Syndromes Flashcards
NF-1
The diagnostic criteria are (2 of the following are required):
Six or more café-au-lait spots or hyperpigmented macules >5mm in diameter in pre-pubertal children and 15mm post-pubertal
Axillary or inguinal freckles (>2 freckles)
Two or more typical neurofibromas or one plexiform neurofibroma
Optic nerve glioma
Two or more iris hamartomas (Lisch nodules), often identified only through slit-lamp examination by an ophthalmologist
Sphenoid dysplasia or typical long-bone abnormalities such as pseudarthrosis
First-degree relative (e.g. mother, father, sister, brother) with NF1
Cardiac- coartation of aorta
Wilson’s disease
In Wilson disease, there is decreased incorporation of copper into apoceruloplasmin and decreased transport of copper from the liver into bile, leading to copper excess in tissue despite low circulating levels of ceruloplasmin (the major form of circulating copper).
reducing the major pathway of hepatic copper elimination that is responsible for the clinical manifestations and pathology of Wilson disease.
Lesch Nyhan
X linked disorder of purine metabolism
Developmental retardation
hypotonia
chorea /dystonia/hyperreflexia/spasticity
Self mutilating behavior usually self biting
XXY
Klinefelter syndrome is the most common congenital abnormality causing primary hypogonadism, occurring in approximately 1 in 1000 live male births. It is the clinical manifestation of a male who has an extra X chromosome.
The most common genotype is 47,XXY (which is shown above).
47,XXY genotype results from nondisjunction of the sex chromosomes of either parent during meiotic division, while mosaicism probably results from nondisjunction during mitotic division after conception.
The greater the number of extra X chromosomes, the greater the phenotypic consequences, both gonadal and extragonadal.
Phenotypic changes would include:
Damage to the seminiferous tubules and, usually, damage to the Leydig cells as well: almost invariably small, firm testes; severely subnormal sperm count; infertility; elevated serum FSH and LH concentrations; variably subnormal serum testosterone concentration and; decreased virilisation
Long bone abnormality, resulting in increased length of the legs, independent of the increased length of both the arms and legs caused by testosterone deficiency.
Behavioural abnormality, unrelated to the hypogonadism, which causes difficulty in social interactions throughout life.
Predisposition to develop morbidities later in life that are unrelated to testosterone deficiency: pulmonary diseases such as chronic bronchitis, bronchiectasis, and emphysema; cancers, including germ cell tumours (particularly extragonadal tumours involving the mediastinum), breast cancer, and possibly non-Hodgkin lymphoma; varicose veins, leading to leg ulcers; diabetes mellitus.
Aicardi syndrome
absence corpus collosum
chorioretinal lacunae –> blindness
seizures
developmental disability
Walker Warburg Syndrome
most severe of congenital muscular dystrophy
hypotonia
coloboma, cataracts
“cobblestone” lissencephaly
fatal within first few years of life
Goldenhar syndrome
AD
- Triad: 1) mandibular hypoplasia resulting in hemifacial asymmetry, 2) ocular (limbal dermoid, eyelid coloboma) and auricular malformations (MICROTIA, preauricular skin tag) and 3) vertebral anomalies (missing vertebare, scoliosis)
- Unilateral facial hypoplasia, mandibular hypoplasia
- Hemivertebre/fused/butterfly vertebrae
- Cleft palate
-Condunctive hearing loss
-Congenital cardiac disease
DDX- Treacher collins syndrome (similar but BILATERAL)
CHARGE
coloboma
heart defects
atresiae choanae
retarted growth and development
genitourinary defects
ear abnormalities
Achondroplasia
Stenosis of spinal canal - spinal cord compression at foramen magnum
- hypotonia, central and obstructive sleep apnoea, sudden death. may need surgical correction
Lumbar stenosis can present in adulthood as parastheia, numbness, claudicaiton in legs
Cleidocranial dysplasia/dysostosis
delayed closure of the cranial sutures, dental abnormalities and hypoplastic clavicles.
Klippel-Feil syndrome
The classic triad of a short neck (C2-3 fusion) low hairline and limited range of movement of the neck occurs in less than 50%.
Duane syndrome
Congenital strabsmus
Abnormal development of 6th cranial nerve (abducens) –> anomalous inneervation of lateral rectus
There are three types and there is a helpful mnemonic to remember this: children with type 1 have difficulty with abduction (one D in abduction), type 2 have difficulty with adduction (two Ds in adduction) and type 3 have difficulty with both (3 Ds in abduction and adduction). Approximately 80% of cases are type 1.
Associated with Klippel Feil and hemifacial macrosmia
L>R eye
Freidereich ataxia
autosomal recessive disorder involving the spinocerebellar tracts, dorsal columns in the spinal cord, the pyramidal tracts, and the cerebellum and medulla. The onset of ataxia is somewhat later than in ataxia-telangiectasia but usually occurs before age 10 years. The ataxia is slowly progressive and involves the lower extremities to a greater degree than the upper extremities. Patients develop a characteristic explosive, dysarthric speech, and nystagmus is present in most children. Typically noted is a marked loss of vibration and position sense caused by degeneration of the posterior columns and indistinct sensory changes in the distal extremities. Absent lower limb reflexes. Friedreich ataxia is also characterised by skeletal abnormalities, including high-arched feet (pes cavus) and hammertoes, as well as progressive kyphoscoliosis.
hyprtrophic cardiomyopathy
Treacher collins syndrome
AD
- External ear abnormalities (bilateral microtia)- conductive hearing loss in 50%
- Eye abnormalities- down slanting eyes, coloboma of lower eyelids
- Hypoplasia of mandible
- Cleft palate
- Obstructive sleep apnoea
- Dental problems
Albright hereditary osteodystrophy (pseudohypoparathyroidism
· Short stature
· Short metacarpals and metatarsals
· Round facies
· Delayed dentition, +/– hypocalcemia and/or subcutaneous calcium or bone deposition (osteoma cutis)
· Precocious puberty
· Mild cognitive deficit
Bardet-Biedl
· Obesity
- Mental retardation
· Hypotonia
· Retinitis pigmentosa/ rod cone dystrophy
· Post axial Polydactyly
· male hypogonadotropic hypogonadism
· +/– glucose intolerance
· Deafness
· Renal disease
22q11 microdeletion
Defective development of 3rd and 4th pharyngeal pouches
Look for lack of thymus on CXR and prolonged QT (hypocalcemia) on ECG
May have SCID phenotype
X linked hypophosphatemia
X linked dominant (both males and females are affected equally)
Most common form of hereditary hypophosphatemic rickets
Loss of function PHEX gene
Renal phosphate wasting
–> hypophosphatemia, slow growth, rickets/osteomalacia
Patau syndrome
T13
haloprosencephaly
scalpdefect
cleft lip/palate
midline anomalies
90% die by 1 year
Edwards syndrome
T18
IUGR
wizened features
rockerbottom feet
90% die by 1 year
why need to do a karyotype for T21 diagnosis
for preconception councelling next pregnancy
4% T21 due to translocation (seen on karyotype but not microarray)
if maternal 14,21 translocation: recurrence risk 10-15%
T21 complications
hypothyroidism 15%
atlanto axial instability
deafness 75%
visual problems 60%
osa 75%
AML
Turners syndrome features
short stature
cardiac- bicuspid aortic valve, CoA
primary ovarian failure (gonadal dysgenesis= streak ovaries)
lymphoedema
HTN
renal anomalies- 50%
increased risk hypothyroidism and celiac
risk aortic dissection
Kleinfelter
47 XXY
hypergonadotropic hypogonadism
raised LH, FSH–> but low testosterone
Almost all infertile
Increased risk germ cell tumors and breast cancer
increased risk metabolic syndrome, hypothyroid, vte, osteoporosis
Ix: karyotype, microarray
22q11
cardiac- conotruncal : TOF 35% , interupted aortic arch 20% , truncus 10%
abnormal facies
thymic hypoplasia
cleft palate
hypocalcemia- check ecg for long QT
hearing loss
failure development 3 +4th branchial arches
Ix: microarray
Psychiatric illness in 60%, autism in 20%
Williams syndrome
Microdeletion 7q
dysmorphic
overly friendly cocktail personality
hypercalcemia
supravalvar aortic (and pulmunary) stenosis
risk GA- MI
what chromosome is affected in PWS/AS
chromosome 15q12
imprinting disorders
absent Paternal allele expression= Prader Willis
absent MAternal allele expression = AngelMAn
Genetics of Prader willis syndrome
MOSTLY DELETION/DUPLICATION
Loss paternal 15q12 (maternal normally imprinted)
1. paternal allele deletion- which is normally active (most common)- 75%
2. maternal UPD (didnt inherit paternal copy)- 20%
3. paternal imprinting defect (paternal allele incorrectly imprinted= switched off) <1%
Ix: Methylation studies/methylation sensitive MLPA , microarray for deletions and some UPD
Genetics of Angelman syndrome
MOSTLY DELETION/DUPLICATION
Loss maternal 15q12 (paternal normally imprinted)
- Maternal allele deletion (which is normally active)- 70% - including UBE3A
- Paternal UPD- 2% (didnt inherit maternal copy)
- Imprinting defect of maternal chromsome at 15q11-13 <1% or mutation in maternally derived UBE3A 10 %
–> no maternal genes, which are needed for normal development
Ix: Methylation studies/methylation sensitive MLPA, UBE3A gene sequencing
Beckwith Weiderman syndrome
MOSTLY IMPRINTING PROBLEMS
· Loss of MATERNAL alleles; only paternal gene present = overactivity of growth promoting alleles = BIG
· Disrupting imprinting of 2 neighboring domains on 11p15.5 (paternal allele growth promoting, maternal allele growth suppressing) - balance between growth promoting and suppressing alleles
· Mechanism
o 50% loss of methylation at mat IC2 on 11p
o 20% paternal UPD 11
o 5% gain of methylation at mat IC1 on 11p
5-10% CDKN1C mutation
Ix: methylation testing at 11p
Key words with Angelman
loves water
no speech
bouts of laughter
hand flapping
ataxia
BWS vs Russell silver syndrome
Mutations at 11p15 chromosome
IGF-2 gene
Paternal gene= growth promoting
Maternal gene= growth restricting
loss of maternal copy –> paternal gene overexpression –> BWS
loss of paternal copy –> maternal gene overexpression –> Russell Silver syndrome
key features BWS
overgrowth
hemihypertrophy
neonatal hypoglycemia
omphalocele, umbi hernia
ears- anterior lobe creases, posterior helix pits
naevus flamus
predisposition to embryonal malignancies (risk greatest until 8 years)
- wilms
- rhabdomyosarcoma
-neuroblastoma
-hepatoblastoma
= abdo uss every 3/12 to age 8 years
Key features Russell Silver Syndrome
IUGR
Short stature
Relative macrocephaly (preserved head circumference)
triangular facies
cafe au lait spots
clindidactyly
Russell Silver Syndrome genetics
· 11p15.5 or chromosome 7
· Absence of PATERNAL gene; only maternal gene present = SMALL
· Mechanism
50-60% 11p methylation defect
<10% maternal UPD chromosome 7
rest unknown
Leber optic neuropathy
most common mitochondrial disease
males most commonly affected
leads to progressive painless central visual loss
also cardiac conduction abnormalities, dystonia
Tuberus sclerosis
AD inheritance
2/3 cases de novo
100% penetrant
Cowden syndrome
Autosomal dominant
characterised by hamartomas in various organs, including breast, thyroid, uterus, brain, and mucocutaneous tissues with increased risk of malignancies.
PTEN mutation
Cohen syndrome
- FTT in infancy
- Truncal obesity in teen years
- Low IQ
- Thick hair and eyebrows
- Wave shaped palpebral fissures
- Hypotonic
- Join hypermobility
- Myopia
- Neutropenia
Klippel Feil Syndrome
short neck
abnormal joining of C2 and C3 cervical vertebrae
Haddad syndrome
congenital central hypoventilation syndrome + Hirsprungs disease
Bernard Soulier syndrome
bleeding disorder - perioperative bleeding, bleeding gums, epistaxis, heavy menstrual periods
Prolonged bleeding time
Thrombocytopenia
GIANT PLATELETS
caused by a deficiency of the glycoprotein Ib-IX-V complex (GPIb-IX-V), the receptor for von Willebrand factor
Chediak Higashi syndrome
mutation in lysosomal trafficking - -> reduced phagocytosis
Occulocutaneous albinism
Infection succeptibility - pyogenic infections
Impaired platelet aggregation –> Bleeding + bruising
Gingivitis + peridontitis
large intracytoplasmic granules
Lowe syndrome
congenital cataracts
Developental delay, hypotonia, hyporeflexia
Renal fanconi syndrome
Waardenburg syndrome
AD
bilateral SN hearing loss
White forelock (patchy depigmentation )
Heterochromic iris or bright blue iris
usher syndrome
progressive vision loss (retinitis pigmentosa)
bilateral SNHL
Noonan syndrome
PTPN gene mutation causative in 50%
dysmorphic: low set and post rotated ears, short webbed neck, low hair line, excess nuchal skin, short stature, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, coagulation defects
Face: down slanting palpebral fissures, epicanthal folds, ptosis
Heart: pulumunary valve stenosis
Hypertrophic cardiomyopathy (superior axis),ASD
Hypotonia leading to gross motor delay, speech and feeding difficulties
Develomental delay/ mild intellectual impairment
JMML, AML, ALL
Ix: targeted gene panel, exome
Rx: Growth hormone
Early intervention and individualised education strategies
Apert syndrome
FGFR2 mutation - single gene mutation
AD but most are de novo –> low recurrence risk
Ix: Sanger sequencing
craniosynestosis
midface hypoplasia
syndactyly
cleft palate
mild ID
Sotos syndrome
single gene mutation - NSD1
Ix: Sanger sequencing, targeted panel, exome
overgrowth, advanced bone age
behavioral issues
joint laxity
renal and heart anomalies
Risk leukemia, lymphotoma, Wilms
Loey Dietz
Marfan like phenotype with aortic root dilatation
hypertelsrism
bifid uvula
Normal IQ
Stickler syndrome
connective tissue disorder
Ocular- myopia, cataracts, retinal detachment
Pierre robin sequence or isolated cleft palate
hearing loss
what is fragile X associated with
tremor ataxia syndrome
primary ovarian insufficiency
extreme shyness in girls
most common mutation in DMD/BMD
exon deletion (70%)- usually LARGE deletions, 20% are point mutations or small frameshift mutations
exon duplication (10%)
single nucleotide variants
Duchenne muscular dystrophy (DMD) is caused by a nonsense or frameshift mutation (out of frame) in the DMD gene, while its milder form, Becker muscular dystrophy (BMD) is caused by an in-frame deletion/duplication or a missense mutation (non frame shift)
Ix: dystrophin gene MLPA and seqencing
Costello syndrome
risk rhabdomyosacoma, neuroblastoma, bladder cancer
MEN2B
Marfanoid habitus
risk medullary thyroid carcinoma, phaeochromocytoma
MEN1
pituitary adenoma
parathyroid hyperplasia
Gorlin syndrome
BCC + meduloblastoma
Bloom syndrome
AML, lymphoma
FASD features
short palpebral fissure length (inner to outer canthus distance)
smooth philtrim
thin vermillion border
diagnostic criteria:
Kabuki syndrome
Associated with coarctation of aorta (and other CHD)
Short stature
cleft palate
premature thelerche
Pendred syndrome
- SN hearing loss
- Dilatation of vestibular aqueduct (inner ear)–> balance issues
Goitre +/- hypothyroidism
Alport syndrome
Most X linked, AR
COL4A3, COL4A4, or COL4A5 mutations
Progressive renal disease
Nephritis - can have periods of hematuria
SN hearing loss (develops over time)
Anterior lenticonus
Retinitis
Basketweave appearance
Rx: ACE-I to reduce disease progression
Allagile syndrome
https://www.ncbi.nlm.nih.gov/books/NBK507827/
VACTERL
Noonan syndrome
Turner syndrome
