Ped Endo

Question 1

What is the genetic etiology of Russell-Silver Syndrome?

Answer 1

THINK Seven Eleven!

Chr 11p15 (30-60%) - loss of methylation of Chr 11p15
Chr 7 (5-10%) - maternal uniparental disomy
In approximately 40% of patients with a clinical diagnosis of RSS, the underlying cause is still not known.

Question 2

Hypothalamic-Pituitary Dysfunction After Cranial Radiotherapy

Prevalence of Pituitary dysfunction as a function of radiation dose

Answer 2

DOSE OF IRRADIATION
GH deficiency ≥ 18 Gy
Central precocious puberty ≥ 18 Gy

FSH/LH deficiency ≥ 30 Gy
TSH deficiency ≥ 30 Gy
ACTH deficiency ≥ 30 Gy

Hyperprolactinemia ≥ 50 Gy

Question 3

Risk for POI

Radiation vs alkylating agents - which has more risk?

Answer 3

Radiation - as low as 2 Gy
Alkylating agents - exposure to high (NOT low) dose

Question 4

Aim of making a Fishbone diagram:
Identify a solution to a problem
Identify root cause
Identify the frequency of (groups) of problems

Answer 4

Fishbone diagram tool (Ishikawa) - TO TRY AND IDENTIFY ROOT CAUSE (has nothing to do with solution(s) to the problem)
● Agree on the problem statement (also referred to as the effect). This is written at the mouth of the “fish.” Be as clear and specific as you can about the problem. Beware of defining the problem in terms of a solution (e.g., we need more of something).
● Agree on the major categories of causes of the problem (written as branches from the main arrow). Major categories often include: equipment or supply factors, environmental factors, rules/policy/procedure factors, and people/staff factors.
● Brainstorm all the possible causes of the problem. Ask “Why does this happen?” As each idea is given, the facilitator writes the causal factor as a branch from the appropriate category (places it on the fishbone diagram). Causes can be written in several places if they relate to several categories.
● Again asks “Why does this happen?” about each cause. Write sub-causes branching off the cause branches.
● Continues to ask “Why?” and generate deeper levels of causes and continue organizing them under related causes or categories. This will help you to identify and then address root causes to prevent future problems.

Question 5

What is the most common indication for starting Rx in a patient with Non-Classical CAH?

Answer 5

Body odor
Adrenarche
Baseline 17-OHP
Level of ACTH stimulated 17-OHP
Increase in ACTH stimulated DHEAS
Increase in ACTH stimulated Testosterone
Compromise in final height prediction based on BA

Question 6

What is the Friedewald formula (FF)?

Answer 6

LDL-cholesterol, as estimated by the Friedewald formula (FF) in routine patient care.
LDL = Total cholesterol (TC) minus high-density lipoprotein (HDL)-cholesterol minus triglycerides (TGs)/5 in mg/dl).
The FF is not valid for patients with TGs >400 and in patients for type 3 dyslipoproteinemia.
A number of studies have studied the impact of TG on the FF. These studies suggest LDL may be underestimated by the FF at low LDL levels and higher TG levels.

Question 7

What endocrinopathies are associated with Duchenne’s Muscular Dystrophy?

Answer 7

• short stature
• pubertal delay
• iatrogenic adrenal insuffiency
• obesity associated co-morbidities
• low bone mineral density

Question 8

What are the major types of hormone receptors?

Answer 8

G protein–coupled receptors
Type 1 cytokine receptors
Receptor tyrosine kinases
Nuclear receptors

Question 9

Examples of G protein–coupled receptors

Answer 9

ACTH and other melanocortins, V2 vasopressin, LH, FSH, TSH, GnRH, TRH, GHRH, corticotropin-releasing factor, somatostatin, glucagon, oxytocin, gastric inhibitory peptide, type 1 PTH, free fatty acid, GPR54, orexin, ghrelin, melanin-concentrating, calcitonin, glucagon-like peptide-1, and calcium-sensing receptors

Question 10

Examples of Type 1 cytokine receptors

Answer 10

Growth hormone, prolactin, and leptin receptors

Question 11

Examples of Receptor tyrosine kinases

Answer 11

Insulin, IGF-1, and fibroblast growth factor receptors

Question 12

Examples of Nuclear receptors

Answer 12

Thyroid hormone, vitamin D3, PPARγ, HNF4A, glucocorticoid, androgen, estrogen, mineralocorticoid, and DAX1
receptors

Question 13

Examples of Type 2 cytokine receptors

Answer 13

Type II cytokine receptors, also commonly known as class II cytokine receptors, are transmembrane proteins that are expressed on the surface of certain cells.
They bind and respond to a select group of cytokines including interferon type I, interferon type II, interferon type III.[1] and members of the interleukin-10 family.
These receptors are characterized by the lack of a WSXWS (Tryptophan Serine x Tryptophan Serine) motif which differentiates them from type I cytokine receptors.

Question 14

Child with
Developmental delay, mild intellectual disability
Unique personality characteristics
Supravalvar aortic stenosis, peripheral pulmonary stenosis, hypertension)
Growth deficiency, endocrine abnormalities (early puberty, hypercalcemia, hypercalciuria, hypothyroidism)
Distinctive facies.
Feeding difficulties often lead to poor weight gain in infancy.

What is the expected abnormality on genetic testing?

Answer 14

Heterozygous 1.5- to 1.8-Mb deletion on chromosome 7q11.23.
FBNi1 gene mutation
FGFR3 gene mutation
CASR gene mutation

Question 16

Types of VDDR

Answer 16

1A - Unable to convert 25(OH)D to 1,25(OH)2D owing to biallelic mutations in the CYP27B1 gene on chromosome 12q13.3 that encodes 25-hydroxyvitamin D3-1α-hydroxylase.
1B - Due to mutations in CYP2R1 that decreases expression or function of the encoded CYP2R1 enzyme, the principal 25-hydroxylase. Decrease/unable to convert calciferols to 25(OH)D Calcidiol.
2A - Biallelic loss-of-function mutations in the gene encoding the vitamin D receptor (VDR) on chromosome 12q13.11, and therefore represents a bona fide form of tissue resistance to vitamin D.
2B - resembles VDDR2a but is not caused by a defect in the VDR gene. Rather, the molecular defect appears to be overexpression of a nuclear protein that specifically interacts with a DNA response element that binds retinoid X receptor-VDR heterodimers. This dominant-negative protein appears to be a member of the family of heterogeneous nuclear ribonucleoproteins (hnRNPs), which attenuate gene transcription via their role as hormone response element-binding proteins. No gene has yet been identified as the cause of VDDR2b.
3 - VDDR3 is due to increased inactivation of vitamin D metabolites
and is caused by a recurrent gain-of-function missense mutation
(p.I301T) in the gene encoding CYP3A4, the most abundant
hepatic CYP450 enzyme.

Question 17

Genotype-Phenotype correlations in CYP21A2 mutations

Answer 17

CYP21A2 variants are classified according to the impact on the enzyme activity.

Group Null consists of deletions or nonsense variants that critically affect the enzyme activity, resulting in a complete loss of function due to altered enzyme stability, steroid or heme binding, and membrane anchoring. The most common variants are:
* Thirty kilobase deletion (30-kb del),
* Eight base pairs del,
* Cluster E6 (p.I237N, p.V238E, p.M240K)
* p.Q319X, p.R357W, and p.L307fs.
Homozygous or compound heterozygote variants with the null group are often associated with the salt-wasting form, but approximately 20% of cases have a simple virilizing phenotype [3].

Group A is composed of a variant in which the enzyme activity is minimal, around 0–1%.
This group is represented by an intron variant IVS2-13A/C>G, which is created by an additional splice acceptor site causing retention of 19 intronic nucleotides of the intron 2.

Group B has a residual activity of 1–10%, which is enough to prevent adrenal crisis.
The p.I173N variant is representative of this group and is associated with the simple virilizing form of 21-hydroxylase deficiency.

Group C has an enzyme activity of about 20-60% and is associated with the mild form of CAH. The variants common in this group are:
* p.V282L, p.P454S, and p.P31L - which show phenotype variability.

Question 18

A low circulating level of GHBP is seen in

Answer 18

GH deficiency
IGF deficiency
ALS deficiency
Laron syndrome due to mutation in the extracellular domain of GHR
Laron syndrome due to mutation in the intracellular domain of GHR

Question 19

What is a Pareto chart?
What is a Pareto principle?

Answer 19

What is a Pareto chart?
A Pareto chart is a quality management tool that provides a way to visualize business problems, analyze them, and come up with ways to improve things. Pareto charts are based on the Pareto principle, also known as the 80/20 rule as it states that 80% of consequences occur as a result of 20% of the known causes.

A Pareto chart resembles a bar chart combined with a line graph. It identifies the different components or aspects of a quality issue and puts them in descending order from the one that has the most impact to the lowest impact. 

Pareto Chart Quality Management Benefits
A Pareto chart is most commonly used to break down quality issues into component problems or groups of problems and analyze the frequency of them. The goal is to highlight the most significant quality issues, allowing them to be addressed in priority order.

Question 20

Which of the following is the main binding protein in circulation for
progesterone:
(1) SHBG
(2) Albumin
(3) CBG
(4) TBG
(5) Does not bind any protein

Answer 20

CBG

Question 21

Histological types of craniopharyngioma

Answer 21

There are two major theories of the development of craniopharyngioma: the embryonic theory and the metaplastic theory.
Two histologic subtypes:
Adamantinomatous craniopharyngioma (ACP)
* The more common subtype - can affect all age groups but especially the pediatric population.
* During embryogenesis outpouching of the ectodermal roof of the stomodeum - Rathke pouch
* Rathke pouch extends cranially towards the floor of the diencephalon to later form the adenohypophysis or anterior pituitary gland.
* While migrating cranially, its extension forms the craniopharyngeal duct which later involutes.
* On some occasions, involution is not total, and remnants of ectodermal cells can be present. These embryonic cells can proliferate around the extension of the craniopharyngeal duct and develop into a craniopharyngioma.
* Somatic mutation in the CTNNB1(codes for β-catenin protein) is proposed to be responsible for ACP development. CTNNb1 mutation is a point mutation in exon 3 leading to excessive β-catenin protein thus activating the WNT signaling pathway leading to cell proliferation, invasion, and development of a tumor.

Papillary craniopharyngioma (PCP)
* Primarily seen in adults.
* The adenohypophyseal cells of the pars tuberalis can undergo metaplasia and result in the formation of squamous cell nests; which further proliferates and leads to PCP.
* Somatic mutation in BRAF has been associated with PCP. BRAF activated the mitogen-activated protein kinase(MAPK) pathways; which are usually upregulated in cancer.