Medical Genetics Flashcards
Neonatal hypoparathyroidism (with hypocalcemia) Immunodeficiency Congenital Heart Disease
DiGeorge Syndrome- 22q11.2 del
What are the etiologies (both environmental and genetic) associated with DiGeorge’s constellation of findings?
Teratogens (maternal alcohol, maternal diabetes, maternal retinoic acid exposure) chromosome abnormalities (10p deletion; 4q deletion; 22q11.2 deletion)
What considerations need to be made when ordering testing for 22q11.2 deletion syndrome?
Order MLPA and microarray
Most deletions are de novo (90%) so lack of fhx is not uncommon
There are several previous names for different combinations of symptoms
TBX1 gene
important developmental gene
traditionally lost in 22q11.2 A-B deletions and thought to be responsible for many associated features of the syndrome (e.g. conotruncal cardiac anomalies)
CRKL1 and SANP29
important developmental genes traditionally lost in 22q11.2 B-D/C-D deletions
individuals do still have typical associated features (even though they have in-tact TBX1 genes)
these kinds of deletions are frequently familial
Not picked up by traditional FiSH studies
Most common causes of congenital heart disease:
- Down syndrome
2. 22q11.2 del syndrome (but TOF is more often seen in this than in Down Syndrome)
Immunodeficiency/Autoimmune disease
Congenital heart disease
Palatal Defects
Hypocalcemia (resulting in seizures)/ Other endocrine abnormalities (e.g. thyroid disease, short stature, growth hormone deficiency, IUGR, etc.)
GU anomalies (renal agenesis, dysplastic kidneys, duplicated collecting system, hydronephorsis, inguinal hernia, cryptorchidism/hypospadias/absent uterus)
GI problems (esophageal dysmotility/severe feeding problems, intestinal malrotation, constipation, umbilical hernia, Hirschprung’s disease, esophageal atresia/TEF, imperforate anus)
Other birth defects (polydactyly, club foot, craniosynostosis)
Global Developmental Delay
Autism Spectrum Disorder
Psychiatric illnesses (Schizophrenia, depression, anxiety, OCD)
22q11.2 deletion syndrome (overall)
What psychosocial things should be considered when thinking about 22q11.2 del syndrome?
Diagnosis is often missed, especially in adolescents, adults, and non-caucasian individuals
Individuals can be diagnosed in adulthood by having a more severely affected child or via NIPS
Presentation is incredibly variable (even in identical twins)
Only about 10% of cases are inherited
What is the current NBS for 22q11.2 del syndrome?
Current trials are in the works, but NBS for SCID has picked up infants with 22q11.2 del syndrome due to low T-cells (67% of these patients have impaired T-cell production)
What signs of 22q11.2 del syndrome can be seen in pregnancy?
NIPS now uses microarray and can detect the deletions
Fetal Echos MAY (but not always) detect some of the associated cardiac anomalies (ductal dependent lesions are hard to detect)- important because early cardiac diagnosis is important for reducing morbidity
Polyhydramnios (can be a clue to a palatal abnormality)- sometimes the only prenatal clue
Prenatal US MAY detect some palatal issues (does NOT detect velopharyngeal dysfunction or submucosal cleft palate/bifid uvula)
IUGR
Rare prenatally (diaphragmatic hernia, polydactyly - pre and post axial -, club foot, radial ray defects, craniosynostosis)
What are the highlights of the guidelines for 22q11.2 del syndrome management?
treatment/monitoring of hypocalcemia/thyroid dysfunction (Ionized calcium, PTH, TSH; esp at times of bio stress like surgery and puberty and pregnancy - caution because can cause nephrocalcinosis)
PRN - infant stimulation and specialized educational interventions, ST, palatal eval/surgery, treatment of psych illnesses
What are pregnancy considerations for women with 22q11.2 Del syndrome?
risk for new onset hypocalcemia
adult congenital heart disease related risk
risks related to treatment for underlying idiopathic seizure disorders (potential teratogen exposures)
associated autoimmune disease
problems associated with underlying psyciatric disease
prenatal monitoring
future preconception counseling
DDx for the following- congenital heart disease renal anomalies ID hearing loss Immunodeficiency
22q11.2 del CHARGE/CHD7 mutation Smith-Lemli-Opitz Goldenhar Alagille Kabuki Jacobsen (11qterdel)
Congenital heart disease Hemifacial microsomia/microtia/anotia Conductive hearing loss Butterfly vertebrae Renal anomalies
Goldenhar
Congenital heart disease (TOF or peripheral pulmknary stenosis most common)
posterior embryotoxon
Butterfly vertebrae
Alagille
Congenital heart disease (HLHS, ASD, PDA, VSD) polydactyly microcephaly with frontal narrowing, growth restriction hypospadias Y-shaped 2-3 toe syndactyly renal anomalies ID (often severe) ptosis, abnormal ears, anteverted nares low cholesterol
Smith-Lemli-Opitz
AR
DHCR7 gene (leads to deficiency of 7-dehydrocholesterol reductase)
Congenital heart disease Growth retardation Hearing Loss GU/renal anomalies ID Tortuous renal vessels
Jacobsen
11qterdel
What is the first line recommendations for children with global developmental delay / ID / ASD of unknown cause?
Chromosomal microarray Fragile X (FMR1) DNA analysis
Top 10 recurrent CNVs with found on CMA for DD/ID/ASD?
22q11. 2 del
16p11. 2 del
1q21. 1 del
15q13. 2-q13.3 del
22q11. 2 dup
7q11. 23 del
16p11. 2 dup
15q11. 2-q13 dup
15q11. 2-q13 del
1q21. 1 dup
Describe the inheritance of Fragile X Syndrome.
most common known inherited cause of ID/ASD
X-linked (Xq27.3) trinucleotide expansion disorder (CGG repeats in 5’ UTR) of the FMR1 gene
Maternal premutations can expand to full mutations in children
Paternal premutations passed to daughters typically have minimal expansion
AGG interruptions stabilize repeats (make less likely to expand)
What are the repeat levels for Fragile X syndrome?
Negative - <45
Intermediate - 45-54
Premutation (FXTAS/FXPOI) - 55-200
Full - >200
What is the mechanism for Fragile X syndrome (both premutation and full mutation)?
Premutation repeat carriers have undermethylation of the gene and produce more FMRP
Full repeat carriers are over-methylated and fail to produce FMRP (which is essential for neuronal functioning throughout life)
Mild to moderate ID, Autism Spectrum Disorder, Learning disabilities, psychiatric disorders
Long face, prominent ears
Poor eye contact, attention problems, shyness, and social anxiety
Females with FMR1 full mutations
Long face, prominent ears
Enlarged testicles
Variable degrees of ID
Autism spectrum disorder, autism symptoms, poor eye contact, hand flapping
Attention deficits, anxiety, speech difficulties
Fragile X syndrome
Decreased ovarian reserve
Infertility
Early Menopause
Onset around 30’s
Fragile X- associated primary ovarian insufficiency (FXPOI)
Progressive gait ataxia Intention tremor Personality changes White matter lesions involving middle cerebellar penduncles (MCP) on MRI or other less specific findings (lesions of white matter or generalized atrophy) Parkinsonism Short term memory changes Executive function deficits Average onset around 60 y/o
Fragile X- associated Tremor Ataxia (FXTAS)
40-50% of premutation males >age50 have symptoms
~8-17% of premutation females develop symptoms late in adulthood
Broad thumbs and great toes (possibly with deviation) Postnatal growth deficiency prominent or beaked nose septum extending below alae nasi maxillary hypoplasia Hirsuitism Cardiac defects (PDA, VSD, ASD) Long eyelashes downslanting palpebral fissures ID (moderate)
Rubenstein-Taybi syndrome AD ~40% de novo CREBBP gene some microdeletions of 16p13.3
malar hypoplasia (sometimes with zygomatic bone cleft) lower lid coloboma absent eyelashes medial to defect projection of scalp hair onto lateral cheek malformation of auricles or microtia external ear defects conductive HL micrognathia normal intelligence downslanting palpebral fissures
Treacher Collins Syndrome
AD
TCOF1 gene (less common in POLR1C and POLR1D)
prenatal growth deficiency microcephaly ID (mild to severe) hoarse voice bushy eyebrows synophrys long, curly eyelashes depressed nasal bridge anteverted nares thin upper lip hirsuitism cutis marmarota GI and GU anomalies syndactyly of 2nd-3rd toes micromelia (of upper and/or lower limbs) oligodactyly 5th finger clinodactyly flexion contracture of elbow
Cornelia de Lange Syndrome
AD
NIPBL gene (~60%)
(some more rare AD/XL genes)
