Intellectual Disability/Dev Delay

Delay

performance below average in a given skill (DQ<70)

Deviancy

typical development in a single stream with milestones out of sequence

An infant rolling at birth with abnormally increased tone is an example of

deviancy

Toddler with no interest in peers is an example of

deviancy

Dissociation

different rate of development between 2+ domains

Child with CP may have normal cognitive skills, but motor delay is an example of

Dissociation

Dev Delay

Child less developed mentally/physically than expected for their age

Dev delay cut off

~5 yo

Intellectual Disability

limitations in intellectual functioning (reasoning, learning, prob solving) and adaptive behavior

Dev quotient equation

DQ = (dev age/chrono age) x 100

What is DQ of developmental delay?

<70%

Calculate DQ: 13 mo who doesn't walk independetly but can walk when led with 2 hands (~10 mo skill)

(10/13)x100 = 77

AL early intervention eligibility criteria

<25% delay in 1 of 5 areas: communication, physical, adaptive, cognitive, social; can also have at risk diagnosis

When can you diagnose ID?

after 5 yo (because you can do IQ test)

What do you need to diagnose ID?

IQ <70; limits in adaptive behavior (ex. communication, self-care, social interactions)

How do pediatricians screen for autism?

M-CHAT

What is gold standard for autism testing>

ADOS

ID seen in ____ of males and females with Fragile X

2%

minor findings (ex. developmental asymmetry) are increased in children with

ID

what is first line test for ID?

array CGH

what could be 1st or 2nd tier test for CA/DD/ID according to ACMG in 2021?

ES/GS

Yield of karyotype in isolated ID/DD

8%; increased with more severe ID and >6 minor anomalies; still warranted even if no dysmorphic ft present

Yield of array CGH in isolated ID/DD

8-17% with norm cyto; 10% with autism

Yield of Fragile X testing in isolated ID/DD

2%

Yield of molecular sequencing in isolated ID/DD

30%

Yield of ES in nonsyndromic ID/DD

16%

Yield of ES in ID w/ microcephaly

30%

Yield of GS in unexplained ID/DD

42%

Patient presents with ID/DD and no other findings. Should metabolic screening be ordered?

No; very low yield if no other finings are present besides ID/DD (also, ES will catch metabolics)

Patient presents with ID/DD and no other findings. Should neuroimaging be ordered?

no; low yield if no indications

What conditions do NOT show up on WES/WGS?

Fragile X

Angleman/Prader-Willi

Teratogens/enviro exposures (non-genetic)

Tall early, then short

macrocephaly

long face, prominent chin, prominent ears

hypotonia

hypermobility of small joints

smooth skin

large testicles post puberty

Fragile X

Older adults (>50) with this condition, especially men, see late onset neurological findings (ataxia, cognitive decline, personality changes, etc.)

Fragile X

Sherman paradox

Not classic x linked pattern

-excess of affected females

-unaffected carrier males

-anticipation

what is cause of fragile X syndrome

unstable, expandable trinucleotide repeats (CGG) in 5' UTR of exon 1

how many repeats are needed for full fragile x mutation?

>200 (gene gets methylated --> shuts down --> leads to symptoms)

Frailge X repeats

5-50= normal

40-55 = risk

55-200 = premutation

>200 = full mutation

Fragile X: carrier females has ____ risk for having a child with fragile x

the greater the expansion, the greater the risk

ONLY IN FEMALES WITH PREMUTATION

Fragile x: 20% of carrier females see ______

premature organ failure and neuropsychiatric issues (depression, anxiety, etc.)

Fragile x premutation: males experience

Fragile x-associated tremor/ataxia syndrome (40% >50years)

criteria for FAS

growth: variable pre and post natal growth failure

CNS: microcephaly, ID

face: short palpebral fissures, smooth philtrum, thin upper lip, short nose, altered palmar creases, small distal phalanges, finger nails, cardiac defects

short nose with flat bridge is indicative of what teratogen usage

hydantoin (dilantin)

neural tube defects are indicative of what teratogen

valproate (depakote)

neural crest issues (branchial arches, face), microtia, ear canal atresia, non-genetic cause of DiGeorge Syndrome are all indicative of what teratogen

Retinoic acid

what teratogen interferes with the action of arylsulfatase E, the gene for X-linked form of chondroplasia punctata?

warfarin

what teratogen is the #1 cause of congenital sensorineural deafness?

congenital CMV

1st trimester exposure of what teratogen causes deafness, cataracts, chorioretinitis, microopthalmia, ASD, VSD

rubella

what maternal infection within 8-20 weeks of pregnancy carries 1-2% risk of cortical atrophy, limb hypoplasia, and cutaneous scars?

varicella

what causes 3x increase in major and minor anomalies?

diabetic embryopathy

increased periconception HvgA1C causes

insults in smomatic mesoderm and associated neural crest cells <7 wks

hypoplastic left colon due to what condition

diabetic embryopathy

spinda bifida, anencephaly, holoprosencephaly, duodenal atresia, hypoplastic left colon, cystic kidney, renal agenesis

diabetic embryopathy

Your patient is a 7-year-old. They currently receive speech and occupational therapies through their school. On the physical exam the child has macrocephaly, prominent forehead, and elongated face. The family reports that the patient's older sister has learning disabilities and trouble with math but reports no other history of developmental delay or intellectual disabilities. During family history intake, the patient's mother makes a comment about only having two children due to her early menopause. What is the BEST test to order for this patient?

A) CMA

B) Whole exome sequencing (WES)

C) Karyotype

D) FMR1 repeat expansion analysis

D) FMR1 repeat expansion analysis

From the description of the patient's symptoms and features (macrocephaly, prominent forehead, and elognated face), a good differential to include would be Fragile X Syndrome. In the powerpoint presentation "Genetic evaluation of intellectual disability/developmental delay", slide 20 mentions that as of July 1, 2021, WES is to be consiered first or second tier testing for congenital anomalies. However, slide 22 mentions that Fragile X Syndrome does not appear on WES. Therefore, in an effort to not miss a possible diagnosis, FMR1 repeat expansion should be ordered. If results are negative, WES or another test could be considered at the point.

Additionally, early menopause is a sign of primary ovarian insufficiency seen in carriers of the fragile X pre-mutation who are assigned female at birth.