GP PAR 3 PREFI

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What enzyme is deficient in reaction 1 of metabolism of galactose

galactokinase

What enzyme is deficient in reaction 2 of metabolism of galactose?

galactose-1-phosphate uridyl transferase (GALT)

polyol metabolite

galactitol

oxidized byproduct of excess galactose

galactonate Signup and view all the answers

increased osmotic pressure by galactitol accumulation leads to

cataract Signup and view all the answers

accumulation of galactose and galactose-1-phosphate that impairs amino acid transport

Aminoaciduria Signup and view all the answers

depressed neutrophil bactericidal activity

E. coli septicemia Signup and view all the answers

➔ Inherited disorder of ion transport ➔ Affects fluid secretion in exocrine glands and epithelial lining of respiratory, gastrointestinal, and reproductive tract

Cystic fibrosis (mucoviscidosis) Signup and view all the answers

Defect in cystic fibrosis

CFTR gene on chromosome 7q31.2 Signup and view all the answers

Mutated CFTR gene in sweat glands inhibits what channel

ENaC Signup and view all the answers

Mutated CFTR inhibits secretion of HCO3 in the lumen producing acidic fluid causing

Increased mucin precipitation and plugging of ducts, Increased binding of bacteria to plugged mucins Signup and view all the answers

Defective protein synthesis , complete lack of CFTR protein at the apical surface

Class I Signup and view all the answers

Abnormal protein folding, processing, and trafficking, Protein does not become fully folded and glycosylated, Most common mutations: deletion of 3 nucleotides coding for phenylalanine at amino acid position 508

Class II Signup and view all the answers

Defective regulation, Prevent activation of CFTR by abrogating ATP binding and hydrolysis o Normal amount of CFTR but nonfunctional

Class III Signup and view all the answers

Decreased conductance, Typically occur in the transmembrane domain o Normal amount but reduced function → milder phenotype

Class IV Signup and view all the answers

Reduced abundance, Affect intronic splice sites of the CFTR promoter → reduced amount of normal protein

Class V Signup and view all the answers

Altered function in regulation of ion channels, Affect regulatory role of CFTR

Class VI Signup and view all the answers

Genetic modifiers

o Mannose Binding Lectin 2 (MBL2) o Alginate producing bacteria o Transforming Growth Factor B1 o Concurrent viral infections o Interferon-Related Developmental Regulator 1 (IFRD1) Signup and view all the answers

Environmental modifiers

o Infection by Pseudomonas aeru ginosa o Alginate producing bacteria o Concurrent viral infections Signup and view all the answers

Accumulation of secretion

Grade I Signup and view all the answers

Exocrine atrophy

Grade II Signup and view all the answers

Atrophy with lipomatosis

Grade III Signup and view all the answers

Grade IV

fibrosis with total obliteration of the exocrine glands and ducts with scattered islets Signup and view all the answers

▪ Increase the function of CFTR channels ▪ Example: increases probability of Gly551Asp-CFTR channel opening

Potentiators (Ivacaftor) Signup and view all the answers

▪ improve the intracellular processing and delivery of mutant CFTR → reach the cell surface ▪ example: lumacaftor in Phe508del-CFTR

Correctors (Lumacaftor) Signup and view all the answers

▪ Promote read-through of premature termination codons in mRNA → generate more CFTR ▪ Example: Ataluren in class I mutations

Production Correctors (Ataluren) Signup and view all the answers

Sudden death of an infant under 1 year of age which remains unexplained , Also referred to as crib death or cot death (because the infant usually dies while asleep)

SIDS Signup and view all the answers

have an unexpected anatomic or biochemical basis discernable at autopsy

Sudden unexpected infant death (SUID) Signup and view all the answers

Most common neoplasms of childhood

soft tissue tumors of mesenchymal derivation Signup and view all the answers

Microscopically normal cells or tissues that are present in abnormal locations

Heterotopia or Choristoma Signup and view all the answers

o Excessive focal overgrowth of cells native to the organ in which it occurs. o Cellular elements are mature and identical to those found in the remainder of the organ.

Hamartoma Signup and view all the answers

o Excessive focal overgrowth of cells native to the organ in which it occurs. o Cellular elements are mature and identical to those found in the remainder of the organ.

Hamartoma Signup and view all the answers

Port wine stains, spontaneously regress, von Hippel-Lindau disease

Hemangioma Signup and view all the answers

characterized by cystic and cavernous spaces

may occur in the skin but more often encountered in deeper regions of neck, axilla, mediastinum

increase in size after birth d/t accumulation of fluid and budding of preexisting spaces

Lymphangiomas Signup and view all the answers

abnormal dilations of pre-existing lymph channels

presents as diffuse swelling of part or all of an extremity

lesion is not progressive

Lymphangiectasis Signup and view all the answers

sparsely cellular proliferations of spindle-shaped cells

Fibromatosis Signup and view all the answers

chromosomal translocation t(12;15)(p13;q25) → ETV6-NTRK3 fusion transcript

Congenital-infantile fibrosarcoma Signup and view all the answers

benign, well-differentiated cystic lesions

mature teratomas Signup and view all the answers

benign, well-differentiated cystic lesions

mature teratomas Signup and view all the answers

lesions of indeterminate potential

immature teratomas Signup and view all the answers

lesions of indeterminate potential

immature teratomas Signup and view all the answers

usually admixed with another germ cell tumor

unequivocally malignant teratomas Signup and view all the answers

most common teratoma in childhood (40% of cases), four times more common in girls than in boys

Sacrococcygeal teratoma Signup and view all the answers

Includes tumors of the sympathetic ganglia and adrenal medulla that are derived from primordial neural crest cells populating these sites

Neuroblastic tumors Signup and view all the answers

o Most common extracranial solid tumor of childhood o Most frequently diagnosed infant malignancy -Median age at diagnosis is 18 months

Neuroblastoma Signup and view all the answers

Important diagnostic feature in neuroblastoma

Catecholamines Signup and view all the answers

Presence of this “bumps” the tumor to the “high”-risk category, irrespective of age, stage, or histology

MYCN amplification Signup and view all the answers

o Most common primary renal tumor of childhood o Fourth most common pediatric malignancy. o Peak incidence: between 2 and 5 years of age, 95% occur <10 years old.

Wilms tumor Signup and view all the answers

first Wilms tumor–associated gene

WT1 Signup and view all the answers

contiguously deleted autosomal dominant gene for aniridia

PAX6 Signup and view all the answers

contiguously deleted autosomal dominant gene for aniridia

PAX6 Signup and view all the answers

Characterized by: ✓ Wilms tumor ✓ Aniridia ✓ Genitourinary anomalies ✓ Intellectual disability (formerly called mental retardation) ▪ Individuals carry constitutional (germline) deletions of 11p13

WAGR Syndrome Signup and view all the answers

Characterized by: ✓ Wilms tumor ✓ Aniridia ✓ Genitourinary anomalies ✓ Intellectual disability (formerly called mental retardation) ▪ Individuals carry constitutional (germline) deletions of 11p13

WAGR Syndrome Signup and view all the answers

Characterized by: ✓ gonadal dysgenesis (male pseudohermaphroditism) ✓ early-onset nephropathy leading to renal failure ▪ Demonstrate germline abnormalities in WT1 involving bi-allelic inactivation

Denys-Drash Syndrome Signup and view all the answers

Characterized by: ✓ gonadal dysgenesis (male pseudohermaphroditism) ✓ early-onset nephropathy leading to renal failure ▪ Demonstrate germline abnormalities in WT1 involving bi-allelic inactivation

Denys-Drash Syndrome Signup and view all the answers

Characterized by enlargement of body organs (organomegaly) ✓ Macroglossia ✓ Hemihypertrophy ✓ Omphalocele ✓ Abnormal large cells in the adrenal cortex (adrenal cytomegaly) ▪ Localized to band 11p15.5 (so-called WT2 locus), distal to the WT1 locus.

Beckwith-Wiedemann Syndrome Signup and view all the answers

IGF2 protein

embryonal growth factor Signup and view all the answers

➔ Gain-of-function mutations of the gene encoding β-catenin (10%) ➔ Mutated genes encoding proteins involved in micro-RNA (miRNA) processing (DROSHA, DGCR8, and DICER1) → 15% to 20%

Sporadic Wilms Tumor Signup and view all the answers

➔ Gain-of-function mutations of the gene encoding β-catenin (10%) ➔ Mutated genes encoding proteins involved in micro-RNA (miRNA) processing (DROSHA, DGCR8, and DICER1) → 15% to 20%

Sporadic Wilms Tumor Signup and view all the answers

➔ Involved in “mesenchymal to epithelial transformation” ➔ If absent leads to persistent blastemal “rests” → evolves to Wilms tumor

miR-200 family Signup and view all the answers

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Questions and Answers

What enzyme is deficient in reaction 1 of metabolism of galactose

What enzyme is deficient in reaction 2 of metabolism of galactose?

polyol metabolite

oxidized byproduct of excess galactose

increased osmotic pressure by galactitol accumulation leads to

accumulation of galactose and galactose-1-phosphate that impairs amino acid transport

depressed neutrophil bactericidal activity

➔ Inherited disorder of ion transport ➔ Affects fluid secretion in exocrine glands and epithelial lining of respiratory, gastrointestinal, and reproductive tract

Defect in cystic fibrosis

Mutated CFTR gene in sweat glands inhibits what channel

Mutated CFTR inhibits secretion of HCO3 in the lumen producing acidic fluid causing

Defective protein synthesis , complete lack of CFTR protein at the apical surface

Abnormal protein folding, processing, and trafficking, Protein does not become fully folded and glycosylated, Most common mutations: deletion of 3 nucleotides coding for phenylalanine at amino acid position 508

Defective regulation, Prevent activation of CFTR by abrogating ATP binding and hydrolysis o Normal amount of CFTR but nonfunctional

Decreased conductance, Typically occur in the transmembrane domain o Normal amount but reduced function → milder phenotype

Reduced abundance, Affect intronic splice sites of the CFTR promoter → reduced amount of normal protein

Altered function in regulation of ion channels, Affect regulatory role of CFTR

Genetic modifiers

Environmental modifiers

Accumulation of secretion

Exocrine atrophy

Atrophy with lipomatosis

Grade IV

▪ Increase the function of CFTR channels ▪ Example: increases probability of Gly551Asp-CFTR channel opening

▪ improve the intracellular processing and delivery of mutant CFTR → reach the cell surface ▪ example: lumacaftor in Phe508del-CFTR

▪ Promote read-through of premature termination codons in mRNA → generate more CFTR ▪ Example: Ataluren in class I mutations

Sudden death of an infant under 1 year of age which remains unexplained , Also referred to as crib death or cot death (because the infant usually dies while asleep)

have an unexpected anatomic or biochemical basis discernable at autopsy

Most common neoplasms of childhood

Microscopically normal cells or tissues that are present in abnormal locations

o Excessive focal overgrowth of cells native to the organ in which it occurs. o Cellular elements are mature and identical to those found in the remainder of the organ.

o Excessive focal overgrowth of cells native to the organ in which it occurs. o Cellular elements are mature and identical to those found in the remainder of the organ.

Port wine stains, spontaneously regress, von Hippel-Lindau disease

characterized by cystic and cavernous spaces may occur in the skin but more often encountered in deeper regions of neck, axilla, mediastinum increase in size after birth d/t accumulation of fluid and budding of preexisting spaces

abnormal dilations of pre-existing lymph channels presents as diffuse swelling of part or all of an extremity lesion is not progressive

sparsely cellular proliferations of spindle-shaped cells

chromosomal translocation t(12;15)(p13;q25) → ETV6-NTRK3 fusion transcript

benign, well-differentiated cystic lesions

benign, well-differentiated cystic lesions

lesions of indeterminate potential

lesions of indeterminate potential

usually admixed with another germ cell tumor

most common teratoma in childhood (40% of cases), four times more common in girls than in boys

Includes tumors of the sympathetic ganglia and adrenal medulla that are derived from primordial neural crest cells populating these sites

o Most common extracranial solid tumor of childhood o Most frequently diagnosed infant malignancy -Median age at diagnosis is 18 months

Important diagnostic feature in neuroblastoma

Presence of this “bumps” the tumor to the “high”-risk category, irrespective of age, stage, or histology

o Most common primary renal tumor of childhood o Fourth most common pediatric malignancy. o Peak incidence: between 2 and 5 years of age, 95% occur <10 years old.

first Wilms tumor–associated gene

contiguously deleted autosomal dominant gene for aniridia

contiguously deleted autosomal dominant gene for aniridia

Characterized by: ✓ Wilms tumor ✓ Aniridia ✓ Genitourinary anomalies ✓ Intellectual disability (formerly called mental retardation) ▪ Individuals carry constitutional (germline) deletions of 11p13

Characterized by: ✓ Wilms tumor ✓ Aniridia ✓ Genitourinary anomalies ✓ Intellectual disability (formerly called mental retardation) ▪ Individuals carry constitutional (germline) deletions of 11p13

Characterized by: ✓ gonadal dysgenesis (male pseudohermaphroditism) ✓ early-onset nephropathy leading to renal failure ▪ Demonstrate germline abnormalities in WT1 involving bi-allelic inactivation

Characterized by: ✓ gonadal dysgenesis (male pseudohermaphroditism) ✓ early-onset nephropathy leading to renal failure ▪ Demonstrate germline abnormalities in WT1 involving bi-allelic inactivation

Characterized by enlargement of body organs (organomegaly) ✓ Macroglossia ✓ Hemihypertrophy ✓ Omphalocele ✓ Abnormal large cells in the adrenal cortex (adrenal cytomegaly) ▪ Localized to band 11p15.5 (so-called WT2 locus), distal to the WT1 locus.

IGF2 protein

➔ Gain-of-function mutations of the gene encoding β-catenin (10%) ➔ Mutated genes encoding proteins involved in micro-RNA (miRNA) processing (DROSHA, DGCR8, and DICER1) → 15% to 20%

➔ Gain-of-function mutations of the gene encoding β-catenin (10%) ➔ Mutated genes encoding proteins involved in micro-RNA (miRNA) processing (DROSHA, DGCR8, and DICER1) → 15% to 20%

➔ Involved in “mesenchymal to epithelial transformation” ➔ If absent leads to persistent blastemal “rests” → evolves to Wilms tumor

➔ Involved in “mesenchymal to epithelial transformation” ➔ If absent leads to persistent blastemal “rests” → evolves to Wilms tumor

increased risk of Wilms tumors in the contralateral kidney

increased risk of Wilms tumors in the contralateral kidney

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Métabolisme du Galactose et Glucides

Galactose Metabolism and Disorders

characterized by cystic and cavernous spaces

may occur in the skin but more often encountered in deeper regions of neck, axilla, mediastinum

increase in size after birth d/t accumulation of fluid and budding of preexisting spaces

abnormal dilations of pre-existing lymph channels

presents as diffuse swelling of part or all of an extremity

lesion is not progressive