Genetics of reproductive and endocrine disorders Flashcards
Provide an overview of the role of genetics in disease
- Every disease, except simple trauma, has a genetic component.
- In monogenic disorders, genetic factors are the major etiologic factor.
- Complex disorders involve multiple genes along with environmental and lifestyle factors. ^[genetic component is often ignored] ^[note that radiation is a predisposing factor for thyroid disease]
- Genetic factors influence disease indirectly by defining susceptibility and resistance, as seen in environmental diseases.
- Diabetes mellitus type 2, obesity, hypertension, heart disease, asthma, and mental illnesses.
- These disorders are complex, influenced significantly by exogenous factors.
Describe cancer as a genetic disease
- Somatic mutations in genes controlling growth and differentiation are key elements in cancer pathogenesis.
- Many cancers are associated with a predisposition conferred by hereditary germline mutations.
Define and describe types of mutations
- Mutations are any changes in the nucleotide sequence of DNA.
- The mutation rate results from the interaction of error-producing and repair processes.
- Mutations can be structurally diverse, affecting one or a few nucleotides or chromosomes or entire genomes.
Provide examples of genes causing disease
A. Cell Differentiation
- Genes encoding transcription factors (e.g., SRY, DAX1). = AHC and HH
B. Hormone Synthesis and Action
- Genes encoding peptide hormone (e.g., AVP). = ADNDI
- Genes encoding hormone synthesis enzyme (e.g., CYP21A2). = CAH
C. Membrane Receptor
- Genes encoding transporter for synthetic materials. = Pendred
- Genes encoding membrane receptor (e.g., PDS, INR). = Insulin resistance or hypersensitivity
D. Nuclear Receptor
- Genes encoding nuclear receptor (e.g., GR). = Glucocorticoid resistance or hypersensitivity
F. Ion Channel
- Genes encoding ion channel (e.g., SCN4A). = Liddle
G. Tumorigenesis Oncogene
- Oncogene (e.g., RET). = MEN2
H. Tumor Suppressor Gene
- Tumor suppressor gene (e.g., MEN1).
Describe chromosmal abnormalities
A. Numeric Abnormalities
- Common aneuploidies: 45,X (Turner syndrome), 47,XXY (Klinefelter syndrome).
B. Structural Defects
- Involving X and Y chromosomes, such as isochromosomes, deletions, duplications, ring chromosomes, and translocations.
C. Congenital Sex Chromosome Abnormalities
- Occur in at least 1 in 448 births.
Describe Klinefelter’s Syndrome
Sex chromosome anueploidy (47XXY)
- Azoospermia is a common feature.
- Increased risk for psychiatric disorders, autism spectrum disorders, and social problems.
- Signs and symptoms include small testes, breast enlargement, increased height, fat accumulation, reduced facial and body hair, reduced libido, poor erections, fatigue, infertility, osteoporosis, and depression.
- Note that this condition can be quite asymptomatic,
Describe Turner’s syndrome
Sex chromosome aneuploidy (45X0)
Occurs in 1 in 2,500 births.
- Associated with various endocrine defects, growth abnormalities = fold of skin, characteristic facial features, short stature, low hariline, small finger nails, brown nevi, no menstruation, poor breat development
- Pathognomic features include short stature and primary ovarina failure
- Can have constriction or coarctation of aorta
List some endocrine defect diseases
- Adrenal hyperplasia.
- Laron Syndrome.
- Diabetes Mellitus.
- Thyroid disease.
Describe adrenal hyperplasia and congenital adrenal hyperplasia and its complications
Adrenal Hyperplasia
- Excessive production of androgens leading to hirsutism, precocious puberty, amenorrhea, and infertility.
- 95% cases involve 21-hydroxylase deficiency (CYP21A2).
- In general: deficiency in one or another of the enzymes of cortisol biosynthesis - accumulation of cholesterol precursors that are converted instead to sex steroids
1-Hydroxylase Deficiency**
I. Inheritance and Incidence
- Inherited as autosomal recessive.
- Incidence: 1 in 5000 births (carrier rate approximately 1 in 35).
II. Phenotypes and Presentation
- Classically affected female fetuses experience virilization of genitalia.
- Genital ambiguity at birth; boys do not show a particular phenotype.
- Later in life: Ambiguous genitalia in females and masculinized boys early during childhood.
III. Newborn Screening
- ACT and NSW started screening in AUGUST.
- The 1st case diagnosed in ACT was a girl with 21-OH deficiency and salt-wasting.
IV. 21-Hydroxylase Deficiency Overview
- Most common cause of congenital adrenal hyperplasia.
- Incidence: 1 in 14,000 live births, equal prevalence among males and females.
- Newborn screening for severe forms is crucial.: adrenal crisis at day 14
- Block in pathway constitutes a metabolic shunt
- Congenital forms of CAH result in GC and MC reduction and androgen increase
- Late onset forms do not have loss of corticosteroids but can present with precocious adrenarche, hirsutism, primary amennorhea, and infertility e.g. in females
A. Severe Forms
- Newborns susceptible to salt-wasting crises in the first few weeks of life.
- Associated with morbidity and mortality.
- Screening is reliable, sensitive, and effective in reducing severe complications (Wu et al., 2011).
Describe Laron syndrome or growth hormone insensitivity
I. Primary GH Insensitivity
- Rare genetic disorder located at 5p13.
- Pituitary dwarfism with craniofacial abnormalities (distinctive), metabolic features, and delayed puberty.
- Low serum levels of IGF-I despite normal or elevated GH levels.
- Dysfunction of GH receptor.
II. Treatment
- Injections of insulin-like growth factor 1 (IGF-1) and a diet with adequate calories.
A. Genetic Basis
- Autosomal recessive, observed in genetic isolates with a founder effect.
- 65% are of known Semitic origin; consanguinity is frequently observed.
- 33 mutations in Growth Hormone Receptor (GHR) described, mostly in the extracellular hormone binding domain.
- Post-receptor defects vs. IGF1 DEFICIENCY (mutations in the IGF1 gene, 12q22) leading to growth retardation with sensori-neural deafness and mental retardation (rare).
vs
- IGF1 DEFICIENCY – mutations in the IGF1 gene (12q22) - leads to growth retardation with sensori-neural deafness & mental retardation
- rare
Describe HLA associations and autoimmune diseases
HLA class I or II alleles can have predisposing or protective effects.
- HLA class II DR3 AND 4 predispose to T1DM, Hashimoto’s
- DR3 predisposes to Addison’s disease
- DR14 and 15 protective for T1DM
- DR15 predisposes to MS, DR14 protects
- DR3 = myasthenia gravis
- HLA lass I some B and As predispose, several A protect against T1DM
- MS certain Cs protect, certain alleles predispose
Provide an overview of T1DM and its inheritance and prevalence
I. Overview
- Genetically heterogeneous autoimmune disease.
- Affects about 0.3% of Caucasian populations.
- Insulin is functionally absent due to the destruction of pancreatic beta cells.
- Hyperglycemia-induced osmotic diuresis and secondary thirst.
- Long-term complications affect eyes, kidneys, nerves, and blood vessels.
II. Inheritance and Prevalence
- Complex inheritance with genes on Xp11.23-q13.3, 12q24.2, 1p13, 6p21.3.
- 30-50% concordance in MZ twins.
- Familial aggregation, more prevalent in Caucasians than Asians.
- Increased prevalence in patients with other autoimmune diseases (e.g., Graves disease, Hashimoto thyroiditis, Addison disease).
- Side note: 16 monogenic DM
Describe the genetics of IDDM and NIDDM
III. Genetics of IDDM – Early Onset
- 95% of patients with type 1 DM have either HLA-DR3 or HLA-DR4.
- Males»_space; females.
- Known association/linkage with PTPN22 (Protein tyrosine phosphatase, nonreceptor-type 22). = RA, Graves, SLE NOT MS
- Genetic heterogeneity and complex inheritance: Despite stronger linkages genes underling DM not well characterized
IV. NIDDM - Non-Insulin Dependent Diabetes (Type 2)
- Late onset/stress-induced/gestational.
- Can usually be controlled by diet and hypoglycemic agents without insulin injections.
- Strongly associated with metabolic syndrome and central adiposity.
- Genetic heterogeneity and complex inheritance.
Describe Grave’s disease
- Autoimmune disorder with antibodies to the thyrotropin receptor.
- In Graves disease, most of the T cells undergo a Th2 differentiation
and activate B cells to produce TSHR antibodies, which stimulate the
thyroid and cause clinical hyperthyroidism - Constitutive activation of the receptor and increased levels of thyroid hormones.
- Clinical hyperthyroidism symptoms: sweating, tachycardia, hyperactivity, weight loss, hyperpyrexia.
- can be life threatening = thyroid storm
- GWAS demonstrate genetic heterogeneity and complexity.
- Likely environmental triggers against a genetically determined susceptibility.
- Note that it can also be asymptomatic
Describe hypothyroidism and HT
- Thyroid dysgenesis with goiter, lethargy, delayed growth, skeletal maturation.
- Hashimoto thyroiditis is caused by Th1 switching of the
thyroid-infiltrating T cells, which induces apoptosis of thyroid follicular
cells and clinical hypothyroidism - Low T4 and high TSH, lowered metabolic rate, and general loss of vigor.
- Whites: 1 in 5,526 vs Blacks: 1 in 32,377, F:M:: 10-20:1.
- Characterized by thyroid enlargement, fibrosis, lymphatic infiltration, and antibody production.
- Treatment= levothyroxine
