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Multiple Congenital Anomaly Syndromes

Terms in this set (77)

Aarskog syndrome:
Gene, protein
Inheritance
-FGD1, Rho/RAC guanine nucleotide exchange factor.
- X- linked recessive (some AR, AD cases reported)
Aarskog syndrome: Features -facial characteristics
- GU
- Skeletal
- Mental/intellectual
- Facial: Hypertelorism, small nose, long philtrum
- GU shawl scrotum, cryptorchidism
- Skeletal: brachydactyly, short stature, cervical vertebral abnormalities
-mental/intellectual: ID (30%)
Aarskog syndrome: can there be symptoms in females?
Yes, but they are usually milder
Aarskog syndrome treatment?
- orchiopexy for cryptorchidism
Antley-Bixler syndrome (ABS)
- Genes (2), proteins, and their inheritance
- Which gene is go-to for sequencing? (*)
- POR*, NADPH-cytochrome P450 reductase, autosomal recessive

- FGFR2, Autosomal dominant
Antley-Bixler syndrome: What kind of syndrome is it?
- Craniosynostosis syndrome
Antley- Bixler syndrome:
Wide spectrum of anomalies including common to both genes, including:
- facial differences (1)
-Other (2)
-musculoskeletal and skeletal (3)
- maleformations (2)
Facial: midface hypoplasia, proptosis

- Choanal and anal stenosis/ atresia

- Craniosynostosis joint contractures, arachnodactyly

- cardiac and renal maleformations
Antley-Bixler syndrome: disease mechanism
- disorder of steroid and cholesterol sythesis due to cytochrome P450 reductase deficiency
True or false: There is an exclusively skeletal form of ABS
True, it is caused by FGFR2
Differences between POR Antley- Bixler syndrome and FGFR2 Antley- Bixler syndrome
POR has ambiguous genitalia/ genital anomalies, as well as disordered pattern of steroidogenesis.
Antley- Bixler syndrome: Mortality has been reported to be as high as ______ in the neonatal period, primarily
due to _________, and prognosis improves with increasing age
Mortality has been reported to be as high as 80% in the neonatal period, primarily
due to airway compromise, and prognosis improves with increasing age.
Antley- Bixler syndrome: treatment
-airway management
- steroid replacement
- surgical correction for GU abnormalities
- Treat other symptoms
Bardet-Biedl Syndrome
How many genes?
Molecular test?
Inheritance
- 19 genes associated with it
- Targeted mutation analysis of BBS1 and BBS10, and/or panel testing on known genes
- AR (10% thought to be caused by mutations at multiple loci)
True or false: Bardet-Biedl syndrome is a genetic diagnosis
False: it is a clinical diagnosis
Bardet-Biedl syndrome: What kind of syndrome?
Ciliopathy- defects in function of cilia or intraflagellar transport
Bardet-Biedl syndrome: features
- ocular (2)
- GU (3)
-morphologic (2)
- mental/ intellectual (1)
- ocular:
Night blindness by age 7-8
Legally blind by age 15.5 yrs
- GU:
renal dysfunction,
male hypogonadotrophic hypogonadism,
complex female GU malformations
-morphologic
truncal obeisity
postaxial polydactyly
- mental/intellectual- ID
Bardet-Biedl associated blindness is caused by a ______ _____ dystrophy
Bardet-Biedl associated blindness is caused by a cone- rod dystrophy
Brancio-Oto- Renal Syndrome:
Genes (3)
Inheritance
genes: EYA1, SIX1, SIX5
AD
Brancio-Oto- Renal Syndrome: features
Otological
Respiratory
Renal- range?
- Otologic: malformations associated with hearing loss
- Respiratory: branchial fistuale and cysts
- renal malformations, ranging
from mild renal hypoplasia to bilateral renal agenesis
Brancio-Oto- Renal Syndrome: types of ear malformations and hearing loss
malformations: of the outer, middle and inner ear
Hearing loss: conductive, sensorineural, and mixed
Brancio-Oto- Renal Syndrome: treatment
Brancial: excision of branchial cleft cysts/ fistula
Hearing: assited devices and education
Brancio-Oto- Renal Syndrome: surveillance
-check for hearing loss every 6 mo
-annual audiometry to monitor hearing loss
-annual examination by nephrologist if indicated
CHARGE association
gene, protein
inheritance
-CHD7, Chromodomain-helicase-DNA-binding protein 7
-Autosomal dominant
Diagnostic criteria for CHARGE association
Must have 4/7 of the following features:
C- Coloboma of the eye
H- Heart anomaly
A- Atresia of the choanae
R- Retardation- both growth and mental
G- Genitourinary malformations (microphallus)
E- Ear anomalies and/ or deafness
Heart defects seen in CHARGE association
conotruncal defects and arch abnormalities
Ear abnormalities in CHARGE
ossicular malformation, Mondini defect
of the cochlea
Other features of CHARGE association besides titular features (4)
1. Facial palsy
2. cleft palate
3. TE fistula
4. behavioral and psychiatric problems
CHARGE: ______ mortality in the first year
CHARGE: 20-25% mortality in the first year
Coffin-Lowry Syndrome:
-gene, protein
- Inheritance
-RPS6KA3, ribosomal protein S6 kinase alpha 3
- X-linked dominant
Coffin-Lowry Syndrome:
- Features in males
Mental/ intellectual
skeletal
Neurological
Behavioral
Cardiac
Mental/ intellectual: -severe to profound ID

Skeletal:
- short, soft, fleshy hands, tapering fingers with small terminal phalanges
- short stature
- kyphoscoliosis
- anterior vertebrae beaking

Neurological:
- micorcephaly
- stimulous induced drop episodes

Behavioral
- can be self-injurious

Cardiac
- Can have severe or life-threatening heart issues
Coffin-Lowry Syndrome facial features
-Maxillary hypoplasia
-prominent brow
-downslanting palpebral fissures
-hypertelorism
- large ears and or unusually thick eyebrows
-hypotonia
Coffin-Lowry Syndrome treatment/ prognosis
- Meds for drop episodes
- Risperidone for self-injurious behaviors
-Annual cardiac exam with echo every 5-10 years.
Coffin-Lowry syndrome features in females
No affect to same seen in males
Cornelia de Lange Syndrome
- gene, protein function
- inheritance
- NIPBL (60% of cases), SMC1A, SMC3, RAD21, HDAC8
-Part of cohesin complex
- Autosomal dominant, X- linked recessive
Cornelia de Lange Syndrome: features
- global
- Skeletal and connective tissue
- Mental/ intellectual
-cardiac
Global
- pre/post natal growth retardation

Skeletal and Connective tissue
- diaphragmatic hernia
- upper limb anomalies ( hypoplastic middle phalax of the index finger, hypoplastic thenar eminence

mental/ intellectual
- Mild-severe ID

Cardiac:
- pulmonary valve stenosis and/ or VSD
Cornelia de Lange Syndrome: Facial features
- low anterior hairline
-synophrys
- ptosis, nystagmus
Cri du chat syndrome
- genetic etiology
- Inheritance
- 5p15.2 deletion
- 85% sporadic, de novo deletions (majority on paternal chromosome)
- 12% due to unequal segregation of a translocation or recombination involving a pericentric inversion in one of the parents
Cri du chat syndrome: features
- Global
- neurological
- Mental/ intellectual
-opthalmologic
Global
- slow growth

Neurological:
- microcephaly
-hypotonia

Mental/ intellectual
- ID

Opthalmologic
- strabismus

Cat- like cry, in some cases (due to abnormal laryngeal development)
Cri du chat syndrome: facial features
- Round face
-hypertelorism
-micrognathia
-epicanthl folds
- low-set ears
-hypotonia
When does a cat- like cry characterize Cri du chat syndrome?
When the deletion is limited to band 5p15.32
Fryns syndrome
- genetic etiology
- inhertiance
- genetic etiology unkown
- Autosomal recessive
Fryns syndrome: Features
- Global
- Facial
- malformations
- neurological
- mental/ intellectual
Global: LGA (Large for gestational age?)

Facial:
Course facies

Malformations
- Cleft lip/ palate
- diaphragmatic defect
- distal digital hypoplasia
- GU malformations

Neurological:
- ageneiss of the corpus callosum
- optic and olfactory tract hypoplasia

mental/ intellectual
- ID in survivors
Fryns syndrome: treatment/ prognosis
Majority are stillborn or die in the early neonatal period
- 14% survive
Greig cephalopolysyndacyly (GCPS)
- gene, protein
-mechanism
- inheritance
- GLI3, zinc finger protein
- GLI proteins regulate the SHH pathway
- Autosomal dominant
Greig cephalopolysyndacyly (GCPS): major findings
-Macrocephaly
- ocular hypertelorism
- preaxial polydactyly
- cutaneous syndactyly

- Less common: DD, ID, seizures
Treacher Collins syndrome:
- gene
- mechanism
- Inheritance
-TCOF1, POLR1C, POLR1D
- code for rRNA
- AD
Treacher Collins syndrome: Features
- Jaw, skull, eyes, hair, ears,
- Jaw: Micrognathia
- skulll: Malar hypoplasia, sometimes with zygomatic bone cleft
-Eyes: lower lid coloboma, absent eyelashes medial to defect, down slanting palpebral fissures
- Hair: projection of scalp hair onto lateral cheek
- Ears: Malformation of auricles, or microtia, external ear defects, hearing loss
True or false: Treacher collins is not associated with intellectual disability
true
Stickler syndrome
- etiology
- inheritance
- mutations in COL2A1, COL11A1, COL11A2
- AD
Stickler syndrome:
- Facial features
- Ocular
- Ears
- malformations
- skeletal
- Facial features: Flat face with prominent eyes, depressed nasal bridge (midface hypoplasia)
- Ocular: High mypopia, cataracts, retinal detachment
- Ears: hearing loss
- malformations: cleft palate (hard, soft, or bifid uvula), Peirre Robin sequence
- Skeletal: joint hypermobility, early onset arthriitis
Kabuki syndrome
- gene
- mechanism
- inheritance
- MLL2
- defects in chromatin remodeling
- AD
Kabuki syndrome features
- global
- facial differences
- skeletal
- cardiac
- mental
- global: postnatal growth deficiency
- facial features:
- long palpebral fissures, eversion of lateral portion of lower eyelid, arched eyebrows with sparse lateral third, prominent and abnormal ears, short nose
- fetal fingertip pads, short 5th finger, joint hypermobility
- cardiac: CHD in half (coarctation of aorta, bicuspid aortic valve, mitral valve prolapse, and more)
- ID (moderate)
Miller-Dieker Syndrome
- etiology, mechanism
- inheritance
- Microdeletion of 17p13.3, loss of LIS1 seems critical for lissencephaly
-involved in neuronal migration
-AD
Lissencephaly features
ID
- microcephaly
- seizures
- feeding issues
- spactistiy
- hypotonia
Miller-Dieker syndrome features
- Typical facies
- other features
- prognosis
- typical facies: high forehead, vertical ridging and furrowing of forehead, small nose, anteverted nares, upslanting palpebral fissures, protruberant upper lip with thin vermillion boarder
- breathing issues, lissencephaly
- Prognosis: death in early childhood, almost no developmental milestone achieved.
Smith-Lemli-Opitz Syndrome
- Gene, inheritance
- mechanism
- DHCR7, Autosomal recessive
- defects in cholesterol biosynthesis with low cholesterol and elevated 7-dehydrocholesterol
- Cholesterol needed for cell membrance structure, myelination, and synthesis of steroids, vitamin D and bile acids
Smith-Lemli-Opitz Syndrome: Features
- Mental
- global
- typical facies
- cardiac
- GU
- morphological
- Mental: ID
- global: growth restriction
- facial: microcephaly with frontal narrowing, ptosis, abnormal ears, anteverted nares
- Cardiac: CHD- hypoplastic left heart syndrome, ASD, PDA, VSD
- GU anomalies, commonly hypospadias
- morphological: Y-shaped 2-3 toe syndactyly
Zellweger syndrome
- etiology, inheritance
- mechanism
-PEX genes, Autosomal recessive
- PEX are requried for peroxisomal biosynthesis and are import peroxisomal proteins
- causes toxic build up of VLCFAs
Zellweger syndrome: features
- facial
- global
- neuromuscular
- skeletal
- Other
- prognosis
- Facial: enlarged anterior fontanelle, tall forehead, flat face, upslanted and narrow palpebral fissures
- global: growth restriction
- neuromuscular: hypotonia, limb contractures, club feet
- skeletal: epiphyseal stippling
-Other: hepatosplenomegaly, ID (if survive), seizures (if survive)
- prognosis: often fatal in first year of life
Oto-palato-digital syndrome:
Gene, inheritance
FLNA, Xlinked
Oto-palato-digital syndrome:
Features
- Ears
-facial
- palatal/ oral
-skeletal and digital
- Ears: hearing loss (any type) due to abnormal ossicles
- Facial: frontal and occipital prominence, hypertelorism, small nose and mouth, midface hypoplasia
- Palatal: cleft soft palate, absent or impacted teeth
- Skeletal/ digital: small trunk, pectus excavatum, small iliac crest, short/ broad distal phalanges ("tree frog digits") (esp thumbs and great toes), widely spaced toes
X- linked hydrocephalus
- gene
-features
- L1CAM
- Hydrocephalus due to aqueductal steonsis
- leads to macrocephaly, spasticity, ID
- agenesis of corpus callosum
- thumb aductionOto-palato-digital syndrome:Oto-palato-digital syndrome:
Russell- Silver syndrome
- etiology
Maternal UPD of chromosome 7
or
hypomethylation of H19/IGF2 region on 11p15.5
Russell- Silver syndrome: Features
- facial
- skin
- global
- Digital
- Facial: small, triangular face, micrognathia
- skin: cafe au lait spots
- pre and post natal growth restriction, head sparing, growth asymmetry, esp of limbs, short stature
- digital: 2-3 toe syndactyly, 5th finger clinodactylly
- NORMAL intelligence
Angelman Syndrome
- etiology
Loss of function of maternal UBE3A via:
Deletion of maternal 15q11-q13
Mutation in maternal UBE3A
Paternal UPD 15
Angelman Syndrome: features
- neurological/ behaivoral
- developmental
- facial
-Neuro/ behavioral:
Seizures
Microcephaly
Happy, excitable demeanor (frequent smiling, laughing, hand flapping, ataxia)
Jerky movements
- DD, notable by 6-12 months, absent speech, severe ID
- Facial: Widely spaced teeth, light hair and eyes in some, fair skin
Prader-Willi Syndrome:
- etiology
- loss of function of genes in paternal region of 15q11-q13
- Maternal UPD 15
- Mutation in imprinting center (rare)
Prader-Willi Syndrome:
Features
Infancy vs childhood
behavioral
facial
Morphological
Infancy: Severe hypotonia, feeding difficulties with FTT
Childhood: DD, insatiable appetite, leading to hyperphagia and obesity.

Behavioral difficulties, with compulsiveness, skin picking, temper outbursts.

Facial: bitemoporal narrowing, almond shaped eyes
Morphological: Small hands and feet, underdeveloped genitals with delayed puberty
Hypohidrotic Ectodermal Dysplasia
- etiology, inheritance
- most common: EDA1, X- linked
- Others: EDAR (AD), EDARADD (AR)
Most female carriers of Hypohidriotic ectodermal dysplasia (due to a mutation in ____) can be identified by _____
Most female carriers of _____________ (due to a mutation in ___) can be identified by a dental examination and sweat test.
Hypohidrotic Ectodermal Dysplasia features
- Skin
- hair
- Dental
-Skin:
hypohidrosis or anhidrosis (no sweating) due to lack of sweat glands, risk of hyperthermia
Thin skin with decreased pigmentation
papular changes on face
periorbital wrinkling and hyperpigmentation

Hair: hypotrichosis of scalp, eyebrows, eyelashes

Dental: conical teeth, oligodontia
Oral-‐facial-‐digital syndrome
- etiology
13 different types
I- X- linked mutations in OFD1
other are mostly AR and not yet well defined
Oral-‐facial-‐digital syndrome: features
Oral
facial
digital
Oral: cleft tongue, tongue hamartomas, hyperplastic frenulum; absent, extra or displastic teeth; cleft palate

Facies: cleaft lip, hypertelorism, wide nose
with broad nasal bridge.

Digital: Polydactyly, syndactyly, brachydactyly, clinodactyly
Type I Oral-‐facial-‐digital syndrome is associated with_______
_______ syndrome is associated with polycystic kidney disease
Alport syndrome
- etiology
- mechanism
- Most common: X- linked mutations in COL4A5
others: AR and AD mutations in COL4A3 or COL4A4
-All involved in production of type IV collagen necessary for basement membrane in renal glomeruli
Alport syndrome: features
- Renal
- Otological
- Ocular
-Renal:
hematuria and proteinuria leading to renal scarring and failure

- Otological: hearing loss due to abnormal inner ear function

Ocular: Misshapen lense affecting vision
Female carriers of X- linked mutations and all carriers of AR mutations causing Alport syndrome may have ______
Female carriers of X- linked mutations and all carriers of AR mutations causing ________ may have hematuria
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