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Genetic Diseases > Collection 1/Presentation > Flashcards

Collection 1/Presentation Flashcards

1
Q

Achondroplasia (Mode of inheritance, Cause(s), Presentation)

A
  • Autosomal dominant; full penetrance; most common cause of dwarfism- Mutation of fibroblast growth factor receptor 3 (FGFR3) inhibits chondrocyte proliferation- Dwarfism (short limbs, larger head, trunk size is normal)
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2
Q

Adult polycystic kidney disease (APKD)(Mode of inheritance, Cause(s), Presentation, Association(s))

A
  • Autosomal dominant- Chrom. 16 mutation of PKD1 gene (85%), Chrom. 4 mutation of PKD2 gene (15%)- Bilateral flank pain, hematuria, hypertension, progressive renal failure- Associated with polycystic liver disease, berry aneurysms, MVP.
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3
Q

Familial adenomatous polyposis (Mode of inheritance, Cause(s), Presentation)

A
  • Autosomal dominant- Chrom. 5 mutation of APC gene- Starts after puberty when the colon becomes covered with adenomatous polyps and progress to colon cancer unless colon is resected
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4
Q

Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)(Mode of inheritance, Cause(s), Presentation, Association(s))

A
  • Autosomal dominant- Mutations involving receptors of transforming growth factor beta-1 (TGF-beta-1) (usually frameshift mutations); a variant was found that also is linked with juvenile polyposis (mutation in an intracellular signaling protein of TGF superfamily receptors)- Telangiectasia, recurrent epistaxis, skin discoloration, AV malformations (lungs [50%], liver [30-70%], and brain [10%])- Portal hypertension, hepatic encephalopathy, and intracranial hemorrhage
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5
Q

Hereditary spherocytosis (Mode of inheritance, Cause(s), Presentation, Diagnosis, Treatment)

A
  • Autosomal dominant - Spectrin, ankyrin, or band 3 protein (red blood cell surface proteins) defect- Hemolytic anemia, with jaundice and splenomegaly - Dx: Increased MCHC and RDW- Rx: Splenectomy is curative
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6
Q

Huntington’s disease (Mode of inheritance, Cause(s), Presentation)

A
  • Autosomal dominant- Chrom. 4 mutation in Huntigtin (HTT) gene, (CAG) trinucleotide repeat, with degeneration of spiny neurons in Caudate nucleus with decrease levels of GABA and Ach, and increased dopamine - Chorea, depression, progressive dementia, and psychosis
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7
Q

Marfan syndrome (Mode of inheritance, Cause(s), Presentation, Association(s))

A
  • Autosomal dominant - Chr. 15 mutation in FBN1 gene encodes for fibrillin 1 (a glycoprotein that acts as a scaffold for alignment of elastic fibers & down regulator of transforming growth factor beta [TGF-beta])- Tall with long extremities, pectus excavatum, pectus carinatum (pigeon chest), hypermobile joints, long fingers (arachnodactyly) - Associated with cystic medial necrosis of aorta (ascending aortic dissection [most common cause of death]), mitral valve prolapse (most common complication), dilatation of aortic ring (potentially lead to aortic valve insufficiency) and subluxation of lenses (upward and outward)
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8
Q

Multiple endocrine neoplasias (MEN)(Mode of inheritance, Cause(s), Presentation)

A
  • Autosomal dominant- MEN1 gene mutation for MEN 1, RET gene mutation for MEN 2a and 2b, RET and NTRK1 genes muations for familial medullary thyroid carcinoma ([FMTC] a form of MEN 2)- Presentation: * MEN 1 (3 Ps): Tumors of pancreas, parathyroid, and pituitary * MEN 2a (2 Ps and 1 M): pheochromocytoma, parathyroid and medullary thyroid carcinoma * MEN 2b (1 P and 2 Ms): pheochromocytoma, medullary thyroid carcinoma and marfanoid habitus/mucosal neuroma
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9
Q

Neurofibromatosis type 1 (von Recklinghausen’s disease)(Mode of inheritance, Cause(s), Presentation, Association(s), Diagnosis, Treatment)

A
  • Autosomal dominant; 90% of all NF (1:3000)- Chrom. 17 mutation of NF1 gene (tumor suppressor gene) that is normally produce a protein called neurofibromin that inhibits p21 ras oncoprotein - Cafe au lait spots (6 or more), multiple neurofibromas which are benign but cab be disfiguring, Lisch nodules (pigmented iris hamartomas), the plexiform variant is diagnostic - There is risk of 3% malignant transformation of neurofibromas, increased risk of meningiomas and pheochromocytoma, and association with scoliosis and optic pathway gliomas - Dx: x-ray, CT scan and MRI, genetic testing and EEG- Rx: surgical removal, and chemotherapy for optic pathway gliomas
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10
Q

Neurofibromatosis type 2 (Bilateral acoustic)(Mode of inheritance, Cause(s), Presentation, Association(s), Diagnosis)

A
  • Autosomal dominant; 10% (1:45,000) - Chrom. 22 mutation of NF2 gene (tumor suppressor gene) that is normally produce a protein called merlin which is a critical regulator of contact-dependent inhibition of proliferation - Cafe au lait spots and neurofibromas (smaller and fewer than type 1), with bilateral acoustic tumor (schwannomas of CN VIII) that may lead to hearing loss and balance problems - Associated juvenile cataracts, and increased risk of meningiomas and ependymomas - Dx: x-ray, CT scan and MRI, genetic testing and EEG
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11
Q

Tuberous sclerosis (Mode of inheritance, Cause(s), Presentation, Association(s))

A
  • Autosomal dominant; Incomplete penetrance, variable presentation- Mutation of either TSC1 which encodes for hamartin or TSC2 which encodes for tuberin (both are tumor growth suppressor genes)- Hamartomas, Adenoma sebaceum, hypopigmented “ash leaf spots” on skin, cortical and retinal hamartomas, seizures, mental retardation, renal cysts and renal angiomyolipomas, cardiac rhabdomyomas- Increased incidence of astrocytomas (from subependymal nodules) and epilepsy
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12
Q

von Hippel-Lindau disease (Mode of inheritance, Cause(s), Presentation, Association(s), Diagnosis)

A
  • Autosomal dominant - Chrom. 3 mutation of VHL gene (tumor suppressor) that is normally produce proteins that tag proteins like hypoxia inducible factor ([HIF] a transcription factor that induces the expression of angiogenesis factors) with ubiquitin for degradation - Hemangioblastomas of retina (von Hippel tumor), cerebellum, brain stem, and spinal cord (Lindau tumor), also cysts of liver, pancreas, and kidneys - Associated with bilateral renal cell carcinoma, pheochromocytoma, and polycythemia (due to erythropoietin secreting hemangioblastomas [especially of cerebellum])- Dx: at least two tumors in persons without family history, southern blot and gene sequencing
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13
Q

Cystic fibrosis (Mucoviscidosis)(Mode of inheritance, Cause(s), Presentation, Association(s), Diagnosis, Treatment)

A
  • Autosomal recessive- Chr. 7 mutation of CFTR gene, deletion of Phe 508 (delta F508) which interferes with proper protein folding and post-translational processing of oligosaccharide chain. the abnormal chloride channel protein is degraded by cytosolic proteasome complex rather than translocated to cell membrane - Recurrent pulmonary infection (Pseudomonas [adolescence] and S. aureus [early infancy]), chronic bronchitis, bronchiectasis, pancreatic insufficiency (malabsorption and steatorrhea), nail clubbing and nasal polyps- Associated with male infertility due to bilateral absence of vas deferens and epididymis, subfertility in women (amenorrhea, abnormally thick cervical mucus), fat soluble vitamin deficiencies, vitamin B12 deficiency, biliary cirrhosis and meconium ileus in newborns - Diagnosis is by sweat test (elevated NaCl [Cl > 60 mEq/L]) or DNA probes. Contraction alkalosis and hypokalemia. Increase immunoreactive trypsinogen (newborn screening)- Rx: Chest physiotherapy, albuterol, aerosolized dornase alpha (DNAse) and hypertonic saline to facilitate mucus clearance. Azithromycin used as anit-inflammatory agent. Pancreatic enzymes for insufficiency
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14
Q

Duchenne muscular dystrophy (Mode of inheritance, Cause(s), Presentation, Association(s), Diagnosis)

A
  • X-linked recessive - Usually due to Frameshift or nonsense mutations leading to deletion of Dystrophin gene (DMD) [the longest known human gene] —> truncated dystrophin (which helps anchor muscle fibers by connecting intracellular cytoskeleton (actin) to transmembrane proteins alpha- and beta-dystroglycan, which are connected to extracellular matrix) —> inhibited muscle regeneration and myonecrosis - Starts before age of 5 as weakness of pelvic girdle and progress superiorly, pseudohypertrophy of calf muscles (due to fibrofatty replacement), Gower maneuver: patients use upper extremities to help them stand up, waddling gait- Dilated cardiomyopathy which is a common cause of death- Dx: Increased CK and aldolase, Western blot and muscle biopsy confirm diagnosis
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15
Q

Becker’s muscular dystrophy(Mode of inheritance, Cause(s), Presentation, Association(s), Diagnosis)

A
  • X-linked recessive- Typically non-frameshift insertions in DMD gene (which lead to partially functional dystrophin) - Less severe than Duchenne and starts in adolescence or early adulthood - Dilated cardiomyopathy which is a common cause of death- Dx: Increased CK and aldolase, Western blot and muscle biopsy confirm diagnosis
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16
Q

Fragile X syndrome (Mode of inheritance, Cause(s), Presentation, Association(s), Diagnosis)

A
  • X-linked dominant; Second most common cause of genetic mental retardation- Defect in methylation and expression of the FMR1 gene with trinucleotide repeat (CGG)- Macro-orchidism, long face with a large jaw, large everted ears- Autism and MVP- Dx: DNA probes
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17
Q

Down syndrome (trisomy 21) 1:700(Cause(s), Distinguishing Features, Associations, Diagnosis)

A
  • 47 XX or XY +21; 95% meiotic nondisjunction of homologous chromosomes during meiosis I (advanced maternal age; 1:25 if > 45), 4% Robertsonian transloction and 1% Down mosaicism due mitotic nondisjunction - Mongoloid facies( low-bridge nose [flat], prominent epicanthal folds), simian crease, Brushfield spots (speckled appearance of iris), gap between 1st and 2 toes- Associated with congenital heart anomalies (e.g., AV septal defect, ASD), duodenal atresia (projectile, bilious vomiting), Hirschsprung disease, increase risk of ALL (ages 3-7), AML-M7 (age < 3) & Alzheimer disease (>35)- Diagnosis: * After birth: karyotype using FISH * First trimester U/S commonly shows increased nuchal translucency and hypoplastic nasal bone; decreased serum PAPP-A and increased free beta-hCG. Also Cell Free Fetal DNA (CFFD) by PCR to detect any trisomy and determine sex of baby * Second trimester: quad screen (decreased alpha fetoprotein & unconjugated estriol with increase in beta- hCG and inhibin A)
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18
Q

Edward’s syndrome (trisomy 18) 1:8000(Cause(s), Distinguishing Features, Associations, Diagnosis)

A
  • 47 XX or XY +18; meiotic nondisjunction of homologous chromosomes during meiosis I- Rocker-bottom feet, overlapping flexed fingers, micrognathia (small jaw), low set ears, and congenital heart disease- Horse-shoe kidney; death usually occurs within 1 year of birth- Diagnosis: * After birth: karyotype using FISH * First trimester: decreased PAPP-A and free beta-hCG * Second trimester: quad screen (decrease in alpha fetoprotein, beta hCG, estriol, and decreased or normal inhibin A)
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19
Q

Patau’s syndrome (trisomy 13) 1:15000(Cause(s), Distinguishing Features, Associations, Diagnosis)

A
  • 47 XX or XY +13; meiotic nondisjunction of homologous chromosomes during meiosis I- Cleft lip/palate, holoprosencephaly (single cerebral hemisphere), polydactyly, cyclopia, congenital heart disease- None; death usually occurs within 2 weeks after birth- Diagnosis: * After birth: karyotype using FISH * First trimester decrease free beta hCG and PAPP-A
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20
Q

Cri-du-chat syndrome (Cause(s), Distinguishing Features, Associations, Diagnosis)

A
  • 46 XX or XY 5p-; due to congenital microdeletion of short arm of Chrom. 5- Microcephaly, moderate to severe mental retardation, high pitched crying, epicanthal folds- Cardiac abnormalities (VSD)- Diagnosis: after birth with karyotype using FISH
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21
Q

Williams syndrome (Cause(s), Distinguishing Features, Associations, Diagnosis)

A
  • 46 XX or XY 7q-; due to congenital microdeletion of long arm of Chrom. 7 (deleted region includes elastin gene)- Distinctive “elfin” facies (puffy eyes, blue eyes with starry pattern, long philtrum, small and widely placed teeth), intellectual disability (mild to moderate), hypercalcemia (increased sensitivity to vitamin D), well developed verbal skills, extreme friendliness with strangers, hyperacusis (sensitive hearing)- Cardiovascular problems (supravalvular aortic stenosis, supravalvular pulmonary stenosis), and ADHD- After birth with karyotype using FISH
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22
Q

22q11.1 deletion syndrome (previously known as Di George syndrome or Velocardiofacial syndrome)(Cause(s), Distinguishing Features, Associations, Diagnosis)

A
  • Microdeletion at Chrom. 22q11, inherited as AD with incomplete penetrance; abnormalities are due to aberrant development of 3rd and 4th branchial pouches - CATCH-22: Cleft palate, Abnormal facies, Thymic aplasia (T-cell deficiency), Cardiac defects (interrupted aortic arch, truncus arteriosus and tetralogy of Fallot), Hypocalcemia and Hypoparathyroidism - Hearing loss (both conductive and sensorineural), autoimmune disorders, early onset Parkinson’s disease and psychiatric disorders - Karyotype using FISH, Multiplex ligation-dependent probe amplification assay (MLPA), or quantitative PCR (qPCR)
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23
Q

Klinefelter Syndrome(Cause(s), Distinguishing Features, Associations, Variations, Diagnosis)

A
  • Male 47,XXY; due to meiotic nondisjunction - Eunuchoid body shape, tall, long extremities, gynecomastia, high-pitched voice, female hair distribution and testicular atrophy (azoospermia)- Autoimmune disorders, breast cancer, venous thromboembolic disease and osteoporosis - 48,XXYY (Clinodactyly, Autism spectrum disorders, ADHD, anxiety and depression), 48,XXXY, 49,XXXXY, 47,XYY (this is not a variation 1:1000 boys and normal phenotype, but may be associated with severe acne, learning disability, autism spectrum disorders)- Diagnosis * Karyotype (Barr body) * Decreased testosterone due to abnormal Leydig cell function —> increased LH —> increased estrogen * Desgenesis of seminiferous tubules —> decreased inhibin B —> increased FSH
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24
Q

Turner Syndrome(Cause(s), Distinguishing Features, Associations, Diagnosis)

A
  • Female 45,XO; due to meiotic nondisjunction or sometimes mitotic error (mosaicism 45,XO/46,XX), or Isochromosome (45,X(i))- Short stature (if untreated), ovarian dysgenesis (streak ovary), shield chest, webbed neck and menopause before menarche (most common cause of primary amenorrhea) [pregnancy is possible in some cases (IVF, exogenous estradiol-17beta and progesterone)]- Bicuspid aortic valve, preductal coarctation of aorta (femoral < brachial pulse), hydrops fetalis, cystic hygroma, lymphedema in feet and hands, and horse-shoe kidney, increased risk of gonadoblastoma (45,XO/46,XY)- Diagnosis: * Prenatal: U/S (cystic hygroma, heart defects and kidney abnormalities) * Postnatal: karyotype (no Barr body) * Decreased estrogen —> increased LH and FSH
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25
Q

Triple X Syndrome (1:1000)(Cause(s), Distinguishing Features, Associations, Variations, Diagnosis)

A
  • 47,XXX; due to meiotic nondisjunction- Phenotypically normal with normal fertility. Occasionally learning difficulties, decreased muscle tone, seizures, kidney problems and clinodactyly- Anxiety and depression- 48,XXXX (Tetrasomy X) [same as triple X syndrome but lower incidence], 49,XXXXX (Pentasomy X) [very rare, associated with short stature, severe intellectual disability and craniofacial abnormalities]- Karyotype
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26
Q

True Hermaphroditism (Ovotesticular disorder of sex development)

A
  • 46,XX > 46,XY or 45,X/XY (mosaics) [genetic sex]- Gonadal sex can be either an ovary on one side and a testis on the other or ovotestes - Ductal sex is often mixed- Phenotypic sex shows ambiguous genitalia
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27
Q

Female Pseudohermaphroditism (46,XX DSD)(Cause(s), Presentation)

A
  • Genetic sex is 46,XX- Gonadal sex normal- Ductal sex normal- Phenotypic sex is abnormal due to ambiguous or virilized external genitalia- Occurs with exposure of a female fetus to androgens in utero, by congenital adrenal hyperplasia (21 and 11); androgen-producing tumors (ovarian Sertoli-Leydig cell tumor) or exogenous androgens - Also can occur in placental aromatase deficiency with inability to synthesize estrogens from androgens. Increased serum testosterone and androstenedione. Can present as maternal virilization during pregnancy (fetal androgens cross the placenta)
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28
Q

Male Pseudohermaphroditism (46,XY DSD)(Cause(s), Presentation)

A
  • Genetic sex is 46,XY- Gonadal sex normal- Ductal sex normal- Phenotypic sex is abnormal with ambiguous or female genitalia- Most common cause is Testicular feminization (complete androgen insensitivity syndrome) due to mutation of the androgen receptor (Xq11-12). Increased testosterone, estrogen and LH- It presents either at puberty with amenorrhea and rudimentary vagina, but no uterus or ovaries and the testes are found usually in labia majora (needs surgical removal because of high risk of germ cell tumors like seminoma) or as a girl baby with inguinal hernia - Other cause is 5alpha-reductase deficiency (AR) with inability to convert testosterone to DHT. Presents with ambiguous genitalia until puberty. Testosterone/estrogen levels are normal; LH is normal or increased- Also 17alpha-hydroxylase deficiency (ambiguous genitalia and undescended testes)
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29
Q

Kallmann Syndrome(Cause(s), Presentation)

A
  • X-linked recessive (KAL-1), AD (KAL-2), AD (KAl-3)- Defective migration of GnRH cells and formation of olfactory bulbs- Presents as failure to start or complete puberty (a form of hypogonadotropic hypogonadism) with anosmia or hyposmia with infertility- Decreased GnRG, FSH, LH, testosterone (males) and estrogen (females)
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30
Q

Phenylketonuria (PKU)(Mode of inheritance, Cause(s), Presentation, Association(s), Diagnosis, Treatment)

A
  • Autosomal recessive (1:10,000)- Decreased phenylalanine hydroxylase or tetrahydrobiopterin cofactor (malignant PKU). Tyrosine becomes essential with excess phenylketons (phenylacetate, phenyllactate, phenylpyruvate) in urine- Profound intellectual disability by 6 months of age, growth retardation, seizures, light-colored fair skin and hair, eczema, and musty (mousy) body odor- Maternal PKU: lack of proper diet therapy during pregnancy. Finding in infant: microcephaly, intellectual disability, growth retardation and congenital heart defects- Screening is done 2-3 days after birth (normal at birth because of maternal enzyme during fetal life)- Rx: Decrease phenylalanine and increase tyrosine in diet, tetrahydrobiopterin supplementation, and avoidance of artificial sweeteners (aspartame)
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31
Q

Alkaptonuria (Ochronosis)(Mode of inheritance, Cause(s), Presentation, Association(s))

A
  • Autosomal recessive- Congenital deficiency of homogentistic acid oxidase in the degradative pathway of tyrosine to fumarate leading to accumulation of homogentistic acid in tissues- Bluish-black connective tissue and sclerae, cartilages (nose and ears), urine turns black on prolonged exposure to air- Early onset degenerative arthritis
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32
Q

Albinism (Mode of inheritance, Cause(s), Presentation, Association(s))

A
  • Autosomal recessive- Lack of the enzyme tyrosinase (copper-containing) that is needed for melanin production- Deficiency of melanin pigment in skin, hair follicles, and eyes (occulocutaneous albinism)- Increased risk of basal and squamous cell carcinoma
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33
Q

Von Gierke disease(Mode of inheritance, Cause(s), Presentation, Diagnosis, Treatment)

A
  • Autosomal recessive; glycogen storage disease type I- Deficiency of glucose-6-phosphatase which leads to impaired gluconeogenesis and glycogenolysis - Severe fasting hypoglycemia, hepatomegaly, increased glycogen in liver, increased blood lactate, increased triglycerides and uric acid (gout)- Liver biopsy and PAS stain (glycogen structure is normal)- Rx: frequent oral glucose/cornstarch, avoidance of fructose and galactose
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34
Q

Pompe disease(Mode of inheritance, Cause(s), Presentation, Diagnosis)

A
  • Autosomal recessive, glycogen storage disease type II- Deficiency of lysosomal alpha-1,4-glucosidase (acid maltase)- Hepatomegaly, skeletal muscle hypotonia with exercise intolerance, cardiomegaly and hypertrophic cardiomyopathy which leads to death by age of 2 years- Biopsy with PAS stain (glycogen like-material in inclusion bodies)
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35
Q

Cori disease(Mode of inheritance, Cause(s), Presentation, Diagnosis)

A
  • Autosomal recessive, glycogen storage disease type III- Deficiency of debranching enzyme (alpha-1,6-glucosidase). Gluconeogenesis is intact - Mild hypoglycemia and hepatomegaly- Biopsy and PAS stain (short outer branches)
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36
Q

Andersen disease (amylopectinosis)(Mode of inheritance, Cause(s), Presentation, Diagnosis)

A
  • Autosomal recessive, glycogen storage disease type IV- Deficiency of branching enzyme- Infantile hypotonia, cirrhosis and death by 2 years- Biopsy with PAS stain (very few branches, especially toward periphery
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37
Q

McArdle disease(Mode of inheritance, Cause(s), Presentation, Diagnosis)

A
  • Autosomal recessive, glycogen storage disease type V- Deficiency of skeletal muscle glycogen phosphorylase (myophosphorylase)- Painful muscle cramps and myoglobinuria (red urine) with strenuous exercise, and arrhythmias from electrolyte abnormalities - Biopsy with PAS stain (normal glycogen structure)
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38
Q

Hers disease(Mode of inheritance, Cause(s), Presentation, Diagnosis)

A
  • X-linked recessive (and can be AR), glycogen storage disease type VI- Deficiency of hepatic glycogen phosphorylase- Mild fasting hypoglycemia, hepatomegaly and cirrhosis- Biopsy and PAS stain (normal glycogen structure)
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39
Q

Tay-Sachs disease(Mode of inheritance, Cause(s), Presentation, Diagnosis, Treatment)

A
  • Autosomal recessive, lysosomal storage disease- Deficiency of hexoaminidase A (mutation of HEXA gene Chrom. 15) which will lead to accumulation of GM2 ganglioside in lysosomes of CNS and retina- Ashkenazi Jews (1:30 carrier), normal children at birth, but by 6 months show onset of progressive mental deterioration and motor incoordination that progress to death by age 2-3 years. Cherry red spot on macula- Dx: * LM: dilated neurons with cytoplasmic vacuoles * EM: distended lysosomes with whorled membranes (onion skin) * Enzyme assay and DNA probes - No Rx
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40
Q

Niemann-Pick disease(Mode of inheritance, Cause(s), Presentation, Diagnosis, Treatment)

A
  • Autosomal recessive, lysosomal storage disease- Deficiency of sphingomyelinase (Chrom. 11) which leads to accumulation of shpingomyelin in lysosomes of CNS and reticuloendothelial system - Ashkenazi Jews, normal children at birth, but by 6 months onset of massive splenomegaly and lymphadenopathy, progressive mental and motor deterioration that progress to death by 2 years. Cherry red spot on macula- Dx: * LM: distended neurons with a foamy cytoplasmic vacuoles (lipid-laden macrophages) * EM: distended lysosomes containing lamellated figures (“zebra bodies”) * Enzyme assay and DNA probes- No Rx
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41
Q

Gaucher disease(Mode of inheritance, Cause(s), Presentation, Diagnosis, Treatment)

A
  • Autosomal recessive, most common lysosomal storage disease (99% is type I)- Deficiency of glucocerebrosidase (beta-glucosidase) [Chrom. 1] which leads to accumulation of glucocerebroside in lysosomes of reticuloendothelial system - Type I presents in adulthood with hepatosplenomegaly, thrombocytopenia/pancytopenia (secondary to hypersplenism), lymphadenopathy, osteoporosis, aseptic necrosis of femur and bone crisis. In type II and III there is also CNS manifestations - Dx: * LM: Gaucher cells (lipid-laden macrophages with fibrillary cytoplasm resembling crumpled tissue paper) * Enzyme assay - Rx: recombinant glucocerebrosidase
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42
Q

Fabry disease(Mode of inheritance, Cause(s), Presentation, Diagnosis, Treatment)

A
  • X-linked recessive, lysosomal storage disease- Deficiency of alpha-galactosidase A which leads to accumulation of ceramide trihexoside - Early onset: triad of episodic peripheral neuropathy, angiokeratomas, and hypohidrosis. Late onset:progressive renal failure and cardiovascular disease (high blood pressure and restrictive cardiomyopathy)- Dx: enzyme assay- Rx: recombinant alpha-galactosidase A
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43
Q

Krabbe disease(Mode of inheritance, Cause(s), Presentation, Diagnosis, Treatment)

A
  • Autosomal recessive, lysosomal storage disease- Deficiency of galactocerebrosidase which leads to accumulation of galactocerebroside and psychosine- Peripheral neuropathy, developmental delay, optic atrophy- Dx: by LM: multinucleated “globoid cells” with nerve demyelination and degeneration - Rx: bone marrow transplantation benefit cases if done early in the course of the disease
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44
Q

Metachromatic Leukodystrophy(Mode of inheritance, Cause(s), Presentation)

A
  • Autosomal recessive, lysosomal storage disease- Deficiency of arylsulfatase A which leads to accumulation of cerebroside sulfate - Central and peripheral demyelination with ataxia and dementia
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45
Q

Mucopolysaccharidoses (MPS)(Mode of inheritance, Cause(s), Presentation, Diagnosis, Treatment)

A
  • MPS I (Hurler syndrome) is AR and MPS II (Hunter syndrome) is XR, a form of lysosomal storage diseases- Deficiency of alpha-L-iduronidase (MPS I) and iduronate sulfatase (MPS II) which in both cases lead to accumulation of heparan sulfate and dermatan sulfate - MPS I: developmental delay, gargoylism, airway obstruction, corneal clouding and hepatosplenomegaly. MPS II: mild MPS I + aggressive behavior and no corneal clouding- Dx: * Urine test for excess mucopolysaccharides * Enzyme assay - No Rx
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46
Q

Maple syrup urine disease(Mode of inheritance, Cause(s), Presentation, Association(s), Diagnosis, Treatment)

A
  • Autosomal recessive- Deficiency of branched-chain alpha-ketoacid dehydrogenase (B1) which leads to decreased degradation of branched amino acids (Isoleucine, Leucine, Valine) and increased blood levels of alpha-ketoacids (especially leucine)- In infancy vomiting, poor feeding, urine smells like maple syrup/burnt sugar- Severe CNS defects, intellectual disability and death- Dx: elevated levels of amino acids in serum- Rx: restriction of alpha-ketoacids in diet and thiamine supplementation
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47
Q

Homocystinuria (Mode of inheritance, Cause(s), Presentation, Association(s), Diagnosis, Treatment)

A
  • All types are autosomal recessive- Either cystathionine synthase deficiency (B6 dependent), or decreased affinity of cystathionine synthase for pyridoxal phosphate, or methionine synthase (homocysteine methyltransferase) deficiency (THF and B12 dependent)- Intellectual disability, osteoporosis, marfanoid habitus, kyphosis, lens subluxation (downward and inward)- Thrombosis, and atherosclerosis (stroke and MI)- Dx: Increased homocysteine in urine- Rx: * Cystathionine synthase deficiency: decrease methionine and increase cysteine, B12 and folate in diet * Cystathionine synthase decreased affinity: increase B6 (alot) and cysteine in diet * Methionine synthase deficiency: increase methionine in diet
48
Q

Cystinuria (1:7000)(Mode of inheritance, Cause(s), Presentation, Diagnosis, Treatment)

A
  • Autosomal recessive - Hereditary defect of renal PCT and intestinal amino acid transporter that prevents reabsorption of Cystine, Ornithine, Lysine, and Arginine (COLA)- Hexagonal cystine stones (cystine is 2 cysteines connected by disulfide bond)- Dx: urinary cyanide-nitroprusside test is diagnostic - Rx: * Urinary alkalinization (e.g., potassium citrate, acetazolamide) * Chelating agents like penicillamine which increase solubility of cystine stones * Good hydration
49
Q

Hyperlipidemia type Ia (Burger-Gruetz syndrome or Familial hyperchylomicronemia)(Mode of inheritance, Cause(s), Presentation, Diagnosis, Treatment)

A
  • Autosomal recessive- Decreased lipoprotein lipase (LPL)- Red-orange eruptive xanthomas, fatty liver, hepatosplenomegaly and acute pancreatitis - Dx: Increased triglycerides and chylomicrons- Rx: diet control
50
Q

Hyperlipidemia type Ib (Familial Apo C2 deficiency)(Mode of inheritance, Cause(s), Presentation, Diagnosis, Treatment)

A
  • Autosomal recessive- Altered Apo C2- Red-orange eruptive xanthomas, fatty liver, hepatosplenomegaly and acute pancreatitis - Dx: Increased triglycerides and chylomicrons- Rx: diet control
51
Q

Hyperlipidemia type Ic(Mode of inheritance, Cause(s), Presentation, Diagnosis, Treatment)

A
  • Autosomal recessive- LPL inhibitor in blood- Red-orange eruptive xanthomas, fatty liver, hepatosplenomegaly and acute pancreatitis - Dx: Increased triglycerides and chylomicrons- Rx: diet control
52
Q

Hyperlipidemia type IIa (Familial hypercholesterolemia)(Mode of inheritance, Cause(s), Presentation, Association(s), Diagnosis, Treatment)

A
  • Autosomal dominant - LDL receptor deficiency (no LDL receptor synthesis [Class I], defect in transport out of ER (misfolding) [Class II], defect in binding [Class III], defect in ability to internalize bound LDL [Class IV], or defect in recycling [Class V]) which leads to loss of inhibition of HMG-CoA reductase, so liver make more cholesterol - Xanthelasmas, xanthomas of Achilles tendon, and corneal arcus - Premature atherosclerosis and coronary artery disease (homozygotes often develop MI in late teens and twenties)- Dx: Increased cholesterol and LDL (Heterozygotes (more common) cholesterol 300, Homozygotes (very rare) cholesterol is 700 or above)- Rx: Bile acid sequestrants, statins and niacin
53
Q

Hyperlipidemia type IIb (Familial combined hyperlipidemia)(Mode of inheritance, Cause(s), Presentation, Association(s), Diagnosis, Treatment)

A
  • Autosomal dominant - Decreased LDL receptor and increased ApoB- Xanthelasmas, xanthomas of Achilles tendon, and corneal arcus - Premature atherosclerosis and coronary artery disease (homozygotes often develop MI in late teens and twenties)- Dx: Increased cholesterol, triglycerides, LDL and VLDL- Rx: fibrate, statins and niacin
54
Q

Hyperlipidemia type III (Familial dysbetalipoproteinemia)(Mode of inheritance, Cause(s), Presentation, Diagnosis, Treatment)

A
  • Autosomal recessive- Defect in ApoE2 synthesis- Palmar xanthomas, orange discoloration of palmar creases, and tuboeruptive xanthomas at elbows and knees - Dx: Increased cholesterol, triglycerides, chylomicron remnants and IDL- Rx: fibrate and statins
55
Q

Hyperlipidemia type IV (Familial hypertriglyceridemia)(Mode of inheritance, Cause(s), Presentation, Diagnosis, Treatment)

A
  • Autosomal dominant- Increased VLDL production and decreased elimination - Pancreatitis- Dx: Increased triglycerides and VLDL- Rx: fibrate, statins, and niacin
56
Q

Hyperlipidemia type V(Mode of inheritance, Cause(s), Presentation, Diagnosis, Treatment)

A
  • Autosomal recessive- Increased VLDL production and decreased LPL- Red-orange eruptive xanthomas, fatty liver, hepatosplenomegaly and acute pancreatitis - Dx: Increased cholesterol, triglycerides, VLDL and chylomicrons - Rx: fibrate and niacin
57
Q

Ehler-Danlos Syndrome(Mode of inheritance, Cause(s), Presentation, Association(s), Diagnosis, Treatment)

A
  • Autosomal dominant except for type 6 (kyphoscoliosis) and type 7C (dermatosparaxis) are AR, also type 3 could be either AD or AR - Defect in either collagen structure or synthesis - Hyperextensible skin that is easily traumatized (type 1 and 2 [collagen I and V, 2 is milder]), hyperextensible joints and adjacent ligaments (type 3 [hypermobility], types 7A and 7B [arthrochalasia], 7 is more severe), very thin translucent skin with ecchymoses that develop without trauma (type 4 [vascular, collagen III]), kyphoscoliosis and blue sclera (type 6 [lysyl hydroxylase deficiency]), extremely fragile and sagging skin (type 7C)- Poor wound healing, frequent joint subluxations and dislocations with or without trauma and chronic pain (type 3), arterial or colonic or uterine rupture (type 4), diaphragmatic hernia (type 1), and retinal detachment (type 6)- Dx: by evaluation of medical history and clinical observations using Brighton criteria- No Rx
58
Q

Menkes disease(Mode of inheritance, Cause(s), Presentation, Diagnosis, Treatment)

A
  • X-linked recessive- Mutation in ATP7A gene, which encodes for a transmembrane protein that transport copper across cell membranes (found in all tissues except liver), in intestine regulates copper absorption, in other cells found in Golgi apparatus and transport copper outside the cell to maintain intracellular copper level (lysl oxidase in cross-linking of collagen)- Kinky hair (under microscope “pili torti”), developmental delay, intellectual disability, hypotonia, seizures, osteoporosis, and deposition of Ca++ at the base of skull (Occipital horn syndrome [seen by x-ray])- Dx: low levels of ceruloplasmin and serum copper. Urine homovanillic acid/vanillylmandelic acid ratio has been proposed as a screening tool- No Rx
59
Q

Osteogenesis Imperfecta (OI)(Mode of inheritance, Cause(s), Presentation, Association(s), Diagnosis, Treatment)

A
  • Autosomal dominant except types VI, VII and VIII which are AR- Collagen type I abnormal quality or quantity or both in connective tissues- Bones fracture easily, bone deformities, blue-gray sclerae (except type IV), respiratory problems, and early hearing loss. * Type I is mild (normal quality and insufficient quantity) * Type II is severe with severe respiratory problems (abnormal quality and quantity) * Type III is progressive and deforming (abnormal quality but normal quantity) * Type IV (normal quantity but quality is not high enough) * Type V: like IV but with histological “mesh-like” bone appearance and calcification of radio-ulnar interosseous membrane * Type VI: like IV but with histological “fish-scale” bone appearance * Type VII is severe to lethal and associated with cartilage associated protein * Type VIII is severe to lethal and associated with the protein leprecan - Basilar invagination (type I), respiratory failure and intracranial hemorrhage (type II)- Dx: usually clinical with DDx of child abuse, rickets and osteomalacia- Rx: bisphosphonates to increase bone mass, surgical correction in severe cases and treat bone infections when they occur
60
Q

Abetalipoproteinemia (Bassen-Kornzweig syndrome)(Mode of inheritance, Cause(s), Presentation, Diagnosis, Treatment)

A
  • Autosomal recessive- Mutation in microsomal triglyceride transfer protein- Failure to thrive, steatorrhea, cerebellar ataxia, pigmentary degeneration of retina, acanthocytes (thorny RBCs) and possible loss of night vision- Dx: Decreased cholesterol, triglycerides, chylomicrons and VLDL- Rx: diet control and giving massive amounts of vitamin E
61
Q

Hypobetalipoproteinemia(Mode of inheritance, Cause(s), Presentation, Diagnosis, Treatment)

A
  • Not known- Mutated ApoB- Physical and mental developmental retardation, and red skin rash- Dx: Cholesterol below 120 mg/dL and decreased LDL- Rx: vitamin E
62
Q

Familial alpha-lipoprotein deficiency (Tangier disease)(Mode of inheritance, Cause(s), Presentation, Diagnosis, Treatment)

A
  • Autosomal recessive- Defective ABCA1 transporter- Hepatosplenomegaly, neuropathy, extremely enlarged and yellow to orange tonsils, and corneal clouding- Dx: Decreased cholesterol and HDL- No Rx
63
Q

Smith-Lemli-Opitz syndrome(Mode of inheritance, Cause(s), Presentation, Diagnosis, Treatment)

A
  • Autosomal recessive- 7-dehydrocholesterol reductase deficiency - A broad spectrum of presentations, ranges from mild intellectual disability and behavioral problems to lethal malformations. Any congenital anomaly especially microcephaly, autism or hyperactivity - Dx: Decreased cholesterol and increased 7-dehydrocholesterol - Rx: dietary cholesterol supplementation
64
Q

Li-Fraumeni syndrome(Mode of inheritance, Cause(s), Presentation)

A
  • Autosomal dominant- Mutation of TP53 (tumor suppressor gene) on Chrom. 17- Tumors at early age especially breast cancer, sarcomas, brain tumors (glioblastomas), leukemia, lymphoma and adrenocortical carcinoma
65
Q

X-linked Hypophosphatemia(Mode of inheritance, Cause(s), Presentation, Diagnosis, Treatment)

A
  • X-linked dominant- Mutation of PHEX gene- Bone pain with rickets or osteomalacia that don’t respond to vitamin D, and osteoarthritis - Dx: hypophosphatemia and abnormally low levels of clacitriol (vitamin D3)- Rx: oral phosphate and calcitriol, and corrective osteotomy as needed
66
Q

Aicardi syndrome(Mode of inheritance, Cause(s), Presentation)

A
  • X-linked dominant; seen in girls and boys with Klinefelter syndrome- Unknown- Partial or complete absence of corpus callosum, retinal abnormalities, seizures in the form of infantile spasms that begin at 3 months of age
67
Q

Myotonic Dystrophy type 1 (Steinert disease)(Mode of inheritance, Cause(s), Presentation)

A
  • Autosomal dominant- CTG (3’ UTR) trinucleotide repeat expansion in DMPK gene on Chrom. 19 leading to abnormal expression of myotonin protein kinase - Muscle wasting, cardiac arrhythmia, testicular atrophy, frontal baldness and cataracts
68
Q

Friedreich Ataxia (Mode of inheritance, Cause(s), Presentation, Association(s))

A
  • Autosomal recessive - Expansion of a GAA (intron 1) repeat in frataxin gene- Early onset progressive gait and limb ataxia, areflexia in all 4 limbs, axonal sensory neuropathy- Kyphoscoliosis and hypertrophic obstructive cardiomyopathy
69
Q

Prader-Willi syndrome(Mode of inheritance, Cause(s), Presentation, Association(s))

A
  • Autosomal dominant- Loss of SNRPN gene and other genes on paternal Chrom. 15 (maternal copy is imprinted) or uniparental disomy (inherit both maternal copies)- Neonatal hypotonia, poor feeding, behavioral problems, moderate mental and developmental retardation, hypogonadism, hyperphagia and obesity by ages 2-4 years, and small hands and feet- Assisted reproductive technology (ART)
70
Q

Angelman syndrome(Mode of inheritance, Cause(s), Presentation, Association(s))

A
  • Autosomal dominant- Loss of UBE3A gene on maternal Chrom. 15 (paternal copy is imprinted) or uniparental disomy (inherit both paternal copies)- Severe mental retardation, seizures, ataxia, puppet-like posture of limbs, and happy dispostion- Assisted reproductive technology (ART)
71
Q

Sickle Cell Anemia

A
  • Autosomal dominant
72
Q

Lesch-Nyhan syndrome

A
  • Autosomal dominant
73
Q

Glucose-6-phosphate dehydrogenase (G6PD) deficiency

A
  • Autosomal dominant
74
Q

Leber Hereditary Optic Neuropathy

A
  • Autosomal dominant
75
Q

MELAS

A
  • Autosomal dominant
76
Q

Myoclonic Epilepsy with ragged red muscle

A
  • Autosomal dominant
77
Q

Hemochromatosis(Mode of inheritance, Cause(s), Presentation, Association(s), Diagnosis, Treatment)

A
  • Autosomal recessive (except type 4 which is AD)- Type 1 due to mutation in HFE gene on Chrom. 6
78
Q

Kartagener syndrome

A
  • Autosomal dominant
79
Q

Thalassemia

A
  • Autosomal dominant
80
Q

Wilson disease(Mode of inheritance, Cause(s), Presentation, Diagnosis, Treatment)

A
  • Autosomal recessive; also called hepatolenticular degeneration - Mutation of ATP7B gene on Chrom. 13 that encodes for hepatocyte copper-transporting ATPase- Liver disease (hepatitis, acute liver failure, cirrhosis), neurological disease (dysarthria, dystonia, tremor “wing-beating”, parkinsonism), psychiatric disease, Kayser-Fleischer rings (deposits in Decement membrane of cornea), hemolytic anemia and renal disease (Fanconi syndrome)- Dx: Decreased ceruloplasmin and increased urinary copper excretion. Liver biopsy - Rx: * Avoid copper containing food like mushrooms, nuts, chocolate, dried fruit, liver and shellfish * Chelating agents like penicillamine, trientin or tetrathiomolybdate * Oral zinc used to maintain stable levels after treatment with chelating agents * Liver transplantation is curative
81
Q

Familial Mediterranean Fever(Mode of inheritance, Cause(s), Presentation, Association(s), Diagnosis, Treatment)

A
  • Autosomal recessive- Two or more mutations in the Mediterranean fever gene (MEFV) on Chrom. 16 which encodes for pyrin - Presented as acute attacks (most attacks are with fever) that develop over 2-4 hrs and last anywhere between 6 hrs to 4 days: * Abdominal pain with all signs of peritonitis and acute abdomen like appendicitis (95% of all cases) * Joint pain: mainly occur in large joints, especially knee joint and one side is affected (75%) * Pleuritis with pain that worsen with breathing and lying flat (40%) * Scrotal attacks that is mistaken for acute scrotum (like testicular torsion) (5%) * Fever alone without any of the above (25%)- AA amyloidosis (It is produced in large amounts during attacks and low rate between them) with renal failure that can occur without overt crisis. It accumulates mainly in kidneys, heart, spleen, GI, and thyroid. Also there is increased risk of Henoch-Schonlein purpura and spondyloarthropathy- Dx: clinical + increased CRP and WBC count during attacks. Genetic testing and Metaraminol Provocative test (MPT) highly specific - Rx: attacks are self-limiting, treat with NSAIDs. Colchicine decreases attack frequency. For resistant cases add anakinra (IL-1 receptor antagonist) to colchicine
82
Q

Sturge-Weber Syndrome(Mode of inheritance, Cause(s), Presentation, Association(s), Diagnosis, Treatment)

A
  • No mode; it occurs sporadically - Activating mutation in GNAQ gene- Port-wine stain birthmark around the distribution of ophthalmic branch of trigeminal nerve, seizures and muscle weakness (both at the opposite side of the stain), vascular headache, development (cognitive) delay, glaucoma and hemianopsia - Associated with ipsilateral leptomeningeal angioma - Dx: CT or MRI of brain- Rx: is symptomatic
83
Q

Hartnup Disease

A
  • Autosomal dominant
84
Q

Cystinosis

A
  • Autosomal dominant
85
Q

Lowe Syndrome

A
  • Autosomal dominant
86
Q

Dent’s Disease

A
  • Autosomal dominant
87
Q

Bartter Syndrome Type 1(Mode of inheritance, Cause(s), Presentation, Association(s), Diagnosis, Treatment, Pseudo Bartter Causes)

A
  • Autosomal recessive; also called Neonatal Bartter 1- Mutation in SLC12A2 on Chrom. 5 that encodes for NKCC2 protein of the Na-K-2Cl symporter in the ascending thick loop of Henle - Metabolic alkalosis, hypokalemia and hypotension; also hypercalciuria and nephrocalcinosis - Polyhydramnios - Dx: high urine K+ and Cl- despite their low serum level, also increased serum renin and aldosterone with hyperplasia of juxtaglomerular apparatus on renal biopsy- Rx: * Increased Na+ and K+ in diet with supplemental K+ and spironolactone * NSAIDs * ACEIs also can be used- Cystic fibrosis and excessive use of laxatives
88
Q

Bartter Syndrome Type 2(Mode of inheritance, Cause(s), Presentation, Association(s), Diagnosis, Treatment)

A
  • Autosomal recessive; also called Neonatal Bartter 2- Mutation in KCNJ1 on Chrom. 11 that encodes for ROMK protein of the K+ channels in the ascending thick loop of Henle (recycling) and collecting ducts (secretion)- Metabolic alkalosis, hypokalemia and hypotension; also hypercalciuria and nephrocalcinosis - Polyhydramnios - Dx: high urine K+ and Cl- despite their low serum level, also increased serum renin and aldosterone with hyperplasia of juxtaglomerular apparatus on renal biopsy- Rx: * Increased Na+ and K+ in diet with supplemental K+ and spironolactone * NSAIDs * ACEIs also can be used
89
Q

Bartter Syndrome Type 3(Mode of inheritance, Cause(s), Presentation, Association(s), Diagnosis, Treatment)

A
  • Autosomal recessive; also called Classic Bartter - Mutation of CLCNKB gene on Chrom. 1 that encodes for CLCNKB protein of Cl- channels in the ascending loop of Henle - Metabolic alkalosis, hypokalemia and hypotension- None- Dx: high urine K+ and Cl- despite their low serum level, also increased serum renin and aldosterone with hyperplasia of juxtaglomerular apparatus on renal biopsy- Rx: * Increased Na+ and K+ in diet with supplemental K+ and spironolactone * ACEIs also can be used
90
Q

Bartter Syndrome Type 4(Mode of inheritance, Cause(s), Presentation, Association(s), Diagnosis, Treatment)

A
  • Autosomal recessive; also called Bartter with sensorineural deafness - Mutation of BSND on Chrom. 1 that encodes for Cl- channels on basolateral membrane of renal tubules and K+ secreting epithelia in the inner ear - Metabolic alkalosis, hypokalemia and hypotension with sensorineural deafness- None- Dx: high urine K+ and Cl- despite their low serum level, also increased serum renin and aldosterone with hyperplasia of juxtaglomerular apparatus on renal biopsy- Rx: * Increased Na+ and K+ in diet with supplemental K+ and spironolactone * ACEIs also can be used
91
Q

Barrter Syndrome Type 5(Mode of inheritance, Cause(s), Presentation, Association(s), Diagnosis, Treatment)

A
  • Autosomal dominant; also called Autosomal Dominant Hypocalcemia (ADH)- Mutation of CaSR gene on Chrom. 3 that encodes for calcium-sensing receptor (CaSR) protein which is found in the parathyroid gland and renal tubules - Metabolic alkalosis, hypokalemia and hypotension with hypocalcemia and hypoparathyroidism - None- Dx: high urine K+ and Cl- despite their low serum level, also increased serum renin and aldosterone with hyperplasia of juxtaglomerular apparatus on renal biopsy- Rx: * Increased Na+ and K+ in diet with supplemental K+ and spironolactone * ACEIs also can be used
92
Q

Gitelman Syndrome(Mode of inheritance, Cause(s), Presentation, Diagnosis, Treatment)

A
  • Autosomal recessive- Mutation in SLC12A3 gene on Chrom. 16 that encodes for NCCT protein of the Na+-Cl- symporter in the DCT - Metabolic alkalosis, hypokalemia and hypotension - Hypomagnesemia (which may worsen hypokalemia and lead to muscle crams, tetany and arrhythmias)- Dx: high urine K+ and Cl- despite their low serum level, also increased serum renin and aldosterone with hyperplasia of juxtaglomerular apparatus on renal biopsy; also low serum Mg++ and low urine Ca++- Rx: * Increased Na+ and K+ in diet with supplemental K+ and Mg++ and spironolactone * ACEIs also can be used
93
Q

Gordon’s Syndrome(Mode of inheritance, Cause(s), Presentation, Diagnosis, Treatment)

A
  • Autosomal dominant; also known as Pseudohypoaldosteronism type II (PHA2)- Increased activity of NCCT protein of Na+-Cl- symporter in DCT due to mutation in NCCT regulator genes WNK1 and WNK4- Short stature and hypertension with calcium renal stones - Dx: hyperkalemia, hyperchloremic metabolic acidosis, increased Ca++ in urine- Rx: Thiazide diuretics
94
Q

Pseudohypoaldosteronism type IA (PHA1A)(Mode of inheritance, Cause(s), Presentation, Diagnosis)

A
  • Autosomal dominant - Mutation of NR3C2 gene on Chrom. 4 that encodes for MLR protein of the mineralocorticoid receptor - Failure to thrive and dehydration- Dx: high sodium in urine, with hyponatremia, hyperkalemia and metabolic acidosis
95
Q

Pseudohypoaldosteronism type IB (PHA1B)(Mode of inheritance, Cause(s), Presentation, Diagnosis)

A
  • Autosomal recessive - Mutation of SCNN1A, SCNN1B and SCNN1G on Chrom. 12, 16, 16 respectively that encode for different subunits of epithelial sodium channels (ENaC) which is found in renal tubules, respiratory airways, female reproductive tract, colon, salivary and sweat glands. Also found in tongue (for perception of salt taste)- Failure to thrive, dehydration, lung infections and skin lesions - Dx: high sodium in urine, with hyponatremia, hyperkalemia and metabolic acidosis
96
Q

Liddle Syndrome(Mode of inheritance, Cause(s), Presentation, Diagnosis, Treatment)

A
  • Autosomal dominant- Mutation of SCNN1B and SCNN1G on Chrom. 16 that leads to deletion of PY motif of the ENaC protein so it can’t be recognized to be degraded by ubiquitin proteosome system- Childhood hypertension that doesn’t respond to Rx- Dx: hypernatremia, hypokalemia, metabolic alkalosis and low serum aldosterone - Rx: amiloride (safe in pregnancy) and triamterene
97
Q

Gullner Syndrome(Mode of inheritance, Cause(s), Presentation, Diagnosis, Treatment)

A
  • Autosomal recessive- Unknown - Metabolic alkalosis, hypokalemia and hypotension; also hypercalciuria and nephrocalcinosis - Dx: high urine K+ and Cl- despite their low serum level, hypomagnesemia, also increased serum renin and aldosterone with normal juxtaglomerular apparatus on renal biopsy- Rx: * Increased Na+ and K+ in diet with supplemental K+ and Mg++ and spironolactone * NSAIDs * ACEIs also can be used
98
Q

Hypokalemic Periodic Paralysis (Mode of inheritance, Cause(s), Presentation, Association(s), Diagnosis, Treatment)

A
  • Autosomal dominant- Mutation of either CACNA1S gene on Chrom. 1 that encodes for voltage-gated Ca++ channels in transverse tubules of skeletal muscles or SCN4A gene on Chrom. 17 that encodes for voltage-gated Na+ channels in NMJ- Muscle weakness or paralysis that usually begin in adolescence; it occurs usually on awakening or after sleep or rest following strenuous exercise, high carb meal or meals with high sodium content, also induced by cold temperature - Misdiagnosed as conversion disorder - Dx: Long exercise test (specialized EMG) which measures amplitude of nerve response (Compound Muscle Action Potential CMAP) for 40 to 50 minutes following a few minutes of exercise; there will be progressive fall in amplitude. Also combined with low K+ level during attacks - Rx: * Prevention by avoiding high Carb meals, strenuous exercise and other triggers, acetazolamide or spironolactone * Acute attack by drinking K+ salts in water like KCl or KHCO3 or the use of time-released K+ tablets
99
Q

SeSAME Syndrome (Mode of inheritance, Cause(s), Presentation, Diagnosis, Treatment)

A
  • Autosomal recessive- Mutation of KCNJ10 gene on Chrom. 1 that encodes for ATP-sensitive inward rectifier K+ channel 10 protein which is found in brain, ear and kidney- SEizures, Sensorineural deafness, Ataxia, Mental retardation, and Electrolytes disturbances. In addition to polyuria and polydipsia- Dx: hyponatremia, hypokalemia, hypomagnesemia, hypocalciuria and metabolic alkalosis - Rx: none
100
Q

Fibronectin Glomerulopathy (Mode of inheritance, Cause(s), Presentation, Diagnosis, Treatment)

A
  • Autosomal dominant- Mutation of FN1 gene on Chrom. 2 that encodes for fibronectin-1 protein (an important extracellular matrix protein) which leads to its deposition in glomeruli - Hypertension and type IV renal tubular acidosis- Dx: hematuria and proteinuria- Rx: none
101
Q

Congenital Hypoaldosteronism (Mode of inheritance, Cause(s), Presentation, Diagnosis, Treatment)

A
  • Autosomal recessive - Mutation of CYP11B2 gene on Chrom. 8 that emcodes for aldosterone synthase which leads to decrease its activity and corticosterone methyl oxidase deficiency type I (decrease in 18-hydroxicorticosterone) and type II (increase in 18-hydroxycorticosterone)- Failure to thrive and salt wasting - Dx: hyponatremia and hyperkalemia - Rx: give mineralocorticoid like Fludrocortisone
102
Q

Cystic Fibrosis-like Syndrome(Mode of inheritance, Cause(s), Presentation, Diagnosis)

A
  • Autosomal recessive- Mutation of CA12 gene on Chrom. 15 that encodes for carbonic anhydrase enzyme - Severe hyponatremic dehydration and hyperkalemia- Dx: low serum Na+, High serum K+ and Cl-; and normal cystic fibrosis transmembrane conductance regulator (CFTR) protein level
103
Q

Nephronophthisis(Mode of inheritance, Cause(s), Presentation, Diagnosis, Treatment)

A
  • Autosomal recessive- Mutation of NPHP gene; it is a form of ciliopathy - Polyuria and polydipsia; and eventually end-stage renal disease- Dx: renal ultrasound which shows fibrosis and formation of cysts at the cortico-medullary junction - Rx: none
104
Q

Hyperkalemic Periodic Paralysis(Mode of inheritance, Cause(s), Presentation, Treatment)

A
  • Autosomal dominant- Mutation of SCN4A that encodes for sodium channels expressed in muscles which impairs channels inactivation leading to sustained Na+ conductance - Muscle weakness or paralysis that usually begin in adolescence; it occurs usually on awakening or after sleep or rest following strenuous exercise, meals with high K+ content, and weather changes- Rx: * IV calcium decreases Na+ channel activity so it can stop sudden attacks * Diuretics (loop, thiazides and carbonic anhydrase inhibitors) * Glucose and insulin to enhance K+ uptake by cells and decrease weakness * High Carb diet is recommended with avoidance of triggers
105
Q

Beckwith-Wiedemann Syndrome(Mode of inheritance, Cause(s), Presentation, Association(s), Diagnosis, Treatment)

A
  • None; 85% is sporadic and 15% is familial- Defect on Chrom. 11 that leads to overactivity of IGF-2 gene and/or no active copy of CDKN1C (inhibitor of cell proliferation gene). One of the defects is paternal uniparental disomy (UPD). Other genes involved are H19 gene (limiting body weight and cell proliferation) and KCNQ1OT1 gene - Macroglossia, macrosomia, midline abdominal wall defects (omphalocele/exomphalos, umbilical hernia, diastasis recti), ear creases or ear pits, neonatal hypoglycemia, hepatoblastoma, nevus flammeus (port-wine stain on forehead or back of neck), and hemihypertrophy - Assisted reproductive technology (ART) and Wilms tumor - No specific diagnostic test- No specific Rx
106
Q

WAGR Syndrome

A
  • Autosomal dominant
107
Q

Denys-Drash Syndrome

A
  • Autosomal dominant
108
Q

Perlman Syndrome

A
  • Autosomal dominant
109
Q

21-hydroxylase deficiency (Mode of inheritance, Cause(s), Presentation, Association(s), Diagnosis, Treatment)

A
  • Autosomal recessive - Recombination on Chrom. 6 between CYP21A2 gene that encodes for the enzyme with the pseudogene (non-functional) CYP21A1P which is near the first one- It can be either: * Salt-wasting congenital adrenal hyperplasia (CAH): at second to third week of life with poor feeding, vomiting, dehydration, hyponatremia, hypoglycemia, hyperkalemia and metabolic acidosis * Simple virilizing CAH: just genital ambiguities and present later in the childhood period * Non-classical CAH: late presentation by appearance of pubic hair in mid-childhood, increased muscle mass, acne, adult body odor and accelerated bone age- Testicular adrenal rest tumors (TART) that leads to infertility in males - Dx: screening is done using 17-alpha-hydroxyprogesterone (highly sensitive but not specific), androstenedione, and cortisol levels- Rx: * Salt-wasting CAH: hydrocortisone and IV saline and dextrose * Non-classical CAH: + Suppression of adrenal testosterone by hydrocortisone + Suppression of central precocious puberty using leuprolide (pituitary GnRH receptors agonist) + Slowing growth and bone maturation by using aromatase inhibitors to reduce conversion of testosterone to estradiol + Stress steroid coverage + Reconstructive surgery
110
Q

11-beta Hydroxylase deficiency

Mode of inheritance, Cause(s), Presentation, Diagnosis, Treatment

A
  • Autosomal recessive
  • Multiple defects in a gene located on Chrom. 8
  • Presents like 21-hydroxylase deficiency as early salt-wasting CAH, early childhood simple virilizing CAH, late non-classical CAH with infertility, in addition to childhood hypertension
  • Dx: elevated 11-deoxycortisol and 11-deoxycorticosterone
  • Rx:
  • Salt-wasting CAH: hydrocortisone and IV saline and dextrose
  • Non-classical CAH:
    + Suppression of adrenal testosterone by hydrocortisone
    + Suppression of central precocious puberty using leuprolide (pituitary GnRH receptors agonist)
    + Slowing growth and bone maturation by using aromatase inhibitors to reduce conversion of testosterone to estradiol
    + Mineralocorticoids replacement
    + Stress steroid coverage
    + Reconstructive surgery
111
Q

17-alpha Hydroxylase deficiency

Mode of inheritance, Cause(s), Presentation, Diagnosis, Treatment

A
  • Autosomal recessive
  • Defects in CYP17A1 gene that results in 2 forms of disease; either deficient 17-alpha hydroxylase activity or deficient 17,20-lyase activity
  • Presents either as:
  • CAH: with normal females until puberty (failure to achieve puberty) and males with ambiguas genitalia or perineal hypospadias, or abdominal or inguinal testes developing gynecomastia at puberty. Both associated with childhood hypertension, hypokalemia and metabolic alkalosis
  • Non-CAH: due to deficient 17,20-lyase activity; isolated sex hormones impairment with elevated gonadotropins
  • Dx:
  • CAH: elevated pregnenolone and progesterone
  • Non-CAH: elevated 17-alpha hydroxypregnenolone and low levels of DHEA
  • Rx:
  • Glucocorticoid replacement to correct hypertension and mineralocorticoid excess
  • Genetic females need estrogen replacement to induce puberty and periodic progestin to regularize menses. Fertility is reduced because egg maturation and ovulation are poorly supported by reduced intra-ovarian steroid production
  • Genetic males either raised as females with testes removal or raised as males with continuous testosterone replacement through life, surgery to correct hypospadias and orchiopexy if possible
112
Q

3-beta Hydroxysteroid dehydrogenase type II (3-beta-HSD II) deficiency
(Mode of inheritance, Cause(s), Presentation, Diagnosis, Treatment)

A
  • Autosomal recessive
  • Mutation of HSD3B2 gene
  • Presents as:
  • Salt-wasting CAH
  • Ambiguous genitalia in both sexes (sometimes difficult to distinguish from 21-hydroxylase deficiency)
  • Dx: elevation of pregnenolone, 17-alpha-hydroxypregnenolone, DHEA and renin
  • Rx:
  • Mineralocorticoid replacement with fludrocortisone
  • Suppressing DHEA and replacing cortisol with a glucocorticoid
  • Stress glucocorticoid coverage
  • Steroids to optimize growth
  • Testosterone, estrogen and progesterone replacement to induce puberty and continued through life
  • Surgical sex assignment when warranted
113
Q

Lipoid Congenital Adrenal Hyperplasia (Lipoid CAH)

Mode of inheritance, Cause(s), Presentation, Diagnosis, Treatment

A
  • Autosomal recessive (most common in Japan,Korea and Palestine)
  • Either a mutation of the gene that encodes for cytochrome 450scc (cholesterol side chain cleavage enzyme) or a mutation in the gene that encodes for StAR on Chrom. 8
  • Salt-wasting CAH, Hyperpigmentation, hypoglycemia, In genetic females there will be enough production of estradiol by ovaries to induce breast development and menarche in some cases, but not enough to produce ovulation and therefore infertility. In genetic males, genitalia is severely undervirilized, with undescended and non-functional testes, failure to achieve puberty and infertility
  • Dx: High ACTH, adrenals are filled with lipid globules derived from cholesterol
  • Rx:
  • Salt-wasting CAH: hydrocortisone and IV saline and dextrose
  • Glucocorticoid supplement at minimal replacement doses (no need for suppression)
  • Stress glucocorticoid coverage
  • In genetic females estrogen replacement at or after puberty, with assisted fertility (intracytoplasmic sperm injection)
  • In genetic males, after diagnosis the testes should be removed surgically and they are raised as females with no reports of later gender identity problems
114
Q

Familial Hypocalciuric Hypercalcemia (FHH)

A

Autosomal dominant

115
Q

Pseudohypoparathyroidism

A

Autosomal dominant

116
Q

Barakat Syndrome

A

Autosomal dominant

117
Q

Carney Complex

A

Autosomal dominant

Genetic Diseases (2 decks)

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