CREW CUT ON x-RAY. MARROW EXPANSION

PHENYLKETONURIA(PKU)

PKU is an inborn error of protein metabolism due to decrease of phenylalanine hydroxilase, or the tetrahydrobiopterin cofactor, causing an impaired ability to metabolize the essential amino acid phenylalanine.

The Phenylketonuria is present when plasma phenylalanine levels exceed 20mg/dl (1200mmol/L).

Phenylalanine hydroxilase deficiency is inherited in an autosomal recessive manner.

A small percentage of children with elevated phenylalanine levels exhibit normal phenylalanine hydroxilase but have a deficiency in synthesis or recycling of the enzyme’s cofactor, tetrahydrobiopterin, this condition is termed Malignant Phenylketonuria.

The biopterin cofactor is also required for hydroxylation of tyrosine, a precursor of dopamine, and tryptophan, a precursor of serotonin.

The patients with biopterin cofactor deficiency have more significant neurological problems that are not fully corrected by dietary phenylalanine reduction.

Almost individuals with PKU appear normal at birth. If newborn screening fails, progressive developmental delay is the most common presentation.

Other finding in untreated children in later infancy and childhood may include vomiting, musty body odor, eczema, seizures, self-mutilation, fair coloring as a result of tyrosine deficiency, and several behavioral disorders.

Laboratory studies: Screening for Phenylketonuria within 2-3 days after birth.

Treatment: Dietary restriction of phenylalanine with tyrosine supplementation.

Most of US facilities recommend that phenylalanine levels be maintained from 2-6 mg/dl (120-360mmol/L).

GLYCOGEN STORAGE DISEASES

TYPES	DEFECT-ENZYME	FINDINGS	ORG-AFFECTED
I (Von Gierke’s disease)	Glucose-6-phosphstase	Severe fasting hypoglycemia, ↑↑ glycogen in liver, ↑ blood lactate, hepatomegaly	Liver Kidneys
II (Pompe’s disease)	α-1,4 glucosidase(acid maltase)	Cardiomegaly and systemic findings leading to early death	All
III ( Cori’s disease)	Debranching enzyme ( α-1,6 glucosidase)	Milder form of type I w/ normal blood lactate levels	Liver Muscle
V ( McArdle’s disease)	Skeletal muscle glycogen phosphorylase	↑ glycogen on muscle, but cannot break it down, leading to painful muscle cramps, myoglobinuria w/ strenuous exercise, all relieve w/ rest	Muscle

LYSOSOMAL STORAGE DISEASES

       

Diseases	Finding	Deficient Enzyme/ Accumulated substrate
SPHINGOLIPIDOSES
Fabry’s diseases (XR)	Peripheral neuropathy of hand/feet, angiokeratomas, cardiovascular/renal diseases	α-galactosidase A Ceramide trihexoside
Gaucher’s disease (most common) (AR)	Hepasplenomegaly, aseptic necrosis of femur, bone crises,. (crumpled tissue paper)	β-glucocerebrosidase/ Glucocerebroside
Niemann Pick disease (AR)	Progressive neurodegeneration, hepatosplenomegaly, cherry red spot on macula, foam cells	Sphingomyelinase/ Sphingomyelin
Tay-Sachs disease (AR)	Progressive neurodegeneration, developmental delay, cherry red spot on macula, lysosome with onion skin	Hexosaminidase A/ GM2 ganglioside
Krabbe’s disease (AR)	Peripheral neuropathy, developmental delay, optic atrophy, globoid cells	Galactocerebrosidase / Galactocerebroside
Metachromatic  leukodystrophy (AR)	Central and peripheral demyelination with ataxia, dementia	Arylsulfatase A/ Cerebroside sulfate
MUCOPOLYSACCHARIDOSES
Hurler’s diseases (AR)	Developmental delay, gargoylism, airway obstruction, corneal clouding, hepatosplenomegaly	α-L-idorunidase/ Heparan sulfate Dermatan sulfate
Hunter’s diseases (XR)	Mild Hurler + aggressive behavior, no corneal clouding	Iduronate sulfatase/ Heparan sulfate Dermatan sulfate

AUTOSOMAL DOMINANT DISEASES

ACHONDRODISPLASIA	Defect of FGFR 3	Dwarfism, associated with advanced paternal age
APKD(adult polycystic kidney disease)	90% due to mutation in APKD 1 (chromosome 16)	Always bilateral, massive enlargement of kidneys due multiples cysts. Associated with polycystic liver disease, berry aneurysm, mitral valve prolapse.
Familial adenomatous polyposis	Deletion on chromosome 5 (APC gene)	Colon becomes---adenomatous polyps after puberty.
Hyperlipidemia type II	Due by a defective or absent LDL receptor	Severe atherosclerotic disease, xanthomas(Achilles tendon), MI <20
Osler-Weber-Rendau syndrome	Disorder of blood vessels. Gene endoglin (ENG) or ALK-1	Telangiectasia, epistaxix, skin discoloration, AVMs
Hereditary Spherocytosis	Due Spectrin or Ankyrin defect	Spheroid erythrocytes, hemolytic anemia, high MCHM. Splenectomy is curative
Huntington’s disease	Gene on chromosome 4 Trinucleotide repeat disorder CAG	Dementia, depression, choreifrom movements, manifest---20-50 yrs old.
Marfan’s  syndrome	Fibrillin gene mutation (FBN 1 gene) on chromosome 15	Toll w/ long extremities Pectus excatum, hyperextension joins, arachnodactyly, berry aneurysm, subluxation of lenses
MEN (1-2A-2B)	MEN 1 – 11q13 MEN 2A-2B—ret gene	Familial endocrine glands(pancreas-parathyroid-pituitary-thyroid-adrenal medulla)
von Recklinghauses disease (NF type 1)	Chromosome 17	Café-au-lait spot, neural tumor, Lisch nodules.
NF type 2	Chromosome 22	Bilateral acoustic neuroma Juvenile cataracts

Tuberous sclerosis	Incomplete Penetrance, variable expression. Mutation on TSC 1-TSC 2 genes	Facial lesion (adenoma sebaceum), “ash leaf spot”, seizure, MR, renal cyst, cardiac rhabdomyomas.
von Hippel-Lindau disease	Deletion of VHL gene (tumor suppressor) on chromosome 3	Hemangioblastoma on retina/cerebellum/medulla. 50% develop bilateral cell carcinomas/ other tumor

 

ACHONDROPLASIA

Achondroplasia, a nonlethal form of chondrodysplasia, is the most common form of short limb dwarfism. It is inherited as a Mendelian autosomal dominant trait with complete Penetrance.

It is caused by mutation in the fibroblast growth factor receptor 3 (FGFR3) gene, this is the only gene know to cause Achondroplasia; it has been mapped to chromosome 4, band p16.3.

The mutation cause an increased function of the FGFR3 gene, resulting in decreased endochondral ossification, inhibited proliferation of chondrocytes in growth plate cartilage, decreased cellular hypertrophy, and decreased cartilage matrix production.

Mortality/Morbidity.

Sudden death within the first year of life is attributed to abnormalities at the craniocervical junctions causing spinal cord compression.

Respiratory disorders are seen frequently.

Severe upper airway obstruction occurs in less than 5% in children with Achondroplasia.

Normal life span and fertility.

Neurologic findings.

Hypotonia in infancy and early childhood.

Delayed motor milestones.

Normal intelligence with possible minor deficit in visual-spatial tasks.

Craniofacial feature.

Large calvarial bones in contrast to the small cranial base and facial bones.

True megalencephaly (large head) with frontal bossing.

Midface hypoplasia.

Dental malocclusion and crowding.

Skeletal features.

Disproportionate short stature.

Normal trunk length that appears long and narrow, small thoracic cage.

Rhizomelic shortening of the proximal limbs with redundant skin folds.

Brachydactyly and trident hand configuration.

Thoracolumbar gibbus in infancy, which is replaced by an exaggerated lumbar lordosis once ambulation begins.

Hyperextensibility of most joints (knee).

Limited elbow extension and rotation.

Genu varum (bow legs).

Causes.

Advance paternal age is identified as a risk factor in de novo cases of Achondroplasia , suggesting that factors influencing DNA replication or repair during the spermatogenesis may predispose men to the occurrence of G1138   FGFR3  mutations.

DDx.

Achondrogenesis

Asphyxiating Thoracic Dystrophy (Jeune syndrome).

Hypochondroplasia.

SADDAN Dysplasia.

Skeletal Dysplasia

Thanotophoric Dysplasia.

Laboratory studies.

Direct DNA analysis of FGFR3 mutations identifies the G1138 mutation in patients with Achondroplasia, and a novel missense mutation (Lys650Met) in tyrosine kinase.

Imaging studies: radiography, MRI, ultrasonography.

GENETIC TERMS

Codominance: Neither of 2 alleles is dominant.

Variable Expression: Nature and severity of phenotype vary from one individual to another.

Incomplete Penetrance: Not all individuals with mutant genotype show a mutant phenotype.

Pleiotropy: One gene has more than one effect on an individual’ phenotype.

Imprinting: Differences in phenotype depend on whether the mutation is of maternal or paternal origin.

Anticipation: The severity of disease worsens or age of onset of disease is earlier in succeeding generation.

Loss of heterozygosity: If a patient inherits or develops a mutation in a tumor suppressor gene, the complementary allele must be deleted/mutated before cancer develops. This is not true in oncogenes.

Dominant negative mutation: Exerts a dominant effect. A heterozygote produces a nonfunctional altered protein that also prevents the normal gene product from functioning.

Linkage disequilibrium: Tendency for certain alleles at two linked loci to occur together more often than expected by chance. Measured in the population, not in a family, and often vary in different populations.

Mosaicism: Occur when cells in the body have different genetic makeup.

Locus heterogeneity: Mutations at different loci can produce same phenotype.

Heteroplasmy: Presence of both normal and mutated mtDNA, resulting in variable expression in mitochondrial inherited disease.

Uniparental disomy: Offspring receive two copies of a chromosome from one parent and no copies from the other parent.