Misc Disorders II (will merge into Misc Disorders I eventually) Flashcards
Alport Syndrome
- 80% are X-linked in COL4A5; 15% are AR and 5% AD in COL4A3 or COL4A4
- Nephritis caused by defects in collagen type IV protein, which is responsible for basement membrane formation in the kidney, ear and eye.
- Progressive renal failure, sensorineural hearing loss, eye abnormalities; persistent microhematuria in early childhood, progressive proteinuria, and anterior lenticonus in late childhood and adolescence
- 1 in 50,000 individuals
RASopathies
E.g., NRAS, KRAS, HRAS, BRAF, MAP2K1/2
- Noonan syndrome, Noonan syndrome with multiple lentigines (aka LEOPARD syndrome), Cardiofaciocutaneous syndrome, Costello syndrome
- Somatic mosaicism has been reported for several RAS/MAPK genes
Alagille syndrome
- JAG1, NOTCH2; AD
- cholestasis, CHD (e.g., pulmonic stenosis), ophthalmic findings, vertebral defects (butterfly vertebrae), deep-set eyes with moderate hypertelorism, broad forehead, prominent pointed chin, long straight nose with a bulbous tip
Branchio-oto-renal syndrome
- EYA1, SIX1, SIX5; AD
- branchial arch defects (branchial fistulas or cysts), hearing loss, renal anomalies (from mild renal hypoplasia to bilateral renal agenesis), ear malformations; preauricular pits and tags; facial asymmetry, palate abnormalities, possible end-stage renal disease later in life
- high clinical heterogeneiety
- onset varies
Cardiofaciocutaneous syndrome
- RASopathy
- high forehead, short, upturned nose, low nasal bridge, prominent ears, hypertelorism, pulmonic stenosis, ASD, CALMs, erythema, keratosis, ichthyosis, eczema, sparse and brittle hair, nail dystrophy, seizures, hypotonia, macrocephaly, DD
Noonan syndrome with multiple lentigines
- RASopathy
- Previously known as LEOPARD syndrome (multiple Lentigines, Electrocardiographic-conduction abnormalities, Ocular hyperterlorism, Pulmonary stenosis, Abnormal genitalia, Retardation of growth, sensorineural Deafness)
- also: CALMs, hypertrophic cardiomyopathy, short stature, mild DD, and abnormal genitalia
Costello Syndrome
- RASopathy
- coarse facial features with wide forehead, depressed nasal bridge and full cheeks; thick and loose skin of the hands and feet; papillomata; heart defects, mainly pulmonary valve stenosis, rhythm disturbances and hypertrophic cardiomyopathy; increased growth at the prenatal stage followed by postnatal growth retardation; short stature; macrocephaly, DD
- At risk of developing tumors, (e.g., rhabdomyosarcoma; also neuroblastoma, bladder carcinoma)
Ciliopathies
- e.g., Bardet-Biedl syndrome, Joubert syndrome, Meckel-Gruber syndrome, Alström syndrome, Polycystic kidney disease, Primary ciliary dyskinesia (Kartagener Syndrome)
- Dandy–Walker malformation (cerebellar vermis hypoplasia, usually with hydrocephalus), Agenesis of the corpus callosum, Situs inversus, Posterior encephalocele, Polycystic kidneys, Postaxial polydactyly, Liver disease, Retinitis pigmentosa, ID
cystic fibrosis
- CFTR; AR
- 1/25 carrier freq (N. European) - 70% of carriers have ΔF508 mutation
- lung infections, pancreatic insufficiency connected to dietary malabsorption; excess Cl- in sweat, absence of the vas deferens
CHARGE syndrome
CHD7; AD
-DD; multiple congenital defects; ocular coloboma; choanal atresia; cranial nerve abnormalities leading to facial palsy, loss of sense of smell, feeding, swallowing and breathing difficulties; ear malformations resulting in hearing loss and reduced sense of balance; hypogonadotropic hypogonadism; absent puberty and infertility; genital hypoplasia; distinctive facial features; CHD; cleft lip/palate; olfactory dysfunction in the form of aplasia or hypoplasia
Kallman syndrome
ANOS1, CHD7, and SEMA3E; various inheritance patterns
-hypogonadotropic hypogonadism and impaired sense of smell as the result of deficient hypothalamic gonadotropin-releasing hormone and agenesis of the olfactory lobes; unilateral failure of kidney development; abnormalities in tooth development; cleft lip/palate; bimanual synkinesis (involuntary movements of one hand that mimic the other hand)
Cornelia de Lange syndrome
- NIPBL, SMC3, RAD21, KMT2A, AFF4 and ANKRD11: AD; but SMC1A, HDAC8: X-linked
- similar to many other disorders: Adams-Oliver syndrome, Coffin-Siris syndrome, CHARGE syndrome, Floating-Harbor syndrome, Rubinstein-Taybi syndrome, Roberts syndrome, FG Syndrome (also known as Opitz-Kaveggia Syndrome), Wiedemann-Steiner syndrome, KDM1A –related cleft palate, psychomotor retardation, and distinctive facial features, as well as intellectual disability related to CTCF, TAF1 and WDR26
Mitochondrial disorders
- Clinically and genetically heterogeneous
- Variable expressivity
- Variable symptoms, often affecting skeletal and cardiac muscle, the endocrine system, and the central nervous system (including vision and hearing)
PWS and Angelman Syndromes
- Imprinting mutation at 15q11.2 - 13; genes involved SNRPN (PWS), UBE3A (Angelman)
- Microdel/dup caused by NAHR caused by LCRs
- If mutation is in IC, inheritance is AD (50% recurrence risk)
- 50% of PWS have a class I mutation (BP1 - BP3)
- 40% of PWS have class II mutation (BP2 - BP3)
- severe hypotonia, global DD, feeding difficulties, FTT followed by hyperphagia & morbid obesity; behavioral problems such as temper tantrums, stubbornness, manipulative behavior, OCD, psychosis; short stature, strabismus, almond-shaped palpebral fissures, narrow nasal bridge, thin upper lip with down-turned mouth, and scoliosis; hypogonadism in males; 1/3 have hypopigmentation
Angelman:
- UBE3A imprinting (loss of maternal copy)
- severe DD, ID, speech impairment, seizures, characteristic behavior with an inappropriate happy demeanor with easily provoked laughter, short attention span, smiling and excitability, autism, reduced need for sleep, 50% with microcephaly
AD Nonsyndromic Hearing Loss
Genes include SOX1, MYO7A, DIAPH1, KCNQ4, GJB3, DSPP, TJP2, FAM189A
AD Syndromic Hearing loss
Waardenburg syndrome, Branchiootorenal disorder spectrum (BOR), NF2, Stickler syndrome
Stickler syndrome
Marshall syndrome is similar
COL11A1; AR
SNHL, myopia and retinal detachment, spondyloepiphyseal dysplasia
Marshall syndrome also has short stature, deafness, and abnormalities in cranial ossification as well as more-pronounced dysmorphic features
AR nonsyndromic hearing loss
GJB2, other genes
AR syndromic hearing loss
Usher syndrome, Pendred syndrome, Jervell and Lange-Nielsen syndrome, biotinidase deficiency, Refsum disease
Usher Syndrome
?
Jervell and Lange-Nielsen syndrome
congenital SNHL, long QT syndrome, may cause sudden death
Pendred syndrome
congenital SNHL, thyroid goiter, develops in puberty or adulthood
Biotinidase deficiency
SNHL, cutaneous features (skin rash, alopecia), hypotonia, seizures, DD
-treatment availability
Refsum disease
Severe progressive SNHL, ataxia, ichthyosis, early retinitis pigmentosa, anosmia
- Caused by phytanic acid metabolism issues
- Treatment available
X-linked nonsyndromic HL
Genes?
Lowe syndrome
OCRL; x-linked
congenital cataracts, infantile glaucoma, renal Fanconi syndrome (increased urination, dehydration, metabolic acidosis), DD, ID, hypotonia
Saethre-Chotzen
TWIST1; AD; 33% de novo
- coronal synostosis, facial asymmetry, ptosis, and small ears with prominent crus syndactyly. Less common feature include short stature, parietal foramina, vertebral fusions, radioulnar synostosis, cleft palate, maxillary hypoplasia, ocular hypertelorism, hallux valgus, duplicated distal hallucal phalanx, and congenital heart malformations
- 1:25,000-1:50,000
Blepharophimosis-Ptosis-Epicanthus Inversus syndrome (BPES)
FOXL2; AD
- at birth: blepharophimosis (shortening of the horizontal palpebral fissure), ptosis (droopy eyelids), epicanthus inversus (a vertical fold of the skin that stretches from the lower eyelid near the inner corner of the eye and towards either side of the nose), and telecanthus (lateral displacement of the inner canthi that leads to abnormal interpupillary distance)
- F can have POF/infertility
Kabuki syndrome
AD; KMT2D/MLL2
X-linked; KDM6A
-dysmorphic facies (e.g., long palpebral fissures with the everted lateral third of the lower eye lids), persistence of fetal fingertip pads, skeletal defects, DD, ID, CHDs, genitourinary anomalies, cleft lip and/or palate, gastrointestinal anomalies, hearing loss, widely spaced teeth, hypodontia, frequent infections, seizures, and feeding problems
Rett syndrome
X-linked
ID, DD with regression, autism
Noonan syndrome
- dysmorphic facial features, growth problems
- Cardiac abnormalities in 80% of patients (pulmonary valve stenosis, atrial septal defect, atrioventricular canal defect, and hypertrophic cardiomyopathy)
- Musculoskeletal abnormalities (short stature, chest deformity with sunken or raised sternum, short webbed neck).
- Renal, genital, hematological, neurologic, cognitive, behavioral, gastrointestinal, dental, and lymphatic abnormalities
- extensive clinical heterogeneity; typically de novo but variable penetrance even when familial
- at risk for juvenile myelomonocytic leukemia (JMML)
- caused by dysregulation of the RAS/mitogen-activated protein kinase (Ras/MAPK) signaling pathway
Rubinstein-Taybi syndrome
- CREBBP and EP300; AD
- AKA broad thumbs-hallux syndrome
- short stature, distinctive facial features, broad thumbs and big toes, moderate to severe ID, postnatal growth retardation, cryptorchidism, microcephaly, speech delay, delayed bone age, gastroesophageal reflux, coloboma, renal abnormalities, congenital heart defects
Waardenburg syndrome
inheritance depends on gene
auditory-pigmentary disorder characterized by congenital SNHL, white forelock, heterochromia.
4 types:
WS I: PAX3; Auditory-pigmentary abnormalities w/ dystopia canthorum (lateral displacement of the inner canthi), caused by mutations in PAX3.
WS II: SOX10, SNAI2, MITF; Auditory-pigmentary abnormalities w/o dystopia canthorum
WS III: PAX3; Type I w/ musculoskeletal abnormalities of upper limb
WS IV: EDNRB, EDN3, SOX10; Type II w/ Hirschsprung disease
