Genetic Disorders of the Endocrine System + Q(Tegay)

FGFR-3 (fibroblast growth factor)

Achondroplasia is caused by mutation of the _____ gene.

Klinefelter Syndrome (47,XXY)

Cause of tall stature in males, caused by an extra X chromosome, and therefore eXtra SHOX gene:

normal

Children with *Constitutional* Delay in Growth usually have parents with _______ stature. (denovo?)

growth spurt

Children with Constitutional Delay in Growth have a delayed pubertal ______ ______. (hint: late bloomers)

asymmetry

Children with Russell Silver Syndrome typically have limb-length __________.

silence

Methylation tends to _____ gene expression.

Smith Magenis Syndrome (17p11.2)

Microdeletion Syndrome characterized by self-injurious behavior and short stature:

Prader Willi Syndrome (15q11-13)

Microdeletion of chromosome 15 that causes *lack of satiety*, characterized by the 5 H's: HYPERphagia and Hypotonia/mentia/pigment/gonad.

DiGeorge Syndrome (22q11.2)

Microdeletion syndrome consisting of hypoparathyroidism, hypocalcemia, and short stature:

de novo

More than 95% of cases of Sotos Syndrome are __ ____.

imprinting center mutation

Normal imprinting can be disrupted by chrosomal deletion, uniparental disomy, or

small

Patients with Beckwith Wiedemann Syndrome have a LARGE BODY and _____ head.

healthy

Patients with Familial Short Stature AND Constitutional Delay in Growth are otherwise _______.

dyslexia

Patients with Klienfelter Syndrome are more likely to be shy and have _____, Eunochoid Habitus, Gynecomastia, and ligamentous laxity. (hint: Normal IQ, verbal learning disorder)

large

Patients with Sotos Syndrome have _____ hands and feet.

jaw

Patients with Sotos Syndrome have a prominent forehead with a long, narrow ___.

Paternal

Prader Willi Syndrome is due to Chromosome 15q11-13 Microdeletion or ______ Methylation Loss.

normal

Routine Karyotype is _____ for microdeletions, which requires Microarray or FISH (fluorescence in situ hybridization).

karyotype

Routine _____ or microarray can be used to detect aneuploidies.

11

Russell Silver Syndrome is an imprinting disorder with *excess maternal* but *HYPOmethylation* of which chromosome?

recurrence

Russell Silver Syndrome is usually sporadic with low risk of __________.

Hypochondroplasia

Similar to achondroplasia but milder: (note: Adult height typically from ~-3SD to ~-2SD on growth charts)

Achondroplasia

Skeletal dysplasia that causes short stature with disproportionately short limbs, and large head with prominent forehead:

Sotos Syndrome (NSD-1)

Syndrome characterized by tall stature and very LARGE HEAD circumference, aka cerebral gigantism:

non pathologic

The most common causes of short stature are ___ __________, such as Familial short stature and Constitutional delay in growth.

IGF-1 (isolated growth factor)

Treat Growth Hormone Receptor (GHR) and IGF-1 Receptor Mutations with _____.

methylated

UPD can result in disease if it occurs with a chromosome that is differentially _______ depending on parent of origin.

Williams Syndrome (7q11.23)

Unlike DiGeorge, this microdeletion is pronounced at birth and with age and usually includes HYPERcalcemia/calcuria

autosomal recessive

What is the inheritance pattern for GH Receptor (GHR) Gene Mutation and IGF-1 Gene Mutation?

autosomal dominant

What is the inheritance pattern for achondroplasia?

Autosomal Dominant

What is the inheritance pattern for the most common forms of Osteogenesis Imperfecta? A. X-Linked Dominant B. X-Linked Recessive C. Mitochondrial D. Autosomal Dominant E. Autosomal Recessive

A 20-year-old with new onset Type II Diabetes Mellitus and a positive family history

Which clinical scenario is most consistent with the diagnosis of MODY? A. A 5-year-old with new onset Type I Diabetes Mellitus and no family history B. A 70-year-old with new onset Type II Diabetes Mellitus and no family history C. A 50-year-old with new onset Type II Diabetes Mellitus and a positive family history D. A 20-year-old with new onset Type II Diabetes Mellitus and a positive family history E. A 25-year-old with new onset Type I Diabetes Mellitus and a positive family history

pulmonic stenosis

Which congenital defect is associated with Noonan Syndrome?

ICR-1

Which control region of chromosome 11 is hypomethylated in Russell Silver Syndrome?

NSD-1 (nuclear set domain 1)

Which gene is involved in Sotos Syndrome?

Methylation abnormalities of imprinting control regions

Which of the following best describes the molecular mechanism that leads to the majority of cases of Russell-Silver and Beckwith-Weidmann syndromes? A. Chromosomal aneuploidy B. A single gene point mutation C. Microscopically detectable deletions D. Submicroscopic copy number variations E. Methylation abnormalities of imprinting control regions

Beckwith-Weidmann Syndrome

Which of the following conditions is associated with large stature? A. Russell-Silver Syndrome B. Smith-Magenis Syndrome C. Noonan Syndrome D. Hypochondroplasia E. Beckwith-Weidmann Syndrome

Laron Dwarfism (Rationale: a. Incorrect. Achondroplasia results from mutations in the FGFR3 gene b. Incorrect. Hypochondroplasia results from mutations in the FGFR3 gene c. Incorrect. Sotos syndrome results from mutations in the NSD1 gene d. Incorrect. Noonan syndrome results from mutations in RAS-pathway genes) e. Correct. Laron Dwarfism results from GH receptor gene mutations

Which of the following conditions typically results from a mutation in the Growth Hormone (GH) Receptor gene? A. Achondroplasia B. Hypochondroplasia C. Sotos syndrome D. Noonan syndrome E. Laron Dwarfism

Russell-Silver syndrome- Hypomethylation of the Imprinting Control Region 1 (ICR1) on the paternal chromosome 11 Rationale: a. Correct. Russell-Silver syndrome can be caused by hypomethylation of the Imprinting Control Region 1 (ICR1) on the paternal chromosome 11 (b. Incorrect. Prader-Willi syndrome can be caused by maternal uniparental disomy for chromosome 15 not paternal uniparental disomy c. Incorrect. Beckwith-Weidemann syndrome is caused by hypermethylation of the Imprinting Control Region 1 (ICR1) on the maternal chromosome 11 not hypomethylation d. Incorrect. Angelman syndrome can be caused by a 15q11-13 deletion on the maternal chromosome 15 not the paternal chromosome 15 e. Incorrect. Noonan Syndrome is caused by a single gene mutation.)

Which of the following genetic syndromes is most correctly linked to its associated molecular etiology? A. Russell-Silver syndrome- Hypomethylation of the Imprinting Control Region 1 (ICR1) on the paternal chromosome 11 B. Prader-Willi syndrome- Paternal uniparental disomy for chromosome 15 C. Beckwith-Weidemann syndrome- Hypomethylation of the Imprinting Control Region 1 (ICR1) on the C. maternal chromosome 11 D. Angelman syndrome- 15q11-13 microdeletion of the paternal chromosome 15 E. Noonan syndrome- Hypermethylation of the maternal imprinting control center on chromosome 11

Pre- and postnatal small stature with a normal head circumference (Rationale: a. Incorrect. Russell-Silver syndrome is typically characterized by small stature with a normal head circumference b. Incorrect. Russell-Silver syndrome is typically characterized by small stature with a normal head circumference c. Incorrect. Russell-Silver syndrome is typically characterized by small stature with a normal head circumference) d. Correct. This is most consistent with the phenotype of Russell-Silver syndrome (e. Incorrect. Russell-Silver syndrome is typically characterized by small stature with a normal head circumference)

Which of the following phenotypes is most consistent with Russell-Silver syndrome? A. Pre- and postnatal large stature with a normal head circumference B. Pre- and postnatal large stature with microcephaly C. Pre- and postnatal large stature with macrocephaly D. Pre- and postnatal small stature with a normal head circumference E. Pre- and postnatal small stature with microcephaly

McCune-Albright Syndrome

You have a 7-year-old female patient with signs of precocious puberty who was just found to have a pituitary adenoma. You recall that she has always had an unusual birthmark, a large irregular shaped café-au-lait spot. Which of the following conditions would best explain all of this patient's findings? A. Multiple Endocrine Neoplasia Type I (MENI) B. Laron Syndrome C. McCune-Albright Syndrome D. Pendred Syndrome E. Albright Hereditary Osteodystrophy

bone

____ age in Sotos Syndrome is usually advanced.

Beckwith Wiedemann Syndrome (pat UPD 11p15.5)

Excess *paternal* methylation of chromosome 11 that causes large stature:

web, shield

Features of Turner Syndrome include lymphedema, ___ neck, and ______ chest.

SHOX

Females with Turner Syndrome only have one copy of the ____ gene, which is important in the growth of the skeleton.

Laron's Syndrome

GH Receptor (GHR) Gene Mutation includes _____ dwarfism with mild midfacial hypoplasia.

Turner Syndrome (45,X or XX/XY mosaicism)

Genetic cause of short stature, characterized by females only having one X chromosome:

low

Growth Hormone Receptor (GHR) Mutations and IGF-1 Gene Mutations both present with *HIGH* GH levels and ___ IGF-1 levels.

Cleidocranial Dysplasia

During the evaluation of a 5-year-old female with unexplained short stature and supernumerary (extra) teeth, a radiologic skeletal survey is performed, which shows that she has no clavicle bones. Which of the following conditions is the most likely reason for this patient's short stature in light of this radiologic finding? A. Russell-Silver Syndrome B. Achondroplasia C. Osteogenesis Imperfecta D. Cleidocranial Dysplasia E. Septooptic Dysplasia

Constitutional Growth Delay (CGD) (Rationale: a. Incorrect. This vignette describes a patient with constitutional growth delay. Achondroplasia would present with disproportionate short stature from birth with a large head and rhizomelic shortening of the limbs b. Incorrect. This vignette describes a patient with constitutional growth delay. FSS would present with short stature appropriate for predicted height and a bone age appropriate for chronological age. c. Incorrect. This vignette describes a patient with constitutional growth delay. Panhypopituitarism could present with short stature, but the patient would have additional signs and symptoms consistent with pituitary hormone deficiencies.) d. Correct. This vignette describes a patient with constitutional growth delay. This patient classically presents with delayed puberty and associated pubertal growth spurt, delayed bone age for chronological age, and a family history of the same presentation. (e. Incorrect. This vignette describes a patient with constitutional growth delay. Laron Dwarfism is growth hormone resistance and presents with short stature since a young age and low glucose.)

A 14-year-old boy tells his Pediatrician that he is concerned because he is not as tall as his peers. On physical exam, you note a young-appearing male, of proportionate short stature (-2.5 S.D.) for his age, with minimal pubic, axillary, and facial hair. There are no facial deformities or physical abnormalities present. You check his bone age which turns out to be behind (less than) his chronological age. Both his parents are of average height for their sex, but his father admits to having a late growth spurt. What is the most likely diagnosis for this patient? A. Achondroplasia B. Familial Short Stature (FSS) C. Panhypopituitarism D. Constitutional Growth Delay (CGD) E. Laron Dwarfism

Loss of a copy of the SHOX gene (Rationale: a. Incorrect. This vignette describes a female with Turners Syndrome. A microdeletetion on chromosome 22 is the cause of DiGeorge Syndrome. b. Incorrect. This vignette describes a female with Turners Syndrome. A gain of a copy of the SHOX gene would be representative of a disorder with an extra sex chromosome, such as Klinefelter Syndrome.) c. Correct. This vignette describes a female with Turners Syndrome. The genotype of an individual with Turner Syndrome is 45 X. The SHOX gene is located on the sex chromosomes and is needed for skeletal growth and maturation. Since females with Turner Syndrome are missing an X chromosome, they are missing a copy of the SHOX gene. (d. Incorrect. This vignette describes a female with Turners Syndrome. A microdeletion on chromosome 7 is responsible for Williams Syndrome. e. Incorrect. This vignette describes a female with Turners Syndrome. An imprinting defect is responsible for syndromes such as Prader Willi and Angelmans.)

A 16-year-old female presents to your office for failure to undergo menarche. On physical exam you note a young woman who is short for her age, with a webbed neck and shield chest. She has no cognitive deficits and reports having a problem with her Aorta that was corrected when she was younger. What is the most likely reason for her short stature? A. Microdeletetion on chromosome 22 B. Gain of a copy of the SHOX gene C. Loss of a copy of the SHOX gene D. Microdeletion on chromosome 7 E. Imprinting defect

Achondroplasia

A 4-year-old female has significant short stature with rhizomelic shortening of her extremities and a relatively large head circumference with a prominent forehead. She has a history of mild infantile hypotonia and motor delay with no family history of short stature. She is found to have a FGFR3 mutation. Which of the following conditions is consistent with this? A. Williams Syndrome B. DiGeorge Syndrome C. Smith-Magenis Syndrome D. Turner Syndrome E. Achondroplasia

Sotos Syndrome

A 6-year-old male is being evaluated for unexplained large stature. He has a history of being large for gestational age at birth with birth length, weight and head circumference all >97%, which has persisted. Endocrine work-up thus far has revealed no abnormalities including normal GH, IGF-1 and IGFBP levels. He does have a history of mild developmental delay and learning disability but no history of any birth defects or family history of large stature. You note that he has a particularly large head circumference even considering his large stature. Which of the following conditions is the most likely given this clinical scenario? A. Klinefelter Syndrome B. Sotos Syndrome C. Beckwith-Weidemann Syndrome D. Marfan Syndrome E. 47, XYY

Uniparental Disomy (UPD)

A situation arising when both copies of a chromosome come from one parent, but no copies come from the other parent

Noonan Syndrome (Rationale: a. Incorrect. This vignette describes a female with Noonan Syndrome. Turner Syndrome can present with similar physical characteristics such as the shield chest and webbed neck, however, females with Turner Syndrome typically have normal intelligence. Ptosis of the eyelids and hypertelorism are not characteristic of Turner Syndrome b. Incorrect. This vignette describes a female with Noonan Syndrome. Angelman Syndrome would present with "happy puppet syndrome", severe mental retardation, and small stature. c. Incorrect. This vignette describes a female with Noonan Syndrome. Williams Syndrome would present with an "elfin facies" cocktail party personality, and mental retardation. d. Incorrect. This vignette describes a female with Noonan Syndrome. Osteogenesis Imperfecta is brittle bone disease and presents with multiple bone fractures with little trauma, skeletal deformities, and blue sclera.) e. Correct. This vignette describes a female with Noonan Syndrome. Children with Noonan Syndrome typically present with a shield chest, webbed neck, short stature, ptosis of the eyelids with hypertelorism, and often have cognitive impairment.)

An 11-year-old female presents to your office for evaluation of short stature. She recently started having regular menstrual periods. On physical exam you note a webbed neck, shield chest, low set ears and hypertelorism with ptosis of her eyelids. Her mother reports that she had mild developmental delays and has been in special education since she started school due to learning disabilities, but she is otherwise healthy. What is the most likely cause for this child‟s presentation? A. Turner Syndrome B. Angelman Syndrome C. Williams Syndrome D. Osteogenesis Imperfecta E. Noonan Syndrome

maternal

Angelman Syndrome is due to _____ Methylation loss. (hint: angel MAMA; praeder POP)

Marfan Syndrome (FBN-1)

Autosomal Dominant Mutation of the Fibrillin 1 gene, leading to excessive length of long bones:

Noonan Syndrome (RAS)

Autosomal Dominant mutation of RAS Pathway Genes that can cause short stature, webbed neck, and shield chest in *both* males and females:

TGF-B (transforming growth factor)

Decreased FBN1 gene causes an inverse association with ___-_ gene expression and inflammation in Marfan syndrome.

PANhypopituitarism

Decreased production of anterior pituitary hormones that presents with short stature, developmental delay, weakness, hypotension and nausea:

Russell Silver Syndrome

Imprinting disorder characterized by short stature and "relative macrocephaly" (head circumference is normal compared to small body) and curved middle finger:

behind

In patients with *Constitutional* Delay in Growth, bone age is ______ chronological age.

corresponds

In patients with *Familial* short stature, bone age ___________ to chronological *age*.

Turner syndrome (Rationale: a. Incorrect. Short stature in Down syndrome is not SHOX gene related b. Incorrect. Short stature in Edwards syndrome is not SHOX gene related c. Incorrect. Short stature in Patau syndrome is not SHOX gene related) d. Correct. Short stature in Turner syndrome is caused in large part by haploinsufficiency for the SHOX gene (e. Incorrect. Short stature in DiGeorge syndrome is not SHOX gene related)

In which of the following conditions is short stature related to a problem with SHOX gene dosage? A. Down syndrome B. Edwards syndrome C. Patau syndrome D. Turner syndrome E. DiGeorge syndrome

growth hormone (GH)

Isolated ______ _______ deficiency can be acquired or inherited and causes short stature and high body fat.