Velocardiofacial Syndrome [22q11.2 deletion]

Congenital heart disease (74%), conotruncal malformations, palatal abnormalities (69%), learning difficulties (70-90%)

Diagnosed by FISH

Traditional Management

AD inheritance 

93% have a denovo mutation

Cardiovascular disease, dictinctive facies, connective tissue abnormalities, intellectual disability, Hypotonia & hyperextensible joints

Clinical diagnosis can be used but can detect a contiguous gene deletion of WBSCR (critical region) which contains the elasltin gene ELN by FISH (over 99% have this deletion)

AD, most cases are de novo

Complex, Multisystem disorder involving the liver (bile duct paucity), heart, eyes, face, and skeleton (10% mortality) 

Associated Genes: JAG1(89%, microdeletion 20p12) NOTCH2 (<1%) using FISH

AD 50-70% de novo, 30-50% inherited mutation

Short stature, developmental delay, congenital heart defects, (webbed neck and weird chest)

Clinical diagnosis or PTPN11 mutation (50%), SOS1 (13%), RAF1 (3-17%) KRAS (<5%)

AD, 30-75% familial

Cardiofaciocutaneous Syndrome

cardiac abnormalities, distincitive craniofacial appearance, cutaneous abnormalities, sparce hair, some neurologic/cognitive delay is seen

Genes: BRAF (75%), MAP2K1/MAP2K2 (25%), KRAS (<2%)

AD, mostly de novo mutations

Failure to thrive in infancy bc severe postnatal feeding difficulties, short stature, developmental delay, coarse facial features, curly/sparce hair, joint laxity

Based on clinical findings, missense mutation in HRAS (80-90%) {if not look at other syndromes in RAS pathway}

AD, most de novo mutation

Smaller than normal lower jaw, tounge that falls in the throat, difficulty breathing (alone or in a syndrome)(can appear with hearing loss, heart defects, clefts)

Caused by anomolies on chromosome 2,4, 11, or 17

Genetics are unkown

Due to a developmental process alteration

1. Lip pits and cleft lift AND/OR palate 2. lip pits and a first degree relative with CLP or 3. CLP and a first degree relative with lip pits

IRF6 gene mutations in exon 1-9 (72%), deletion in IRF6 (<2%)

AD, most mutations familial, incomplete penetrance

Progressive neurodevelopmental disorder-normal psychomotor development during the first six to 18 months of life, then a period of developmental stagnation, then rapid regression in language and motor skills, & long-term stability. During the phase of rapid regression, repetitive, stereotypic hand movements replace purposeful hand use.

MECP2 (80%) mutation, (8%) deletion

X-linked (99% de novo)

AD/AR polycystic kidney disease

use renal imaging

AR-neonatal, enlarged kidneys, liver abnormalities (hepatomegaly)

AR-PKHD1

AD-late onset, bilateral renal cysts, & cyts in other organs

AD- PKD1 (85%) PKD2 (15%) (95% familial)

CNS malformation, polycytic or hypoplastic kidneys, pre/post axial polydactyly, early demise

Gene: MKS3 (testing is research only)

AR

Affects the epithelia of the respiratory tract, endocrine, pancrease, ect. Cannot transport water/ions properly, thick mucus throughout the body.  

CFTR gene mutations (lots!)

AR

The body does not make enough of the protein that protects the lungs and the liver, emphysema or liver disease

SERPINA1 gene 

Codominant M>S>Z allele

Wilms tumor, aniridia, genital anomalies, retardation (WAGR)

deletions of 11p13 (WT1 & PAX6 gene)

Undescribed inheritance

undermasculinized external genitalia in an individual with a 46,XY karyotype that can range from ambiguous to normal-appearing female, diffuse mesangial sclerosis leading to early-onset renal failure, and Wilms tumor

GENE: WT1 mutation

undermasculinized external genitalia in an individual with a 46,XY karyotype that can range from ambiguous to normal-appearing female, focal segmental glomerulosclerosis, and gonadoblastoma (NOT/rarely associated with Wilms tumor)

GENE: WT1

Photoreceptor abnormality that leads to vision loss (first night blindness, peripheral vision, central vision)

35 differnet genes/loci

AR: RLBP1

AD: RP1, RHO

AD, AR, Xlinked

Slow, progressive macular dystrophy (presents in childhood/teens) Loss of central vision (retain peripheral and darkness vision)

GENE: BEST1=VMD2

AD, mostly familial

bilateral vision failure that develops during young adulthood (men 4-5x more likely to be affected)[blurring in central vision]

Diagnosis, look at fundus most have 1/3 pt mutations in mito

gender/age-dependent penetrance

maternal inheritance

TYPE 1:

Congenital, bilateral, profound sensorinural hearing loss, vestibuar areflexia, and adolescent onset RP

 AR MYO7A, USH1B, USH1C, USH1D, USH1F, USH1G

TYPE 2:

Congenital, bilateral, sensorinural hearing loss thats mild in low frequencies & severe in lower frequencies

AR: USH2A (80%) GPR98, DFNB31

Varying degrees of developmental delay/ID (50%) Turribrachycephalic skull shape; moderate-to-severe midface hypoplasia, Soft tissue and bony ('mitten glove') syndactyly of fingers and toes, Fused cervical vertebrae (68%) hydrocephalus; occasionalcardiac and gastrointestinal defects

GENE: FGFR2

AD, mostly de novo

TYPE 1:: normal intelect, moderate-severe midface hypoplasia, medially divided thumbs/big toes (possible hearing loss/hydrocephalus)

TYPE 2::common ID/dev delay, cloverleaf skull, extreme proptosis, medially divided thumb/big toe, choanal stenosis, cleft palate

TYPE 3:: common ID/ dev delay, Uni- or bilateral coronal craniosynostosis, mild to significant midface hypoplasia; ocular hypertelorism, Unicoronal synostosis is more frequently in males, Carpal-tarsal fusion is diagnostic when present, Bilateral, symmetric, low- to mid-frequency sensorineural hearing loss

GENE: FGFR2/AD

Normal intellect, Significant proptosis, external strabismus, mandibular prognathism, normal extremities, Progressive hydrocephalus (30%), often with tonsillar herniation

GENE: FGFR2

AD

syndrome (TCS) is characterized by hypoplasia of the zygomatic bones and mandible, external ear abnormalities, coloboma (notching) of the lower eyelid, absence of the lower eyelashes, and preauricular hair displacement onto the cheeks, 40-50% have conductive hearing loss

GENES: TCOF1 (78-93%), POLR1C or POLR1D (8%)

AD, 1% AR

60% due to de novo mutations

Oculo-auriculo-vertebral syndrome

Features of hemifacial microsomia, plus themuscles in the mouth and tongue may be weaker and speech therapy is often advisable. Teeth may erupt later than usual and some may be missing. A cleft lip, a cleft palate, or a cleft lip and palate may be present. Cleft palate alone is more common than cleft lip or cleft lip and cleft palate together. About 35% have a dermoid (cyst on the eye), which is usually not harmful and does not impair vision.

Gene unknown

AD, mostly sporadic

Mainly affects males, hypertelorism, small noce, long philtrum, widows peak, hand abnormalities, syndactyly, some w/ clefting, single planar crease, some ID, shawl scrotom

GENE: FGD1 (20%)

X linked recessive

malformations of the outer, middle, and inner ear associated with conductive, sensorineural, or mixed hearing impairment, branchial fistulae and cysts, and renal malformations

GENE: EYA1 (40%) SIX5 (5%) SIX1 (4%)

AD

severe-to-profound bilateral sensorineural hearing impairment (that is usually congenital and non-progressive) vestibular dysfunction, temporal bone abnormalities, and development of euthyroid goiter in late childhood/early adulthood

GENE: SLC26A4 (50%) FOXI1 (<1%) KCNJ10 (<1%)

AR

Connexin 26

mild-profound sensorinural hearing loss 

DFNB1 gene

AR

Type A

deficiency in factor 8 for clotting, bleeding in joints common

Type B

deficient in factor 9, only difference

Xlinked

Type 1: (70%)mild mucocutaneous bleeding 

Type 2: (25%) subtypes 2A, 2B, 2M, 2N, increase in severity

Type 2: (<5%) severe mucocutaneous and mucoskeletal bleeding

TESTING: testing for Von Willibrand factors, and VWF gene

AD: most type one and type 2A, 2B, 2M

AR: some type one, type 2N, type 3

presence of multiple arteriovenous malformations (AVMs) that lack intervening capillaries and result in direct connections between arteries and veins

So, lots of nosebleeds, GI bleeding, and severe brain, liver, lung, etc if severe

GENES: ENG, ALK1, SMAD4 (80-87%)

AD with varied expressivity

50% familial/50% de novo

NF1::multiple café au lait spots, axillary and inguinal freckling, multiple cutaneous neurofibromas, and iris Lisch nodules. Learning disabilities are present in at least 50% of individuals with NF1. Less common but potentially more serious manifestations include plexiform neurofibromas, optic nerve and other central nervous system gliomas, malignant peripheral nerve sheath tumors, scoliosis, tibial dysplasia, and vasculopathy

NF1 mutation, AD

NF1:: bilateral vestibular schwannomas + associated symptoms of tinnitus, hearing loss/balance dysfunction. (age of onset is 18 to 24 years). may also develop schwannomas of other cranial and peripheral nerves, meningiomas, ependymomas. Posterior subcapsular lens opacities are common ocular findings. Mononeuropathy that occurs in childhood is an increasingly recognized finding; it frequently presents as a persistent facial palsy, a squint, or hand/foot drop.

NF2 mutation, AD (mosaics)

involves abnormalities of the skin (hypomelanotic macules, facial angiofibromas, shagreen patches, fibrous facial plaques, ungual fibromas); brain (cortical tubers, subependymal nodules [SENs] and subependymal giant cell astrocytomas [SEGAs], seizures, intellectual disability/developmental delay); kidney (angiomyolipomas, cysts, renal cell carcinomas); heart (rhabdomyomas, arrhythmias); and lungs (lymphangioleiomyomatosis [LAM]).

GENE: TSC2(69% w/ found mutation), TSC1(31% with found mutation)

AD (2/3) de novo mutation