral pitted scars or radial scars As prolidase deficiency is associated with chronic recalcitrant lower extremity ulcers, an increased risk of squamous cell carcinoma of the skin could be expected, and indeed has been reported in one individual .Dysmorphic facial features. Although not a universal finding, facial features typically described include prominent forehead, widely spaced eyes, proptosis, depressed nasal bridge, prognathism, thin vermilion of the upper lip, and low anterior and posterior hairlines . See Figure 2.Figure 2. Prominent forehead, proptosis, depressed nasal bridge, and thin vermilion of the upper lip can be appreciated. Neurologic manifestations. Intellectual disability of | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. , and indeed has been reported in one individual .Dysmorphic facial features. Although not a universal finding, facial features typically described include prominent forehead, widely spaced eyes, proptosis, depressed nasal bridge, prognathism, thin vermilion of the upper lip, and low anterior and posterior hairlines . See Figure 2.Figure 2. Prominent forehead, proptosis, depressed nasal bridge, and thin vermilion of the upper lip can be appreciated. Neurologic manifestations. Intellectual disability of variable degree has been described in approximately 75% of individuals with prolidase deficiency . Table 3 summarizes IQ scores reported in the medical literature to date.In a review 12 of 30 individuals with molecularly confirmed prolidase deficiency had intellectual disability .In a case series of 12 individuals with prolidase deficiency, one had speech delay, two had mild developmental delay, and six had intellectual disability; three had no delays .In a case series of 20 Druze and Arab Muslims | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. Neurologic manifestations. Intellectual disability of variable degree has been described in approximately 75% of individuals with prolidase deficiency . Table 3 summarizes IQ scores reported in the medical literature to date.In a review 12 of 30 individuals with molecularly confirmed prolidase deficiency had intellectual disability .In a case series of 12 individuals with prolidase deficiency, one had speech delay, two had mild developmental delay, and six had intellectual disability; three had no delays .In a case series of 20 Druze and Arab Muslims with prolidase deficiency living in northern Israel all had some degree of developmental delay, mainly moderate cognitive or speech delay . More specifically, two had speech delay, eight had mild developmental delay, five had moderate delay, and three had severe delay.Table 3. IQ Scores Reported in Individuals with Prolidase DeficiencyView in own windowIQ ScoreTest UsedReference30NRArata et al 48NROgata et al 52WISC-RFreij et al 52NR | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. e and Arab Muslims with prolidase deficiency living in northern Israel all had some degree of developmental delay, mainly moderate cognitive or speech delay . More specifically, two had speech delay, eight had mild developmental delay, five had moderate delay, and three had severe delay.Table 3. IQ Scores Reported in Individuals with Prolidase DeficiencyView in own windowIQ ScoreTest UsedReference30NRArata et al 48NROgata et al 52WISC-RFreij et al 52NRSekiya et al 55WISC-RMonafo et al 61WISC-RTiller 66NRCleary et al 74WISC-RDunn et al 85WISC-RPowell et al 87Peabody Picture Vocabulary Test, Form BPowell et al 80-90NRGoodman et al NR = not reported; WISC-R = Wechsler Intelligence Scale for Children – RevisedMicrocephaly was described in five | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. reij et al 52NRSekiya et al 55WISC-RMonafo et al 61WISC-RTiller 66NRCleary et al 74WISC-RDunn et al 85WISC-RPowell et al 87Peabody Picture Vocabulary Test, Form BPowell et al 80-90NRGoodman et al NR = not reported; WISC-R = Wechsler Intelligence Scale for Children – RevisedMicrocephaly was described in five of 11 individuals .Seizures have been described in rare cases .Brain MRI findings include:Multiple microthromboses bilaterally in the cerebral white matter Multiple bilateral subcortical white matter lesions (mainly in the parieto-occipital area), accompanied by leptomeningeal enhancement (one affected individual) Findings compatible with vasculitis Normal (one affected individual) On nerve conduction studies one affected individual had decreased amplitude of motor action potentials and sensory action potentials .Organomegaly. Hepatomegaly and splenomegaly are common | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. ephaly was described in five of 11 individuals .Seizures have been described in rare cases .Brain MRI findings include:Multiple microthromboses bilaterally in the cerebral white matter Multiple bilateral subcortical white matter lesions (mainly in the parieto-occipital area), accompanied by leptomeningeal enhancement (one affected individual) Findings compatible with vasculitis Normal (one affected individual) On nerve conduction studies one affected individual had decreased amplitude of motor action potentials and sensory action potentials .Organomegaly. Hepatomegaly and splenomegaly are common and variable in severity; in one instance massive splenomegaly (spleen measuring 35 cm) has been reported .Liver enzymes may be mildly elevated .Hematologic manifestations. Anemia can be either mild microcytic hypochromic anemia or normocytic normochromic anemia .Hemolysis has been described , with reticulocytosis varying from 5.9% to 8.6% .Thrombocytopenia is fairly common .Immunologic manifestations. Recurrent episodes of otitis media, sinusitis, pneumonia, and gastroenteritis are common .Elevated levels of | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. Hepatomegaly and splenomegaly are common and variable in severity; in one instance massive splenomegaly (spleen measuring 35 cm) has been reported .Liver enzymes may be mildly elevated .Hematologic manifestations. Anemia can be either mild microcytic hypochromic anemia or normocytic normochromic anemia .Hemolysis has been described , with reticulocytosis varying from 5.9% to 8.6% .Thrombocytopenia is fairly common .Immunologic manifestations. Recurrent episodes of otitis media, sinusitis, pneumonia, and gastroenteritis are common .Elevated levels of IgG, IgA and IgM, and hypocomplementemia have been reported , as has decreased neutrophil chemotaxis . Serum levels of C1q have been normal .Increased serum IgE levels have been reported :Martins et al reported a patient with an IgE level of 20,000 IU/mL, which was as high as 77,600 IU/mL on follow up, with a Grimbacher score of 34 .Fukumura et al reported an individual with a level of | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. are common .Elevated levels of IgG, IgA and IgM, and hypocomplementemia have been reported , as has decreased neutrophil chemotaxis . Serum levels of C1q have been normal .Increased serum IgE levels have been reported :Martins et al reported a patient with an IgE level of 20,000 IU/mL, which was as high as 77,600 IU/mL on follow up, with a Grimbacher score of 34 .Fukumura et al reported an individual with a level of 23,000 IU/mL.Hershkovitz et al reported a patient with levels of 1,000-2,000 IU/mL with a Grimbacher score of 41, suggestive of autosomal dominant hyper IgE syndrome.Pulmonary manifestations. Asthma-like chronic reactive airway disease was described in three of four Amish individuals with prolidase deficiency .Bronchiectasis, chronic lipoid pneumonia, and a cystic fibrosis phenotype including elevated sweat chloride and transepithelial potential difference has been | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. an individual with a level of 23,000 IU/mL.Hershkovitz et al reported a patient with levels of 1,000-2,000 IU/mL with a Grimbacher score of 41, suggestive of autosomal dominant hyper IgE syndrome.Pulmonary manifestations. Asthma-like chronic reactive airway disease was described in three of four Amish individuals with prolidase deficiency .Bronchiectasis, chronic lipoid pneumonia, and a cystic fibrosis phenotype including elevated sweat chloride and transepithelial potential difference has been described .One male developed severe progressive restrictive lung disease at age 45 years .A Druze woman age 24 years had progressive lung disease with chest CT findings of mainly cystic lung lesions and ground glass opacity . She experienced further deterioration in her pulmonary function and secondary pulmonary hypertension, and became oxygen dependent.An Amish boy age six years with pulmonary hypertension required supplemental oxygen .Systemic lupus erythematosus-like findings. An association between systemic lupus erythematosus (SLE) and prolidase deficiency has | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. and transepithelial potential difference has been described .One male developed severe progressive restrictive lung disease at age 45 years .A Druze woman age 24 years had progressive lung disease with chest CT findings of mainly cystic lung lesions and ground glass opacity . She experienced further deterioration in her pulmonary function and secondary pulmonary hypertension, and became oxygen dependent.An Amish boy age six years with pulmonary hypertension required supplemental oxygen .Systemic lupus erythematosus-like findings. An association between systemic lupus erythematosus (SLE) and prolidase deficiency has been described in at least ten individuals, including three of 23 individuals from northern Israel .This association, first described by Bissonnette et al in a female age 16 years, included Raynaud's phenomenon, photosensitivity, arthritis, nephritis (with segmental mesangial deposits of IgA, IgM, and C3), antinuclear antibodies 1:650, and a positive rheumatoid factor.Shrinath et al reported two cousins with prolidase deficiency and SLE: | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. ) and prolidase deficiency has been described in at least ten individuals, including three of 23 individuals from northern Israel .This association, first described by Bissonnette et al in a female age 16 years, included Raynaud's phenomenon, photosensitivity, arthritis, nephritis (with segmental mesangial deposits of IgA, IgM, and C3), antinuclear antibodies 1:650, and a positive rheumatoid factor.Shrinath et al reported two cousins with prolidase deficiency and SLE:One had a malar facial rash, joint swellings, thrombocytopenia, neutropenia, proteinuria, pericarditis, hypocomplementemia, positive antinuclear antibody test (ANA), and strongly positive anti-dsDNA;The other had recurrent mouth ulcers, a malar rash, thrombocytopenia, neutropenia, positive ANA, positive anti-dsDNA, and positive pANCA.A boy age 11 years had photosensitivity, malar erythema, and a positive ANA of 1:40 .A boy | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. prolidase deficiency and SLE:One had a malar facial rash, joint swellings, thrombocytopenia, neutropenia, proteinuria, pericarditis, hypocomplementemia, positive antinuclear antibody test (ANA), and strongly positive anti-dsDNA;The other had recurrent mouth ulcers, a malar rash, thrombocytopenia, neutropenia, positive ANA, positive anti-dsDNA, and positive pANCA.A boy age 11 years had photosensitivity, malar erythema, and a positive ANA of 1:40 .A boy age six years diagnosed with SLE was treated for two years with steroids and azathioprine, with amelioration of the immunologic abnormalities but worsening of the skin lesions .A male age 25 years had bilateral and symmetric synovitis affecting hands, elbows, and knees, a positive rheumatoid factor (516 IU/mL) and homogeneous ANA (1:640), and low C4 and CH50 (0.07 g/L and 61%) . He fulfilled the American College of Rheumatology ( | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. 1:40 .A boy age six years diagnosed with SLE was treated for two years with steroids and azathioprine, with amelioration of the immunologic abnormalities but worsening of the skin lesions .A male age 25 years had bilateral and symmetric synovitis affecting hands, elbows, and knees, a positive rheumatoid factor (516 IU/mL) and homogeneous ANA (1:640), and low C4 and CH50 (0.07 g/L and 61%) . He fulfilled the American College of Rheumatology (ACR) criteria for rheumatoid arthritis and SLE (rhupus). Although he was diagnosed with prolidase deficiency based on increased imidodipeptiduria, prolidase enzymatic activity was not measured and PEPD sequencing was not performed. This patient did have increased bone turnover, a known cause of imidodipeptiduria in the absence of prolidase deficiency.An Amish boy age 2.5 years with fever of unknown etiology had urinalysis with 2+ | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. the American College of Rheumatology (ACR) criteria for rheumatoid arthritis and SLE (rhupus). Although he was diagnosed with prolidase deficiency based on increased imidodipeptiduria, prolidase enzymatic activity was not measured and PEPD sequencing was not performed. This patient did have increased bone turnover, a known cause of imidodipeptiduria in the absence of prolidase deficiency.An Amish boy age 2.5 years with fever of unknown etiology had urinalysis with 2+ proteinuria and hypoalbuminemia, ANA of 1:1080 with speckled pattern, and a positive anti-dsDNA .Of two sibs reported by Klar et al :A girl age eight years had Raynaud's phenomenon, a positive ANA (1:1280; homogenous pattern), a positive anti ds-DNA >1:160, positive anti-ENA, anti-RNP and anti-Smith;Her brother, age | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. urinalysis with 2+ proteinuria and hypoalbuminemia, ANA of 1:1080 with speckled pattern, and a positive anti-dsDNA .Of two sibs reported by Klar et al :A girl age eight years had Raynaud's phenomenon, a positive ANA (1:1280; homogenous pattern), a positive anti ds-DNA >1:160, positive anti-ENA, anti-RNP and anti-Smith;Her brother, age 12 years, had Raynaud's phenomenon, a positive ANA (1:40; homogeneous) and anti ds-DNA (1.6 μg/mL), and low C3 (30-74 mg/dL).An individual with positive ANA and anti-dsDNA titers, as well as low complement levels had no hematologic, renal, or articular problems; although he was given a diagnosis of SLE, he did not fulfill ACR diagnostic criteria .Falik | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. ;Her brother, age 12 years, had Raynaud's phenomenon, a positive ANA (1:40; homogeneous) and anti ds-DNA (1.6 μg/mL), and low C3 (30-74 mg/dL).An individual with positive ANA and anti-dsDNA titers, as well as low complement levels had no hematologic, renal, or articular problems; although he was given a diagnosis of SLE, he did not fulfill ACR diagnostic criteria .Falik-Zaccai et al reported two individuals:One with Coombs-positive hemolytic anemia, severe medication-resistant thrombocytopenia which required splenectomy, high levels of ANA and anti-cardiolipin antibodies, and a strongly positive anti-dsDNA;One with aphthous stomatitis, macroscopic hematuria and proteinuria eventually leading to renal failure (with a renal biopsy compatible with lupus nephritis), seizures, pancytopenia, Coombs-positive hemolytic anemia, hypocomplementemia | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. diagnostic criteria .Falik-Zaccai et al reported two individuals:One with Coombs-positive hemolytic anemia, severe medication-resistant thrombocytopenia which required splenectomy, high levels of ANA and anti-cardiolipin antibodies, and a strongly positive anti-dsDNA;One with aphthous stomatitis, macroscopic hematuria and proteinuria eventually leading to renal failure (with a renal biopsy compatible with lupus nephritis), seizures, pancytopenia, Coombs-positive hemolytic anemia, hypocomplementemia, and elevated ANA and anti-dsDNA antibodies).Butbul Aviel et al reported three individuals with the SLE/prolidase deficiency association:A boy age 4.5 years with a rash consistent with hypertrophic discoid lupus on biopsy, proteinuria and mild hematuria with a renal biopsy consistent with WHO Class IV lupus nephritis, low C3 and C4 levels, positive ANA (1:640; homogeneous pattern), anti ds-DNA, anti-RNP, anti- | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. anemia, hypocomplementemia, and elevated ANA and anti-dsDNA antibodies).Butbul Aviel et al reported three individuals with the SLE/prolidase deficiency association:A boy age 4.5 years with a rash consistent with hypertrophic discoid lupus on biopsy, proteinuria and mild hematuria with a renal biopsy consistent with WHO Class IV lupus nephritis, low C3 and C4 levels, positive ANA (1:640; homogeneous pattern), anti ds-DNA, anti-RNP, anti-SM, anti Ro (SS-A) and anti La (SS-B)A girl age 16 years with macroscopic hematuria and proteinuria, with a renal biopsy demonstrating WHO Class IV lupus nephritis; she had low C3 and C4, as well as a highly positive ANA and positive anti ds-DNA titerA woman age 24 years with thrombocytopenia, a positive Coombs test, low C3 and C3 levels, and positive ANA and anti ds-DNA titersPositive ANA | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. -RNP, anti-SM, anti Ro (SS-A) and anti La (SS-B)A girl age 16 years with macroscopic hematuria and proteinuria, with a renal biopsy demonstrating WHO Class IV lupus nephritis; she had low C3 and C4, as well as a highly positive ANA and positive anti ds-DNA titerA woman age 24 years with thrombocytopenia, a positive Coombs test, low C3 and C3 levels, and positive ANA and anti ds-DNA titersPositive ANA, anti-dsDNA, anti-ENA (anti-Ro), anti-Sm and anti-chromatin have been found in individuals with prolidase deficiency even in the absence of clinical findings of SLE .Bone manifestations. Among 12 affected individuals reported by Besio et al , short stature was described in seven, osteopenia in six, and genu valgum in four.Other bone findings include spina bifida of C3 and 13 thoracic vertebrae ; fusion of C2 and C3 | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. DNA titersPositive ANA, anti-dsDNA, anti-ENA (anti-Ro), anti-Sm and anti-chromatin have been found in individuals with prolidase deficiency even in the absence of clinical findings of SLE .Bone manifestations. Among 12 affected individuals reported by Besio et al , short stature was described in seven, osteopenia in six, and genu valgum in four.Other bone findings include spina bifida of C3 and 13 thoracic vertebrae ; fusion of C2 and C3 ; and delayed bone age .Digital clubbing, in the presence and in the absence of pulmonary abnormalities, has also been reported .Other manifestationsJoint laxity , including hip dislocation Protuberant abdomen in five of the first 17 cases reported Obesity Optic and chorioretinal atrophy , keratitis and pathologic myopia Erosive cystitis (one individual) Dental dysplasia Autoimmune adrenal failure (one individual) Prognosis. The severity of prolidase deficiency is quite variable: in some individuals skin ulcerations lead to amputation | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. ; fusion of C2 and C3 ; and delayed bone age .Digital clubbing, in the presence and in the absence of pulmonary abnormalities, has also been reported .Other manifestationsJoint laxity , including hip dislocation Protuberant abdomen in five of the first 17 cases reported Obesity Optic and chorioretinal atrophy , keratitis and pathologic myopia Erosive cystitis (one individual) Dental dysplasia Autoimmune adrenal failure (one individual) Prognosis. The severity of prolidase deficiency is quite variable: in some individuals skin ulcerations lead to amputation of one or all toes , whereas others remain entirely asymptomatic.Two individuals diagnosed through systematic urinary newborn screening in Quebec remained asymptomatic 14 years later .A man age 26 years, whose younger sister was affected, had imidodipeptiduria and prolidase deficiency in erythrocytes but no clinical manifestations .A woman age 29 years, the sister of an affected individual, had absence of prolidase activity in serum or erythrocytes, but no skin ulcers or other clinical manifestations of prolidase | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. skin ulcerations lead to amputation of one or all toes , whereas others remain entirely asymptomatic.Two individuals diagnosed through systematic urinary newborn screening in Quebec remained asymptomatic 14 years later .A man age 26 years, whose younger sister was affected, had imidodipeptiduria and prolidase deficiency in erythrocytes but no clinical manifestations .A woman age 29 years, the sister of an affected individual, had absence of prolidase activity in serum or erythrocytes, but no skin ulcers or other clinical manifestations of prolidase deficiency .In most instances, individuals with prolidase deficiency experience severe morbidity and early death, usually due to infection.The individual with probable prolidase deficiency reported by Goodman et al had died of influenza by the time of a follow-up biochemical report four years later . He was about age 50 years at the time of death .The female reported by Lapiere & Nusgens died at age 36 years ; she had superinfection of skin ulcers with Pseudomonas | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. other clinical manifestations of prolidase deficiency .In most instances, individuals with prolidase deficiency experience severe morbidity and early death, usually due to infection.The individual with probable prolidase deficiency reported by Goodman et al had died of influenza by the time of a follow-up biochemical report four years later . He was about age 50 years at the time of death .The female reported by Lapiere & Nusgens died at age 36 years ; she had superinfection of skin ulcers with Pseudomonas aeruginosa, which lead to septic shock and disseminated intravascular coagulation .A female died of a fungal infection and disseminated intravascular coagulation .A girl age 16 years with prolidase deficiency and SLE developed cellulitis of the leg, followed by adult respiratory distress syndrome and death .A male died at 15 years of age of unknown reasons .A patient age 15 years died of terminal liver failure and cardiac failure .A patent age 11 years died of unknown causes .A boy age eight years with prolidase | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. infection of skin ulcers with Pseudomonas aeruginosa, which lead to septic shock and disseminated intravascular coagulation .A female died of a fungal infection and disseminated intravascular coagulation .A girl age 16 years with prolidase deficiency and SLE developed cellulitis of the leg, followed by adult respiratory distress syndrome and death .A male died at 15 years of age of unknown reasons .A patient age 15 years died of terminal liver failure and cardiac failure .A patent age 11 years died of unknown causes .A boy age eight years with prolidase deficiency and SLE died after developing a facial abscess and septicemia .The youngest reported death was at age four years .Genotype-Phenotype CorrelationsThere are no known genotype-phenotype correlations. Marked phenotypic variability has been found among affected individuals from the same family (who have the same pathogenic variants) .NomenclatureProlidase deficiency was also known as hyperimidodipeptiduria, although increased excretion of imidodipeptides is not exclusive to prolidase deficiency. Other | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. age eight years with prolidase deficiency and SLE died after developing a facial abscess and septicemia .The youngest reported death was at age four years .Genotype-Phenotype CorrelationsThere are no known genotype-phenotype correlations. Marked phenotypic variability has been found among affected individuals from the same family (who have the same pathogenic variants) .NomenclatureProlidase deficiency was also known as hyperimidodipeptiduria, although increased excretion of imidodipeptides is not exclusive to prolidase deficiency. Other names used in the past include imidodipeptidase deficiency and peptidase D deficiency.PrevalenceApproximately 90 affected individuals have been reported in the literature; however, prolidase deficiency likely remains underdiagnosed as a result of under-recognition by physicians.The Québec Newborn Urine Screening Program (Programme québécois de dépistage neonatal Urinaire, PQDNU) identified two affected infants out of 2,469,929 screened between 1973 and 2006, | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. to prolidase deficiency. Other names used in the past include imidodipeptidase deficiency and peptidase D deficiency.PrevalenceApproximately 90 affected individuals have been reported in the literature; however, prolidase deficiency likely remains underdiagnosed as a result of under-recognition by physicians.The Québec Newborn Urine Screening Program (Programme québécois de dépistage neonatal Urinaire, PQDNU) identified two affected infants out of 2,469,929 screened between 1973 and 2006, for an incidence of 1:1,235,000 . Thus, a few thousand cases would be predicted to exist worldwide, as opposed to only 90 cases reported to date.Prolidase deficiency has been diagnosed throughout the world .A founder variant has been described in the Geauga County settlement in Ohio , as well as in the Druze population in northern Israel, the latter with a carrier frequency of 1:21 .Differential DiagnosisDisorders with Imidodipe | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. screened between 1973 and 2006, for an incidence of 1:1,235,000 . Thus, a few thousand cases would be predicted to exist worldwide, as opposed to only 90 cases reported to date.Prolidase deficiency has been diagnosed throughout the world .A founder variant has been described in the Geauga County settlement in Ohio , as well as in the Druze population in northern Israel, the latter with a carrier frequency of 1:21 .Differential DiagnosisDisorders with ImidodipeptiduriaImidodipeptiduria has been described in bone disorders, presumably originating from collagen under conditions of high bone turnover.Glycylproline has been found in the urine of:A child with severe bone disease and hyperphosphatasia ;Two sisters with multiple fractures and striking bone deformities of unknown etiology ;A woman age 28 years with osteomalacia and severe hyperparathyroidism who excreted large amounts of glycylproline, equivalent to ~1 g/day ; | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. Disorders with ImidodipeptiduriaImidodipeptiduria has been described in bone disorders, presumably originating from collagen under conditions of high bone turnover.Glycylproline has been found in the urine of:A child with severe bone disease and hyperphosphatasia ;Two sisters with multiple fractures and striking bone deformities of unknown etiology ;A woman age 28 years with osteomalacia and severe hyperparathyroidism who excreted large amounts of glycylproline, equivalent to ~1 g/day ;Three individuals with rickets who excreted decreasing amounts of glycylproline concomitant with clinical improvement, until the imidodipeptiduria disappeared with recovery from the disease.Disorders with Skin UlcersWerner syndrome is characterized by cancer predisposition and the premature appearance of features associated with normal aging. Findings shared by prolidase deficiency and Werner syndrome are chronic lower extremity ulcers , premature graying of the hair, and a "bird-like" facial appearance . Imidodi | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. ~1 g/day ;Three individuals with rickets who excreted decreasing amounts of glycylproline concomitant with clinical improvement, until the imidodipeptiduria disappeared with recovery from the disease.Disorders with Skin UlcersWerner syndrome is characterized by cancer predisposition and the premature appearance of features associated with normal aging. Findings shared by prolidase deficiency and Werner syndrome are chronic lower extremity ulcers , premature graying of the hair, and a "bird-like" facial appearance . Imidodipeptiduria has not been reported in Werner syndrome. Werner syndrome is caused by biallelic pathogenic variants in WRN and inherited in an autosomal recessive manner.Sickle cell disease (SCD) is characterized by intermittent vaso-occlusive events and chronic hemolytic anemia. Leg ulcers which are relatively common in SCD were found in 2.5% of patients from the Cooperative Study of Sickle Cell Disease in the US , in 43% in the Jamaican | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. " facial appearance . Imidodipeptiduria has not been reported in Werner syndrome. Werner syndrome is caused by biallelic pathogenic variants in WRN and inherited in an autosomal recessive manner.Sickle cell disease (SCD) is characterized by intermittent vaso-occlusive events and chronic hemolytic anemia. Leg ulcers which are relatively common in SCD were found in 2.5% of patients from the Cooperative Study of Sickle Cell Disease in the US , in 43% in the Jamaican Cohort Study , and in 1.7% to 13.2% of Africans.Although urinary excretion of hydroxyproline has been shown to be significantly increased in persons with sickle cell disease compared to controls (presumably due to bone involvement), glycylprolinuria has not been reported in SCD. More importantly, although individuals with prolidase deficiency can have mild findings of hemolysis, they do not have veno-occlusive episodes. SCD is caused by biallelic pathogenic variants | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. % in the Jamaican Cohort Study , and in 1.7% to 13.2% of Africans.Although urinary excretion of hydroxyproline has been shown to be significantly increased in persons with sickle cell disease compared to controls (presumably due to bone involvement), glycylprolinuria has not been reported in SCD. More importantly, although individuals with prolidase deficiency can have mild findings of hemolysis, they do not have veno-occlusive episodes. SCD is caused by biallelic pathogenic variants in HBB and inherited in an autosomal recessive manner.Beta-thalassemia is characterized by reduced synthesis of the hemoglobin subunit beta (hemoglobin beta chain) that results in reduced amounts of hemoglobin A, microcytic hypochromic anemia, and an abnormal peripheral blood smear with nucleated red blood cells. Affected individuals with other hemoglobinopathies such as β-thalassemia can also have chronic leg ulcers , but again no imidopeptiduria is known to occur. Persons with prolidase deficiency should | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. by biallelic pathogenic variants in HBB and inherited in an autosomal recessive manner.Beta-thalassemia is characterized by reduced synthesis of the hemoglobin subunit beta (hemoglobin beta chain) that results in reduced amounts of hemoglobin A, microcytic hypochromic anemia, and an abnormal peripheral blood smear with nucleated red blood cells. Affected individuals with other hemoglobinopathies such as β-thalassemia can also have chronic leg ulcers , but again no imidopeptiduria is known to occur. Persons with prolidase deficiency should have a normal hemoglobin electrophoretic pattern. β-thalassemia is caused by biallelic pathogenic variants in HBB and inherited in an autosomal recessive manner.Acquired causes of lower-extremity ulcers include arterial insufficiency, venous insufficiency, pressure ulcers, vasculitis, systemic lupus erythematosus, and infectious etiologies, among others. Although glycineprolinuria could be anticipated in cases of secondary skin ulcers given the high content of collagen in the dermis, a number of patients with extensive skin ulceration have been tested | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. Persons with prolidase deficiency should have a normal hemoglobin electrophoretic pattern. β-thalassemia is caused by biallelic pathogenic variants in HBB and inherited in an autosomal recessive manner.Acquired causes of lower-extremity ulcers include arterial insufficiency, venous insufficiency, pressure ulcers, vasculitis, systemic lupus erythematosus, and infectious etiologies, among others. Although glycineprolinuria could be anticipated in cases of secondary skin ulcers given the high content of collagen in the dermis, a number of patients with extensive skin ulceration have been tested, and imidodipeptiduria was only found when accompanied by severe concurrent bone disease (e.g., multiple fractures) .Disorders with Hyper IgEAutosomal dominant hyper IgE syndrome (AD-HIES) is a primary immune deficiency syndrome characterized by the classic triad of recurrent skin boils, cyst-forming pneumonias, and extreme elevations of serum IgE. It is now recognized that other common manifestations include eczema, mucocutaneous candidiasis, and several | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. extensive skin ulceration have been tested, and imidodipeptiduria was only found when accompanied by severe concurrent bone disease (e.g., multiple fractures) .Disorders with Hyper IgEAutosomal dominant hyper IgE syndrome (AD-HIES) is a primary immune deficiency syndrome characterized by the classic triad of recurrent skin boils, cyst-forming pneumonias, and extreme elevations of serum IgE. It is now recognized that other common manifestations include eczema, mucocutaneous candidiasis, and several connective tissue and skeletal abnormalities like osteopenia, minimal trauma fractures, and scoliosis. AD-HIES is caused by mutation of STAT3. A Grimbacher score of >40 is suggestive of AD-HIES.Autosomal recessive hyper IgE syndrome (AR-HIES) (OMIM 243700) is a distinct clinical disorder, characterized by elevated serum concentration of IgE, severe eczema, and recurrent skin and lung infections , all of which can also be seen | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. eous candidiasis, and several connective tissue and skeletal abnormalities like osteopenia, minimal trauma fractures, and scoliosis. AD-HIES is caused by mutation of STAT3. A Grimbacher score of >40 is suggestive of AD-HIES.Autosomal recessive hyper IgE syndrome (AR-HIES) (OMIM 243700) is a distinct clinical disorder, characterized by elevated serum concentration of IgE, severe eczema, and recurrent skin and lung infections , all of which can also be seen in prolidase deficiency. Prolidase deficiency differs from AD-HIES by an increased incidence of neurologic abnormalities, an increased occurrence of viral infections of the skin (e.g., Molluscum contagiosum, warts) and virus-driven malignancies, as well as absence of the non-immunologic findings of AD-HIES (e.g., connective tissue, skeletal and dental involvement) . AR-HIES is caused by biallelic pathogenic | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. of which can also be seen in prolidase deficiency. Prolidase deficiency differs from AD-HIES by an increased incidence of neurologic abnormalities, an increased occurrence of viral infections of the skin (e.g., Molluscum contagiosum, warts) and virus-driven malignancies, as well as absence of the non-immunologic findings of AD-HIES (e.g., connective tissue, skeletal and dental involvement) . AR-HIES is caused by biallelic pathogenic variants in K8.ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease and needs in an individual diagnosed with prolidase deficiency, the following evaluations are recommended:Review of systems to assess for the possibility of pulmonary complications. In those with a history of pulmonary complications, consider chest imaging, pulmonary function tests, an echocardiogram to assess for pulmonary hypertension, and consultation with a pulmonologist.Physical examination to evaluate for splenomegaly. If present, perform an abdominal ultrasound examination to | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. caused by biallelic pathogenic variants in K8.ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease and needs in an individual diagnosed with prolidase deficiency, the following evaluations are recommended:Review of systems to assess for the possibility of pulmonary complications. In those with a history of pulmonary complications, consider chest imaging, pulmonary function tests, an echocardiogram to assess for pulmonary hypertension, and consultation with a pulmonologist.Physical examination to evaluate for splenomegaly. If present, perform an abdominal ultrasound examination to evaluate the extent of splenomegaly.Complete blood count to evaluate for anemia and thrombocytopeniaLiver function tests to assess for the possibility of elevated liver enzymesDevelopmental assessmentConsultation with a wound care specialistConsultation with a clinical geneticist and/or genetic counselorTreatment of ManifestationsNo curative treatment is available.Care is preferably provided by a multidisciplinary team. Supportive treatment of skin, lung, and immunologic manifestations has been efficacious in some (but not in all) | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. perform an abdominal ultrasound examination to evaluate the extent of splenomegaly.Complete blood count to evaluate for anemia and thrombocytopeniaLiver function tests to assess for the possibility of elevated liver enzymesDevelopmental assessmentConsultation with a wound care specialistConsultation with a clinical geneticist and/or genetic counselorTreatment of ManifestationsNo curative treatment is available.Care is preferably provided by a multidisciplinary team. Supportive treatment of skin, lung, and immunologic manifestations has been efficacious in some (but not in all) patients. Caution is warranted in the treatment of infections, which can be fulminant and fatal.Click here (pdf) for further details, including treatments in which only partial or short-term benefit was reported.Prevention of Secondary ComplicationsThose who have undergone splenectomy should be appropriately immunized and treated promptly with antibiotics at the first sign of infection.Antibiotic prophylaxis should also be considered in the appropriate setting.SurveillanceIn the absence of formal surveillance guidelines, the authors recommend:Annual:Skin | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. (but not in all) patients. Caution is warranted in the treatment of infections, which can be fulminant and fatal.Click here (pdf) for further details, including treatments in which only partial or short-term benefit was reported.Prevention of Secondary ComplicationsThose who have undergone splenectomy should be appropriately immunized and treated promptly with antibiotics at the first sign of infection.Antibiotic prophylaxis should also be considered in the appropriate setting.SurveillanceIn the absence of formal surveillance guidelines, the authors recommend:Annual:Skin examination for evidence of malignant transformation in persons with chronic recalcitrant skin ulcersComplete blood countLiver function testsAbdominal ultrasound examination to assess liver and spleen sizeFollow up as recommended by a pulmonologist and immunologist;Follow-up assessments of motor and cognitive development as recommended for educational planning.Agents/Circumstances to AvoidIndividuals with prolidase deficiency who have splenomegaly should avoid contact sports given the increased risk for splenic rupture.Evaluation of Relatives at RiskSee Genetic | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. authors recommend:Annual:Skin examination for evidence of malignant transformation in persons with chronic recalcitrant skin ulcersComplete blood countLiver function testsAbdominal ultrasound examination to assess liver and spleen sizeFollow up as recommended by a pulmonologist and immunologist;Follow-up assessments of motor and cognitive development as recommended for educational planning.Agents/Circumstances to AvoidIndividuals with prolidase deficiency who have splenomegaly should avoid contact sports given the increased risk for splenic rupture.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationAdenovirus-mediated gene transfer.
Ikeda et al performed transfer of the human prolidase cDNA into fibroblasts from patients with prolidase deficiency. This increased the fibroblast prolidase activity up to 75 times normal.Intracellular delivery of liposome-encapsulated prolidase.
Perugini et al showed that active prolidase encapsulated in liposomes was completely transported via endocytosis into fibroblasts six days after incubation | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK299584/ | NrrA826 | Prolidase Deficiency | C0268532 | 31,758 | prolidase deficiency. of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationAdenovirus-mediated gene transfer.
Ikeda et al performed transfer of the human prolidase cDNA into fibroblasts from patients with prolidase deficiency. This increased the fibroblast prolidase activity up to 75 times normal.Intracellular delivery of liposome-encapsulated prolidase.
Perugini et al showed that active prolidase encapsulated in liposomes was completely transported via endocytosis into fibroblasts six days after incubation.Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for access to information on clinical studies for a wide range of diseases and conditions. | [
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orphanet | https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=99657 | Q4DAqj3 | Primary dystonia, DYT2 type | C1857093 | 31,759 | primary dystonia, dyt2 type. Primary dystonia DYT2 type is characterized by segmental dystonia that manifests with involuntary posturing affecting predominantly the feet.
Epidemiology
The exact prevalence is unknown. The disease is reported in a limited number of Jewish and Gypsy families.
Clinical description
The onset of the symptoms is early in childhood or adolescence. Progression to generalized dystonia is possible.
Genetic counseling
The DYT2 locus is unknown. Autosomal recessive transmission is suggested. | [
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omim | https://www.omim.org/entry/251945 | O0gYNLn | MITOCHONDRIAL MYOPATHY WITH A DEFECT IN MITOCHONDRIAL-PROTEIN TRANSPORT | C1855034 | 31,760 | mitochondrial myopathy with a defect in mitochondrial-protein transport. Schapira et al. (1990) described the 14-year-old daughter of an English father and Chinese mother who had had muscle weakness and exercise intolerance since early infancy. Fetal movements had been reduced during pregnancy. There were no clinical manifestations related to systems other than skeletal muscle. Deficiency of respiratory-chain Complexes I to IV was found. Mitochondrial preparations showed specific deficiencies of both the iron-sulfur protein of Complex III ('Rieske' protein) and the 27.2-kD subunit of succinate dehydrogenase. Similar experiments with muscle homogenates indicated a deficiency of the subunit of succinate dehydrogenase, but normal levels of the precursor Rieske protein. The findings were interpreted as indicating a defect in the transport of the Rieske protein into mitochondria. Schapira et al. (1990) speculated that some iron-sulfur proteins of the mitochondrial respiratory chain may be encoded by a cluster of nuclear genes and that a mutation affecting a single | [
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] |
omim | https://www.omim.org/entry/251945 | O0gYNLn | MITOCHONDRIAL MYOPATHY WITH A DEFECT IN MITOCHONDRIAL-PROTEIN TRANSPORT | C1855034 | 31,760 | mitochondrial myopathy with a defect in mitochondrial-protein transport. eske' protein) and the 27.2-kD subunit of succinate dehydrogenase. Similar experiments with muscle homogenates indicated a deficiency of the subunit of succinate dehydrogenase, but normal levels of the precursor Rieske protein. The findings were interpreted as indicating a defect in the transport of the Rieske protein into mitochondria. Schapira et al. (1990) speculated that some iron-sulfur proteins of the mitochondrial respiratory chain may be encoded by a cluster of nuclear genes and that a mutation affecting a single coding sequence could account for the double deficiency. This could lead to a reduced synthesis of the 27.2-kD polypeptide and produce changes in the coding of the Rieske precursor sequence such that its receptor-mediated transport into mitochondria is defective.
Muscle
- Muscle weakness
- Exercise intolerance
Misc
- Fetal movements reduced
Lab
- Deficiency of respiratory-chain Complexes I to IV
- Mitochondrial deficiencies of both the iron-sulfur protein of Complex III (' | [
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] |
omim | https://www.omim.org/entry/251945 | O0gYNLn | MITOCHONDRIAL MYOPATHY WITH A DEFECT IN MITOCHONDRIAL-PROTEIN TRANSPORT | C1855034 | 31,760 | mitochondrial myopathy with a defect in mitochondrial-protein transport. by a cluster of nuclear genes and that a mutation affecting a single coding sequence could account for the double deficiency. This could lead to a reduced synthesis of the 27.2-kD polypeptide and produce changes in the coding of the Rieske precursor sequence such that its receptor-mediated transport into mitochondria is defective.
Muscle
- Muscle weakness
- Exercise intolerance
Misc
- Fetal movements reduced
Lab
- Deficiency of respiratory-chain Complexes I to IV
- Mitochondrial deficiencies of both the iron-sulfur protein of Complex III ('Rieske' protein) and the 27.2-kD subunit of succinate dehydrogenase
- Defective transport of the Rieske protein into mitochondria
Inheritance
- Autosomal recessive
▲ Close | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK99495/ | JOqrnDM | Proteus Syndrome | C0085261 | 31,761 | proteus syndrome. SummaryClinical characteristics.Proteus syndrome is characterized by progressive segmental or patchy overgrowth most commonly affecting the skeleton, skin, adipose, and central nervous systems. In most individuals Proteus syndrome has modest or no manifestations at birth, develops and progresses rapidly beginning in the toddler period, and relentlessly progresses through childhood, causing severe overgrowth and disfigurement. It is associated with a range of tumors, pulmonary complications, and a striking predisposition to deep vein thrombosis and pulmonary embolism.Diagnosis/testing.The diagnosis of Proteus syndrome is based on clinical criteria that include all three general characteristics (mosaic distribution of lesions, sporadic occurrence, progressive course) and additional specific clinical criteria. Identification of a mosaic, somatic, heterozygous pathogenic variant in AKT1 by molecular genetic testing can establish the diagnosis if the clinical criteria are inconclusive.Management.Treatment of manifestations: Management of overgrowth is the chief concern; the approaches are diverse and include various orthopedic procedures to delay or halt linear bone growth; rehabilitation | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK99495/ | JOqrnDM | Proteus Syndrome | C0085261 | 31,761 | proteus syndrome. .Diagnosis/testing.The diagnosis of Proteus syndrome is based on clinical criteria that include all three general characteristics (mosaic distribution of lesions, sporadic occurrence, progressive course) and additional specific clinical criteria. Identification of a mosaic, somatic, heterozygous pathogenic variant in AKT1 by molecular genetic testing can establish the diagnosis if the clinical criteria are inconclusive.Management.Treatment of manifestations: Management of overgrowth is the chief concern; the approaches are diverse and include various orthopedic procedures to delay or halt linear bone growth; rehabilitation medicine care including physical and occupational therapy; correction of skeletal deformities such as scoliosis; dermatologic management of the skin manifestations, especially the cerebriform connective tissue nevi with pedorthic intervention as needed; monitoring for and treating deep vein thrombosis and pulmonary embolism; monitoring and treating bullous pulmonary disease; developmental intervention or special education for developmental delays; psychosocial counseling is warranted in most instances.Surveillance: Monitoring should be tailored to individual presentation; routine monitoring for evidence of tumor development is by medical history | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK99495/ | JOqrnDM | Proteus Syndrome | C0085261 | 31,761 | proteus syndrome. linear bone growth; rehabilitation medicine care including physical and occupational therapy; correction of skeletal deformities such as scoliosis; dermatologic management of the skin manifestations, especially the cerebriform connective tissue nevi with pedorthic intervention as needed; monitoring for and treating deep vein thrombosis and pulmonary embolism; monitoring and treating bullous pulmonary disease; developmental intervention or special education for developmental delays; psychosocial counseling is warranted in most instances.Surveillance: Monitoring should be tailored to individual presentation; routine monitoring for evidence of tumor development is by medical history and physical examination; periodic imaging is not indicated.Agents/circumstances to avoid: Medications that increase the risk of deep vein thrombosis or are procoagulant; medications that increase growth (e.g., androgenic steroids or growth hormone).Genetic counseling.All individuals with clinically confirmed Proteus syndrome known to these authors have been simplex occurrences caused by somatic mosaicism for the specific de novo pathogenic variant c.49G>A (p.Glu17Lys). It is hypothesized | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK99495/ | JOqrnDM | Proteus Syndrome | C0085261 | 31,761 | proteus syndrome. development is by medical history and physical examination; periodic imaging is not indicated.Agents/circumstances to avoid: Medications that increase the risk of deep vein thrombosis or are procoagulant; medications that increase growth (e.g., androgenic steroids or growth hormone).Genetic counseling.All individuals with clinically confirmed Proteus syndrome known to these authors have been simplex occurrences caused by somatic mosaicism for the specific de novo pathogenic variant c.49G>A (p.Glu17Lys). It is hypothesized that a non-mosaic (i.e., germline) AKT1 c.49G>A pathogenic variant would be lethal in early development. There is no known risk to offspring of an affected individual; however, the number of affected individuals who have reproduced is very small. Thus, the risks to the parents of an affected child and to affected persons who do reproduce are not increased compared to the general population. Because Proteus syndrome is not inherited, prenatal testing is | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK99495/ | JOqrnDM | Proteus Syndrome | C0085261 | 31,761 | proteus syndrome. ). It is hypothesized that a non-mosaic (i.e., germline) AKT1 c.49G>A pathogenic variant would be lethal in early development. There is no known risk to offspring of an affected individual; however, the number of affected individuals who have reproduced is very small. Thus, the risks to the parents of an affected child and to affected persons who do reproduce are not increased compared to the general population. Because Proteus syndrome is not inherited, prenatal testing is not indicated.DiagnosisSuggestive FindingsProteus syndrome (PS) should be suspected in a proband with the following.Major findingsDistorting, progressive overgrowth, typically of postnatal onset often resulting in asymmetric distortion of the skeletal architecture. Hemimegencephaly can be prenatal.Cerebriform connective tissue nevi (CCTN), a specific type of connective tissue nevus that is characterized by deep grooves and gyrations as seen on the surface of the brainLinear verruc | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK99495/ | JOqrnDM | Proteus Syndrome | C0085261 | 31,761 | proteus syndrome. inherited, prenatal testing is not indicated.DiagnosisSuggestive FindingsProteus syndrome (PS) should be suspected in a proband with the following.Major findingsDistorting, progressive overgrowth, typically of postnatal onset often resulting in asymmetric distortion of the skeletal architecture. Hemimegencephaly can be prenatal.Cerebriform connective tissue nevi (CCTN), a specific type of connective tissue nevus that is characterized by deep grooves and gyrations as seen on the surface of the brainLinear verrucous epidermal nevus (LVEN), a streaky, pigmented, rough nevus that often follows the lines of Blaschko and can be present anywhere on the bodyAdipose dysregulation including lipomatous overgrowth and lipoatrophyOther:Vascular malformations including cutaneous capillary malformations, prominent venous patterning or varicosities, and lymphatic malformationsOvergrowth of other tissues, most commonly spleen, liver, thymus, and gastrointestinal tractTumors, most commonly meningiomas | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK99495/ | JOqrnDM | Proteus Syndrome | C0085261 | 31,761 | proteus syndrome. the brainLinear verrucous epidermal nevus (LVEN), a streaky, pigmented, rough nevus that often follows the lines of Blaschko and can be present anywhere on the bodyAdipose dysregulation including lipomatous overgrowth and lipoatrophyOther:Vascular malformations including cutaneous capillary malformations, prominent venous patterning or varicosities, and lymphatic malformationsOvergrowth of other tissues, most commonly spleen, liver, thymus, and gastrointestinal tractTumors, most commonly meningiomas. Ovarian cystadenomas, breast cancer, parotid monomorphic adenoma, mesothelioma, and others have also been reported.Bullous pulmonary degenerationDysmorphic facial features including dolichocephaly, long face, downslanting palpebral fissures, and/or minor ptosis, depressed nasal bridge, wide or anteverted nares, and open mouth at restEstablishing the DiagnosisThe diagnosis of Proteus syndrome (PS) is established in a | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK99495/ | JOqrnDM | Proteus Syndrome | C0085261 | 31,761 | proteus syndrome. s, most commonly meningiomas. Ovarian cystadenomas, breast cancer, parotid monomorphic adenoma, mesothelioma, and others have also been reported.Bullous pulmonary degenerationDysmorphic facial features including dolichocephaly, long face, downslanting palpebral fissures, and/or minor ptosis, depressed nasal bridge, wide or anteverted nares, and open mouth at restEstablishing the DiagnosisThe diagnosis of Proteus syndrome (PS) is established in a proband with the following general and specific criteria. Identification of a mosaic, somatic, heterozygous pathogenic variant in AKT1 by molecular genetic testing (see Table 1) can establish the diagnosis if clinical criteria are inconclusive.ALL of the following general criteria:Mosaic distribution of lesionsSporadic occurrenceProgressive courseANDSpecific criteria from categories A-C:One from category A; ORTwo from category B; ORThree from category CCategories of Specific Criteria to Establish | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK99495/ | JOqrnDM | Proteus Syndrome | C0085261 | 31,761 | proteus syndrome. ) is established in a proband with the following general and specific criteria. Identification of a mosaic, somatic, heterozygous pathogenic variant in AKT1 by molecular genetic testing (see Table 1) can establish the diagnosis if clinical criteria are inconclusive.ALL of the following general criteria:Mosaic distribution of lesionsSporadic occurrenceProgressive courseANDSpecific criteria from categories A-C:One from category A; ORTwo from category B; ORThree from category CCategories of Specific Criteria to Establish the Diagnosis of Proteus SyndromeCategory A. Cerebriform connective tissue nevus (CCTN). See Suggestive Findings.Category BLinear epidermal nevusAsymmetric, disproportionate overgrowth (≥1 of the following):Note: Asymmetric, disproportionate overgrowth should be carefully distinguished from asymmetric, proportionate, or ballooning overgrowth.LimbsHyperostosis of the skullHyperostosis of the external auditory canalMegaspondylodysplasia (i.e., abnormal growth of vertebrae | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK99495/ | JOqrnDM | Proteus Syndrome | C0085261 | 31,761 | proteus syndrome. of Specific Criteria to Establish the Diagnosis of Proteus SyndromeCategory A. Cerebriform connective tissue nevus (CCTN). See Suggestive Findings.Category BLinear epidermal nevusAsymmetric, disproportionate overgrowth (≥1 of the following):Note: Asymmetric, disproportionate overgrowth should be carefully distinguished from asymmetric, proportionate, or ballooning overgrowth.LimbsHyperostosis of the skullHyperostosis of the external auditory canalMegaspondylodysplasia (i.e., abnormal growth of vertebrae)Viscera: spleen/thymusSpecific tumors with onset before the second decade (either of the following):Bilateral ovarian cystadenomaParotid monomorphic adenomaCategory CDysregulated adipose tissue (either of the following):Lipomatous overgrowthRegional lipoatrophyVascular malformations (one of the following):Capillary malformationVenous malformationLymphatic malformationBullous pulmonary degenerationFacial phenotype (all of the following): | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK99495/ | JOqrnDM | Proteus Syndrome | C0085261 | 31,761 | proteus syndrome. , abnormal growth of vertebrae)Viscera: spleen/thymusSpecific tumors with onset before the second decade (either of the following):Bilateral ovarian cystadenomaParotid monomorphic adenomaCategory CDysregulated adipose tissue (either of the following):Lipomatous overgrowthRegional lipoatrophyVascular malformations (one of the following):Capillary malformationVenous malformationLymphatic malformationBullous pulmonary degenerationFacial phenotype (all of the following):DolichocephalyLong faceDownslanting palpebral fissures and/or minor ptosisDepressed nasal bridgeWide or anteverted naresOpen mouth at restMolecular Genetic TestingApproaches can include targeted analysis, use of a multigene panel, and more comprehensive genomic testing:Targeted analysis for pathogenic variant c.49G>A (p.Glu17Lys) in the affected tissue, if possible, is | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK99495/ | JOqrnDM | Proteus Syndrome | C0085261 | 31,761 | proteus syndrome. of the following):DolichocephalyLong faceDownslanting palpebral fissures and/or minor ptosisDepressed nasal bridgeWide or anteverted naresOpen mouth at restMolecular Genetic TestingApproaches can include targeted analysis, use of a multigene panel, and more comprehensive genomic testing:Targeted analysis for pathogenic variant c.49G>A (p.Glu17Lys) in the affected tissue, if possible, is performed first.Note: (1) Although a single AKT1 variant has been reported, it is possible that other variants in this gene detectable by sequence analysis could be causative of disease. (2) Because all AKT1 c.49G>A pathogenic variants reported to date are somatic and mosaic, more than one tissue sample may be required for diagnosis. Identification of an AKT1 pathogenic variant requires analysis of affected tissues, typically a punch biopsy of an affected area | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK99495/ | JOqrnDM | Proteus Syndrome | C0085261 | 31,761 | proteus syndrome. , if possible, is performed first.Note: (1) Although a single AKT1 variant has been reported, it is possible that other variants in this gene detectable by sequence analysis could be causative of disease. (2) Because all AKT1 c.49G>A pathogenic variants reported to date are somatic and mosaic, more than one tissue sample may be required for diagnosis. Identification of an AKT1 pathogenic variant requires analysis of affected tissues, typically a punch biopsy of an affected area of skin. (3) A minority of affected individuals (2/31 reported by Lindhurst et al ) with the AKT1 c.49G>A pathogenic variant identified in one or more tissues had the pathogenic variant identified in a peripheral blood sample. Therefore, the absence of a pathogenic variant in a peripheral blood sample is not sufficient to exclude the diagnosis.A multigene panel that includes AKT1 and other genes of interest (see Differential Diagnosis) may | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK99495/ | JOqrnDM | Proteus Syndrome | C0085261 | 31,761 | proteus syndrome. biopsy of an affected area of skin. (3) A minority of affected individuals (2/31 reported by Lindhurst et al ) with the AKT1 c.49G>A pathogenic variant identified in one or more tissues had the pathogenic variant identified in a peripheral blood sample. Therefore, the absence of a pathogenic variant in a peripheral blood sample is not sufficient to exclude the diagnosis.A multigene panel that includes AKT1 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 pathogenic variants in genes that do | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK99495/ | JOqrnDM | Proteus Syndrome | C0085261 | 31,761 | proteus syndrome. 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 pathogenic variants in genes that do not explain the underlying phenotype. (3) 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.More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., a variant | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK99495/ | JOqrnDM | Proteus Syndrome | C0085261 | 31,761 | proteus syndrome. variants in genes that do not explain the underlying phenotype. (3) 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.More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., a variant in a different gene or genes that results in a similar clinical presentation).For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.Note: The methodology used for testing must be designed to detect mosaic variants: that is, variants at a less than 50% allelic level. Some individuals with PS have had variant allele frequencies below 1%, which can be challenging (or impossible) to detect with some assay techniques.Table | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK99495/ | JOqrnDM | Proteus Syndrome | C0085261 | 31,761 | proteus syndrome. g., a variant in a different gene or genes that results in a similar clinical presentation).For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.Note: The methodology used for testing must be designed to detect mosaic variants: that is, variants at a less than 50% allelic level. Some individuals with PS have had variant allele frequencies below 1%, which can be challenging (or impossible) to detect with some assay techniques.Table 1. Molecular Genetic Testing Used in Proteus SyndromeView in own windowGene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This MethodAKT1Targeted analysis33/70 3, 4Sequence analysis 4See footnote 5Gene-targeted deletion/duplication analysis 6Unknown 71. 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/NBK99495/ | JOqrnDM | Proteus Syndrome | C0085261 | 31,761 | proteus syndrome. some assay techniques.Table 1. Molecular Genetic Testing Used in Proteus SyndromeView in own windowGene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This MethodAKT1Targeted analysis33/70 3, 4Sequence analysis 4See footnote 5Gene-targeted deletion/duplication analysis 6Unknown 71. 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. Somatic mosaicism for the AKT1 c.49G>A variant is the only pathogenic variant identified to date in individuals with clinically confirmed PS .4. The c.49G>A variant can be detected by sequence analysis of the surrounding region. 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; | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK99495/ | JOqrnDM | Proteus Syndrome | C0085261 | 31,761 | proteus syndrome. in this gene.3. Somatic mosaicism for the AKT1 c.49G>A variant is the only pathogenic variant identified to date in individuals with clinically confirmed PS .4. The c.49G>A variant can be detected by sequence analysis of the surrounding region. 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.5. Although a single AKT1 variant has been reported, it is possible that other variants in this gene detectable by sequence analysis could be causative of disease.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 ( | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK99495/ | JOqrnDM | Proteus Syndrome | C0085261 | 31,761 | proteus syndrome. 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.5. Although a single AKT1 variant has been reported, it is possible that other variants in this gene detectable by sequence analysis could be causative of disease.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.6. No data on detection rate of gene-targeted deletion/duplication analysis are available.Clinical CharacteristicsClinical DescriptionProteus syndrome (PS) displays a wide range of severity. Some individuals are minimally affected, but others are quite severely affected. Among the individuals in the NIH PS cohort, there was a projected 25% mortality before the age of 20 years .Most affected | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK99495/ | JOqrnDM | Proteus Syndrome | C0085261 | 31,761 | proteus syndrome. -dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.6. No data on detection rate of gene-targeted deletion/duplication analysis are available.Clinical CharacteristicsClinical DescriptionProteus syndrome (PS) displays a wide range of severity. Some individuals are minimally affected, but others are quite severely affected. Among the individuals in the NIH PS cohort, there was a projected 25% mortality before the age of 20 years .Most affected individuals have little or no manifestations at birth. Most typically, the first manifestations of the disorder occur between age six and 18 months with the onset of asymmetric overgrowth; it is most commonly of the feet or hands but may occur anywhere. An exception is that a few (probably <5%) first manifest PS with hemimegencephaly, often associated with CNS migration defects and later intellectual disability. This manifestation is prenatal. In most other affected individuals, the congenital | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK99495/ | JOqrnDM | Proteus Syndrome | C0085261 | 31,761 | proteus syndrome. 20 years .Most affected individuals have little or no manifestations at birth. Most typically, the first manifestations of the disorder occur between age six and 18 months with the onset of asymmetric overgrowth; it is most commonly of the feet or hands but may occur anywhere. An exception is that a few (probably <5%) first manifest PS with hemimegencephaly, often associated with CNS migration defects and later intellectual disability. This manifestation is prenatal. In most other affected individuals, the congenital manifestations are so subtle as to be discounted or missed. These include subtle degrees of asymmetry or faint linear nevi.Overgrowth. The overgrowth in PS can be startling in its severity and rapidity of progression in contrast to most segmental overgrowth disorders. The overgrowth in individuals with PS is, for most parts of the skeleton (except congenital hemimegencephaly), absent or minimal at birth, does not typically manifest until age six to 18 months, and has had its onset | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK99495/ | JOqrnDM | Proteus Syndrome | C0085261 | 31,761 | proteus syndrome. affected individuals, the congenital manifestations are so subtle as to be discounted or missed. These include subtle degrees of asymmetry or faint linear nevi.Overgrowth. The overgrowth in PS can be startling in its severity and rapidity of progression in contrast to most segmental overgrowth disorders. The overgrowth in individuals with PS is, for most parts of the skeleton (except congenital hemimegencephaly), absent or minimal at birth, does not typically manifest until age six to 18 months, and has had its onset as late as age 12 years. The typical progression of an area of overgrowth in an individual with PS is 15% larger at age one year, 30% larger at three years, and 100% larger at age six years. On plain radiographs the bones affected by PS, especially the tubular bones of the limbs, the vertebral bodies, and the skull, develop distorting, bizarre, irregular calcified overgrowth that can render the bone unrecognizable with time. The rapid and | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK99495/ | JOqrnDM | Proteus Syndrome | C0085261 | 31,761 | proteus syndrome. and has had its onset as late as age 12 years. The typical progression of an area of overgrowth in an individual with PS is 15% larger at age one year, 30% larger at three years, and 100% larger at age six years. On plain radiographs the bones affected by PS, especially the tubular bones of the limbs, the vertebral bodies, and the skull, develop distorting, bizarre, irregular calcified overgrowth that can render the bone unrecognizable with time. The rapid and severe nature of the overgrowth poses a challenge to orthopedic management. It is not uncommon for the overgrowth to accelerate rapidly in childhood, with leg length discrepancies of 20 cm being reported. Scoliotic curves of more than 90° are not uncommon. Any bone can be affected.Many individuals with PS have (often unilateral) overgrowth of the tonsils/adenoids. Splenic overgrowth and asymmetric enlargement of the kidneys and testes are also not uncommon in individuals with PS.Dermatologic findings. Cereb | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK99495/ | JOqrnDM | Proteus Syndrome | C0085261 | 31,761 | proteus syndrome. time. The rapid and severe nature of the overgrowth poses a challenge to orthopedic management. It is not uncommon for the overgrowth to accelerate rapidly in childhood, with leg length discrepancies of 20 cm being reported. Scoliotic curves of more than 90° are not uncommon. Any bone can be affected.Many individuals with PS have (often unilateral) overgrowth of the tonsils/adenoids. Splenic overgrowth and asymmetric enlargement of the kidneys and testes are also not uncommon in individuals with PS.Dermatologic findings. Cerebriform connective tissue nevi (CCTN) are present in most individuals with PS, and are nearly pathognomonic. CCTNs are rarely present in infancy, typically developing in childhood and progressing through adolescence. They are most commonly found on the sole, hand, alae, ear, and lacrimal puncta. True CCTNs are firm and have a distinct pattern resembling the brain's sulci and gyri (hence the term "cerebriform"). They | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK99495/ | JOqrnDM | Proteus Syndrome | C0085261 | 31,761 | proteus syndrome. .Dermatologic findings. Cerebriform connective tissue nevi (CCTN) are present in most individuals with PS, and are nearly pathognomonic. CCTNs are rarely present in infancy, typically developing in childhood and progressing through adolescence. They are most commonly found on the sole, hand, alae, ear, and lacrimal puncta. True CCTNs are firm and have a distinct pattern resembling the brain's sulci and gyri (hence the term "cerebriform"). They should not be confused with prominent plantar or palmar wrinkling seen in other forms of overgrowth (see Sapp et al for photographic examples of lesions with similar appearance to a CCTN). CCTNs rarely progress in adulthood . The sulci of CCTNs commonly get deep enough in late adolescence to pose challenges with cleanliness and malodor.Linear verrucous epidermal nevi are streaky, pigmented, rough nevi that often follow the lines of Blaschko. | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK99495/ | JOqrnDM | Proteus Syndrome | C0085261 | 31,761 | proteus syndrome. form"). They should not be confused with prominent plantar or palmar wrinkling seen in other forms of overgrowth (see Sapp et al for photographic examples of lesions with similar appearance to a CCTN). CCTNs rarely progress in adulthood . The sulci of CCTNs commonly get deep enough in late adolescence to pose challenges with cleanliness and malodor.Linear verrucous epidermal nevi are streaky, pigmented, rough nevi that often follow the lines of Blaschko. They can be present anywhere on the body. They are most commonly recognized in the first months of life and are generally stable over time .Overgrowth of lipomatous tissue / lipoatrophy. It is common for individuals to manifest overgrowth of adipose tissue, most commonly in infancy. Overgrowth of adipose tissue can continue to appear in novel locations throughout childhood and into young adulthood. Similarly, many individuals with PS experience marked regional lipoatrophy, and many manifest both | [
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gene_reviews | https://www.ncbi.nlm.nih.gov/books/NBK99495/ | JOqrnDM | Proteus Syndrome | C0085261 | 31,761 | proteus syndrome. Blaschko. They can be present anywhere on the body. They are most commonly recognized in the first months of life and are generally stable over time .Overgrowth of lipomatous tissue / lipoatrophy. It is common for individuals to manifest overgrowth of adipose tissue, most commonly in infancy. Overgrowth of adipose tissue can continue to appear in novel locations throughout childhood and into young adulthood. Similarly, many individuals with PS experience marked regional lipoatrophy, and many manifest both regional lipomatous overgrowth and lipoatrophy. Persons with PS do not have the typical ovoid, encapsulated lipomas common in the elderly and so the term "lipoma" is technically incorrect, but in wide usage. Fatty infiltration of the myocardium, particularly the intraventicular septum, has been observed in a number of children and adults with PS with no functional consequences .Vascular malformations. Many individuals with PS have cutaneous capillary malformations and prominent venous patterning or varicosities | [
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