Med Gen Exam 2

diabetes mellitus

the elevation of blood glucose caused by reduced glucose by insulin from pancreatic beta cells

type 1 diabetes mellitus

autoimmune, young onset, associated with normal body weight, no strong familt history but there are genetic factors

pancreas is damaged and does not make enough insulin

type 2 diabetes mellitus

insulin resistance, adult onset, strong familial predisposition, genes and multifactorial

enough insulin is made but tissues do not respond to it

secondary diabetes mellitus

caused by damage to pancreas, such as the pancreas being surgically removed

maturity onset diabetes of the young (MODY)

a genetic diabetes mellitus with onset in the early 20s, does not fit clinical pictures of type 1 or 2, AD inheritance pattern, all patients with over 5% risk should undergo genetic testing for it via panel

GCK (MODY2)

common, 30-50% of MODY, no phenotypic features, absence of microvascular and macrovascular complications, AD

HNF1A (MODY3)

common, 30-50% of MODY, low renal threshold for glucose in the early stages of diabetes, AD

HNF1B (MODY5)

uncommon, 5% of MODY, variable phenotype, renal cysts or dysplasia, urogenital tract malformations in females, low fecl elastase, AD

CEL (MODY8)

very rare, <1% of MODY, exocrine pancreatic dysfunction, low fecl elastase, AD

neonatal diabetes

often due solely to genetic influences

KCNJ11 (30%), INS (20%), ABCC8 (19%), GCK (4%), PDX1 (<1%)

Combined Pituitary Hormone Deficiency (CPHD)

majority is non-genetic, 10% is familial (AD, AR, or XR), PROP1 is 50% of the familial cases, POU1F1 can cause isolated GH deficiency, also septo-optic-dysplasia (AD through HESX1, OTX2, and SOX2)

isolated pituitary tumors

can be caused by autosomal dominant AIP mutations

Laron pituitary dwarfism

isolated growth hormone deficiency, AR, defect in human growth hormone receptors

adrenal cortex hormones

epinephrine (aka adrenaline) and norepinephrine (stress hormone - fight or flight)

adrenal medulla hormones

aldosterone (controls Na and K in kidneys), cortisol (involved in metabolism), androgens (sex hormones)

Congenital Adrenal Hyperplasia (CAH)

enlarged adrenal glands most often caused by 21-Hydroxylase deficiency (CYP21A2 - AR)

can cause salt wasting (lethal in infancy) or atypical (androgen excess late in life, too much hair, irregular menses, virilization) form

salt-wasting is part of newborn screening

testing for adrenal enzyme deficiencies

genetic testing not really useful unless reproductive, as it can be diagnosed by just looking at biochemical levels

CAH has complicated sequencing because there are pseudogenes

McCune-Albright Syndrome

overactive GNAS, CALM with coast of Maine, polyostotic fibrous dysplasia (outer edge of bones are lighter), precocious puberty, hormone excess, hypophosphatemia (low blood phosphate)

pseudohypoparathyroidism

caused by underactive GNAS, common is Albright hereditary osteodystrophy phenotype (round face, short stature, obesity, short digits),

hypophosphatemia

FGF23 mutation (AD), PHEX mutation (XL - most common)

abnormally low levels of phosphate in the blood

primary amenorrhea

absence of menstrual cycle

syndromes: Turner syndrome, isolated hypogonadotropic hypogonadism, Kallmann syndrome, galactosemia

Kallmann syndrome

low gonadotropes and loss of sense of smell, delayed or absent puberty

secondary amenorrhea

absence of menstrual periods for at least 3 cycles in individuals with previously regular cycles or for 6 months

syndromes: Fragile X syndrome, Fragile X-associated tremor/ataxia syndrome, FMR1-related primary ovarian insufficiency

Klinefelter syndrome (XXY, XXXY, XXXXY)

mostly intellectually typical, tall stature, fibrosis of testes, primary hypogonadism, can have many X chromosomes, more X chromosomes usually correlates with more ID

azoospermia

no sperm in semen

caused by: Y chromosome microdeletions (20%), cystic fibrosis

XX DSD

formerly female pseudohermaphroditism, expect female characteristics bu have male features

XY DSD

formerly male pseudohermaphroditism, expect male characteristics but have some female features

gonadal disgenesis

absence of gonads

ovotesticular DSD

true hermaphroditism, have both ovaries and testes

gonadal sex

the internal structures associated with sexual development

phenotypic sex

the external structures associated with sexual development

SRY

gene on Y chromosome which drives male development

if you lack this gene = female development

can be tested through FISH

46 XX DSD Pathogenesis

most causes are realted to congenital adrenal hyperplasia
common genes: CYP21A2, CYP11B1, POR

Antley-Bixler Syndrome

POR mutations (AR), FGFR2 mutations (AD), craniosynostosis, skeletal dysplasia

46 XY DSD Pathogenesis

problems of gonadal development (SRY, WT1)

problems of androgen synthesis (17 beta HSD deficiency, StAR deficiency)

problems of testosterone metabolism (5 alpha reducatase deficiency)

problems of testosterone action (complete androgen insensitivity syndrome, partial androgen insensitivity syndrome)

WAGR Syndrome (or Aniridia-Wilms Tumor Association)

continuous gene deletion on 11p13 (including WT1 and PAX6)

PAX6 loss causes aniridia

WT1 is the Wilms tumor gene that confers with kidney cancers

5 alpha reductase deficiency

SRD5A1 and SRD52, involved in testosterone pathway, results in normal male development internally but not externally

androgen receptor deficiency (in 46 XY individuals)

XL recessive, phenotype is variable from woemn with amenorrhea to undervirilized men, impacts urogenital tract, normal to high testosterone and DHT, elevated estradiol, they drive hair development too so some with too little will have practically no body hair

teratogens affecting stature

toxoplasmosis, rubella, CMV, Zika, alcohol, nicotine, maternal PKU

postnatal factors affecting stature

prematurity, malnutrition, chronic disease, untreated hypothyroidism, acquired pituitary insufficiency (through birth trauma, cancer treatment, tumors, and infection), and medication (ADHD medication, steroids)

genetic mechanisms for prenatal onset short stature

chromosomal abnormalities (aneuploidies and del/dup syndromes), epigenetic changes, cohesinopathies, defects of cell replication and DNA repair

SHOX

the gene that is haploinsufficient in Turner syndrome and responsible for the short stature, and the gene with an increased copy number in Klinefelter that is responsible for tall stature

Russell Silver Syndrome

epigenetic changes on chromosome 7 or 11p15, kids have IUGR and persistent growth delays, characterized by triangular face, relative macrocephaly, clinodactyly, and DD/learning difficulty risk

Cornelia de Lange Syndrome

NIPBL (80%), a cohesinopathy, distinctive facial features, hypertrichosis (excessive hair), upper limb reduction defects, variable cognitive delay

MOPDII (microcephalic osteodysplastic primordial dwarfism type II)

PCNT, distinctive facial features, high-pitched nasal voice, abnormal dentition, vascular disease, chronic kidney disease, diabetes, defect of cell replication

Coffin Siris Syndrome

APID1B (37%) and other genes, distinctive facial features, 5th digit nail hypoplasia, variable cognitive delay, hypotonia, hirsutism (back, arms, and face) with sparse hair

Aarskog Syndrome

FGD1, distinctive facial features, wide and flat feet, brachydactyly/clinodactyly, shawl scrotum, eye problems (optic nerve hypoplasia, retinal vessel totuosity, hyperopia), variable cognitive delays

Smith Lemli Opitz

DHCR7, microcephaly, ID, cleft palate, heart defects, polydactyly, 2-3 toe syndactyly, disorder of cholesterol metabolism due to enzyme deficiency

Bloom Syndrome

BLM, immune abnormalities, sensitivity to sunlight, insulin resistance, high cancer risk at early age, normal intellect, microcephaly, male infertility

Ataxia-telangiectasia Syndrome

ATM, progressive neurologic symptoms (ataxia, neuropathy), immunodeficiency, pulmonary disease, cancer risk (lymphoma, leukemia)

Fanconi Anemia

FANCA (60%) + other genes, limb malformations, microcephaly, cafe-au-lait macules or hypopigmentation, progressive bone marrow failure with pancytopenia, increased leukemia and solid tumor risk

postnatal onset of short stature should see which specialty?

endocrinology for growth hormone stimulation tests

Cockayne Syndrome

ERCC6 and ERCC8, symptoms are a spectrum, postnatal growth failure, progressive microcephaly, DD, photosensitivity, retinopathy/cataracts, hearing loss, dental anomalies

Rubenstein Taybi

CREBBP and EP300, distinctive facial features, broad thumbs and big toes, ID, respiratory and feeding difficulties, recurrent infections, constipation

Kabuki Syndrome

KDM6A and KMT2D, distinctive facial features, persistent fetal fingertip pads, ID, vertebral anomalies, brachydactyly, clinodactyly

Hutchinson-Gilford Progeria

LMNA, features that resemble accelerated aging, failure to thrive before 1 year, distinctive facial features, loss of subcutaneous fat, delayed dentition, alopecia, typical motor and cognitive development, shortened life expectancy

CHARGE Syndrome

CHD7, Coloboma, Heart defect, Atresia of the choanae, Retardation of growth, Genital hypoplasia, Ear anomalies (SNHL)

Costello Syndrome

HRAS, coarse features, macrocephaly, curly or sparse/fine hair and loose skin, feeding difficulties, failure to thrive in infancy, hypotonia, hypertrophic cardiomyopathy (60%), ID (80%)

Cardiofaciocutaneous Syndrome

BRAF, MAP2K1, MAP2K2, KRAS, distinctive features, cardiac abnormalities (pulmonic stenosis, hypertrophic cardiomyopathy, arrhythmia), variable cognitive delay, skin/hair findings

Beckwith-Wiedemann Syndrome

abnormal expression of imprinted genes in 11p15.5, macroglossia, macrosomia, hemihyperplasia, hypoglycemia as a newborn, increased embryonal tumor risk

Sotos Syndrome

NSD1, distinctive facial features, variable ID, overgrowth

Weaver Syndrome

EZH2-related overgrowth, distinctive facial features, soft/doughy skin, tall stature, microcephaly, advanced bone age, variable cognition

Proteus Syndrome

AKT1, segmental and rapidly progressive overgrowth in skeleton, skin, adipose, and CNS beginning as a toddler, increased tumor risk, pulmonary complications, deep vein thrombosis

PTEN Hamartoma Tumor Syndrome

PTEN, overall increased risk for cancer and neurodevelopmental disorders

Cowden Syndrome

PTEN, trichilemmomas, papilomatous papules, macrocaphaly

Bannayan-Riley-Ruvalcaba Syndrome

PTEN, high birth weight, ID, pigmented macules, macrocephaly, intestinal hamartomatous polyposis

PTEN-related Proteus and Proteus-like Syndrome

PTEN, segmental overgrowth, moles, disfigurement, multiple tissues

PIK3CA-related Overgrowth Spectrum

PIK3CA; includes megalencephaly-capillary malformation, CLOVES, and Kippel-Trenunay syndrome; segmental overgrowth in brain, limbs, trunk, and face; vascular and lymphatic malformations; polydactyly or syndactyly

What are the three cardinal features of Sotos syndrome?

overgrowth, learning differences, distinctive facial features

What is the most common mechanism for acquiring BWS?

loss of methylation on the maternal chromosome

Classic Hutchinson-Gilford Progeria syndrome is caused by what type of mutation?

synonymous mutation causing a cryptic splice site activation

What is the inheritance pattern of KMT2D-related Kabuki syndrome?

autosomal dominant (typically de novo)

What digit anomaly is most often associated with Rubinstein-Taybi syndrome?

broad thumbs and great toes

What is the median age of onset of the first malignancy in ataxia telangiectasia?

12 years old

What do fanconi anemia, ataxia-telangiectasia, and bloom syndrome have in common?

they are all chromosome breakage syndromes

What type of testing is most likely to pick up Russell-Silver Syndrome?

methylation testing

What is the most common gene implicated by Cornelia de Lange Syndrome?

NIBPL

What molecular testing results would confirm McCune-Albright syndrome?

A somatic activating pathogenic variant in GNAS

Variants in which gene are responsible for the cardiac defects in Williams syndrome?

ELN

Marfan syndrome is caused by mutations that affect which cellular structure?

Extracellular matrix

How does the Loeys-Dietz phenotype differ from Marfan’s?

presence of cleft palate, bifid uvula, and craniosynostosis

Which gene is most often associated with classic ehlers danlos syndrome?

COL5A1

The newborn screen tests for CF by measuring which pancreatic pro-enzyme?

trypsinogen

What is the most common cause of Stickler Syndrome?

COL2A1

Which lab abnormality is characteristic of Smith-Lemli-Opitz syndrome?

elevated 7-dehydrocholesterol

What is the most common cardiac abnormality seen in Noonan syndrome?

pulmonary valve stenosis

What does the C in CHARGE syndrome stand for?

coloboma

What does the H in CHARGE syndrome stand for?

heart defects

What does the A in CHARGE syndrome stand for?

atresia of the choanae

What does the R in CHARGE syndrome stand for?

restricted growth

What does the G in CHARGE syndrome stand for?

genital hypoplasia

Loss of which of the five senses is associated with Waardenburg syndrome type 1?

hearing

Deletion of which gene causes the cardiac findings in 22q11.2?

TBX1

Which autoimmune diseases can be seen in Turner Syndrome?

celiac disease and thyroiditis

Which gene in the pseudoautosomal region of the X chromosome is associated with the tall stature seen in Klinefelter Syndrome?

SHOX

What ocular symptom can be seen in patients with myotonic dystrophy type I?

cataracts

What gene is most commonly involved in Charcot Marie Tooth disease?

PMP22

What type of imaging is needed annually in patients with Friedreich ataxia?

echocardiogram

Which gene is most often implicated in Alagille syndrome?

JAG1

What hand anomaly is most commonly seen in Bardet-Biedl Syndrome?

postaxial polydactyly