Syndromes Flashcards
Cafe au lait irregular border Fibrous dysplasia - limp/pain/fracture - scoliosis - face deformity Precious puberty - ovarian cyst, excess GH Macro-orchidism Hyperthyroidism - goitre/nodules Renal phosphate wasting Cushing's
? Inheritance ? Gene
McCune Albright
Random somatic mutation in GNAS
Low GnRH Hypogonadatrophic hypogonadism Hyposmia/anosmia Micropenis, undescended testes Midline facial defect Congenital solitary kidney
? Inheritance
? Rx
Kallmann syndrome
X linked recessive - KAL1
Hormone replacement
Peutz Jegher syndrome
Inheritance
Gene
Associations
Autosomal dominant
94% LKB1/STK1
2/3 have family history of hyperpigmented lesions (esp lips/intraoral) and multiple GI hamartomas (small intestine, colon, stomach).
Increased risk intussusception, cancer (GI, breast, reproductive)
Cowden syndrome
Inheritance
Gene
Associations
Autosomal dominant
80% PTEN gene (phosphatase and tension homolog)
Mucocutaneous lesions - facial trichilemmomas (often perioral), acral keratosis, papillomatous papules
Minor criteria but in 80% - GI hamartomas and oesophageal glycogenic acanthosis
Other associations - breast fibroadenomas, breast cancer, goitres, thyroid cancers macrocephaly, genitourinary cancers and intellectual disability
Alagille syndrome
Gene. Inheritance
Associations
JAG1/NOTCH2
Autosomal dominant
Paucity of bile ducts - often require transplant Cardiac - pulmonary stenosis Face - triangular Davies, deep set eyes Eyes - posterior embryotoxin Butterfly vertibrae
UBE3A
Angelman syndrome
DHCR7 gene
Smith lemli Opitz syndrome
Bloom syndrome
short stature; a sun-sensitive, red rash that occurs primarily over the nose and cheeks; mild immune deficiency with increased susceptibility to infections; insulin resistance that resembles type 2 diabetes; and most importantly, a markedly increased susceptibility to many types of cancer, especially leukemia, lymphoma and gastrointestinal tract tumors. Diagnosis typically involves identification
Liddle’s Syndrome
AKA
pseudoaldosteronism
pseudoprimary hyperaldosteronism
Inherited form of HTN Autosomal dominant (rare)
SCNN1B or SCNN1G gene -> ENaC
In the kidney, ENaC channels open in response to signals that sodium levels in the blood are too low, which allows sodium to flow into cells.
Mutations in theSCNN1BorSCNN1Ggene change the structure of the respective ENaC subunit. The changes alter a region of the subunit that is involved in signaling for its breakdown (degradation) when it is no longer needed. As a result of the mutations, the subunit proteins are not degraded, and more ENaC channels remain at the cell surface. The increase in channels at the cell surface abnormally increases the reabsorption of sodium (followed by water), which leads tohypertension. Reabsorption of sodium into the blood is linked with removal of potassium from the blood, so excess sodium reabsorption leads to hypokalemia.
Low renin, low aldosterone
Low potassium
Gordon Syndrome
AKA
Pseudohypoaldosteronism type 2
Familial hyperkalemia hypertension
This syndrome is characterized by short stature, intellectual impairment, dental abnormalities, muscle weakness, severe hypertension by the third decade of life, low fractional excretion of sodium, normal renal function, hyperchloremic metabolic acidosis, and low renin and aldosterone levels
Hyperkalemia, another hallmark of this syndrome
WNK1 and WNK4
increased co-transporter activity, excessive chloride and sodium reabsorption, and volume expansion
Treatment consists of either a low-salt diet or thiazide diuretics, aimed at decreasing chloride intake and blocking Na-Cl co-transporter activity, respectively.
CHARGE syndrome
renal hypoplasia and ocular abnormality is found to have mutation of the CHD7 gene.
CHARGE = Coloboma, Heart defects, choanal Atresia, Retarded growth, GU defects, Ear anomalies – caused by mutations of CHD7 on chromosome 8q12. The combination of renal hypoplasia and coloboma could be caused by CHARGE or Renal-coloboma. You need to know that CHARGE is caused by CHD7 mutation.
Mayer-Rokitansky-Kuster-Hauser syndrome
Primary ammenorrhea + renal/vaginal agenesis
Turner syndrome can present with primary amenorrhoea and renal abnormalities are common. However, you would expect the patient to be short and you would not expect vaginal agenesis. This scenario describes Mayer-Rokitansky-Kuster-Hauser syndrome – also known as vaginal agenesis or Mullerian agenesis. The cause is unknown and up to 50% will have associated renal abnormalities.
An infant with joint laxity, ocular abnormality and renal hypoplasia is found to have mutations in the PAX2 gene.
Renal-coloboma syndrome is associated with mutations in the PAX2 gene. It is an autosomal disorder associated with coloboma, renal abnormalities, SNHL, seizures and joint laxity. Marfan syndrome is associated with joint laxity and ocular abnormalities – specifically ectopia lentis – but is not usually associated with renal abnormalities.
Crigler-Najjar Syndrome
Gene/inheritance
Cause
Presentation
Disorder of bilirubin metabolism
Gene/locus:UGT1A1gene; 2q37
Inheritance: Autosomal recessive
UGT1A1gene codes for the enzyme Uridyl diphosphate glycosyltransferase (UGT), which is involved in bilirubin conjugation. Deficiency of the enzyme leads toincreased levels of unconjugated bilirubin.
Type 1 - almost complete absence of UGT enzyme
Type 2 - Partial deficiency
Jaundice:
Present soon after birth (Type 1) or later in infancy or childhood (Type 2).
If untreated, Type 1 Crigler-Najjar syndrome can lead to kernicterus and death.
Note: Gilbert syndrome and Crigler-Najjar syndrome are two ends of a spectrum of variability of the same condition.
McCune-Albright syndrome
Gene/inheritance
Cause
Features
Rx
GNAS1gene, (20q13).
Inheritance: Post zygotic mutation. Sporadic condition.
McCune-Albright syndrome is syndrome caused by a somatic mutation in the G-protein that stimulates cyclic-AMP. It thus causes a variable expression depending on which tissues are affected.
Endocrine dysfunction (precocious puberty in females initially noted, pituitary, thyroid and adrenal abnormalities also noted) - The most common endocrine presentation is peripheral precious puberty, which is more common in girls than boys due to ovarian cyst formation with autonomous estrogen production. - (with suppressed LH, FSH levels and no response to GnRH stimulation) Other endocrine abnormalities: - Hyperthyroidism, Cushings syndrome, Gigantism (increased growth hormone).
Large cafe-au-lait patches with irregular margins (coast of Maine). Does not cross the midline and usually seen over the nape of neck
Fibrous dysplasia of the skeletal system
- most commonly affecting proximal femur & craniofacial bones.
Aromatase inhibitors or anti-oestrogen medications may be used to limit oestrogen effects on pubertal and bone development, but have variable success.
Kallmann syndrome
Gene/inheritance
Cause
Salient features
Rx
Genes/loci/inheritance: Genetically heterogeneous. multiple genes identified.
Commonly identified genes includeKAL1(Xp22),FGFR1(8p12), ,PROKR2(20p12) andPROK2(3p21).
X linked, AD and AR inheritance patterns described.
Neurons which migrate from the olfactory placode to the hypothalamus are impaired, resulting in inability to produce sufficient GnRH to stimulate pubertal development.
Endocrine: Hypogonadotrophic hypogonadism.
Most cases present with delayed/absent puberty.
Some males may have undescended testes & micropenis.
Anosmia: Due to hypoplasia of the olfactory bulbs
Partial or complete anosmia.
Often need olfactometry to confirm.
Other features: include mirror movements of the hands (synkinesia), cleft lip/palate, renal agenesis, sensorineural deafness.
Hormone replacement is the mainstay of treatment.
Rett syndrome
MECP2
X linked dominant. Most are de novo mutations. Lethal in most males.
Developmental regression.
Microcephaly and loss of speech
Natural history generally classified into 4 stages, although symptoms may overlap.
Stage 1(Early onset stagnation period):
Occurs between 6 months - 1.5 years
less interest in social interaction. Mild delay in achieving developmental milestones.
Stage 2(Rapid developmental regression period):
Occurs between 1-4 years
Loss of previously acquired fine motor and language skills. Social withdrawal.
Behavioural problems like hair pulling and bruxism.
Slowing of head growth. Acquired microcephaly.
Stage 3(Pseudo-stationary period):
Occurs between 2-10 years, once the regression phase is over.
Hand stereotypies become more prominent and include hand wringing, clapping and hand washing.
lrregular breathing patterns (breath holding, periods of slow/rapid breathing) becomes more prominent.
About 70% children develop seizures
Communicates mainly by eye pointing/eye gaze
Cold feet with or without atrophic changes
Stage 4(Late motor deterioration):
Occurs when individual becomes wheelchair bound.
Scoliosis
Velo cardio facial syndrome
AKA DiGeorge 22q11.2 deletion. TBX1 gene Autosomal dominant. About 90% arede novo. Rest are inherited from a parent.
C: Cardiac defects especially conotruncal defects (TOF, Interrupted aortic arch, Truncus arteriosus and TGA)
A: Abnormal facies - Narrow palpebral fissures, hypertelorism, short philtrum, antimongoloid slant, bulbous nose, low set ears
T: Thymic hypoplasia, Immunodeficiency (mainly T cell)
C: Cleft Palate. Palatal problems include velopharyngeal insufficiency (most common), cleft palate, nasal speech, choanal atresia
H: Hypocalcemia, secondary to hypoparathyroidism. May present as neonatal seizures.
Other features: include feeding difficulties in infancy, thrombocytopenia, autoimmune disorders, renal anomalies, behavioral & psychiatric problems and learning difficulties.
Fragile X
Inheritance
Features
X linked
FMR1gene
Males with Full mutation
Development:developmental delay - mainly speech.
Behaviour:Hyperactivity, autistic features, temper tantrums in childhood. Usually shy as adults.
Intellectual difficulties:moderate to severe
Physical features: Prominent forehead, long face, prominent jaw, large ears, joint hypermobility. Large testes (post-pubertal feature)
Females with Full mutation
Around 50% have intellectual difficulties and behavioural problems (usually milder than males).
Beckwith-Wiedemann Syndrome (BWS)
Antenatal: Polyhydramnios, large placenta, cytomegaly of adrenal cortex
Growth: Prenatal and postnatal overgrowth. The height and weight are usually around the 97th centile while the head circumference is usually around the 50th centile. The adult height is usually normal. Some cases have hemihypertrophy.
Craniofacial:
Forehead: Capillary hemangioma (naevus flammeus/stork bite)
Ears: anterior ear lobe crease (horizontal), pits on the helix
Macroglossia
Cleft palate: seen in some cases withCDKN1Cgene mutation
Endocrine: Hyperinsulinism leading to hypoglycaemia in the neonatal period
Anterior abdominal wall defectsincluding umbilical hernia and exomphalos
Malignancies: Wilms tumour, hepatoblastoma, rhabdomyosarcoma, neuroblastoma
Other features: Renal anomalies, cardiomyopathy
Stickler
Eyes:
Abnormal vitreous development: The various vitreous phenotypes include Membranous, Beaded and Hypoplastic. This can lead onto retinal detachment and blindness.
Congenital Myopia, astigmatism.
Congenital cataracts - especially quadrantic lamellar cataracts.
Risk of glaucoma.
Note:COL11A2mutations do not usually have eye findings.
Craniofacial: Flat midface, depressed nasal bridge, short nose with anteverted nostrils, bifid uvula, cleft palate (midline), Pierre-Robin sequence.
Skeletal system: Joint hypermobility, premature onset of arthritis, joint enlargements (due to epiphyseal dysplasia), chronic back pain. Spine abnormalities including kyphoscoliosis.
Ears: Conductive and/or sensorineural deafness.
Hallerman Streiff syndrome
Brachycephaly (flat head) with frontal bossing + beak shaped nose
Ocular and dental abnormalities common
Skin atrophy of face and telangiectasia
Conradi
Aka congenital X linked dominant chondrodysplasia punctate type 2
Ichthyosiform erthoderma (resolves with time) Limbs defects and cataracts
Bardet-Biedl syndrome
Inheritance
Features
Autosomal recessive
Genetically heterogeneous; More than 10 different genes identified.
Growth: Increased weight gain which starts in infancy. Obesity in later life (72-95%).
Eyes: Retinitis pigmentosa (Rod-cone dystrophy). Childhood onset of visual loss. Earliest symptom is usually night blindness which becomes apparent by 7-8 years of age.
Hands/Feet: Post axial polydactyly, syndactyly, brachydactyly
Kidneys: Various structural abnormalities of the kidney. Leads to chronic renal failure in some cases.
Genitalia: Hypogonadism in males, irregular menstrual cycles in females.
Development: Developmental delay (50%) and Learning disabilities (62%).
Cornelia de Lange Syndrome
Aka Bushy syndrome
1 in 10,000-30,000
NIPBLandSMC3related CdLS are inherited in an autosomal dominant manner. Most arede novomutations.
SMC1Arelated CdLS is inherited in an X linked manner.
Craniofacial:
Microcephaly, brachycephaly, hairy forehead, low anterior and posterior hair line.
Arched eyebrows which meet in the midline (synorphrys), long eye lashes.
Short nose with anteverted nares, long and smooth philtrum, thin upper lip.
High arched palate, cleft palate in 20% cases.
Growth: Pre & post natal growth failure. Proportionate short stature,
Development: Developmental delay, learning difficulties (moderate to profound).
Limbs:
Short forearms, small hands, feet and disproportionately short 1st metacarpal.
Upper limb malformations range from oligodactyly, ectrodactyly (split hand malformation due to absence of central digits) to hypoplastic or absent forearms.
Other features include syndactyly, 5th finger clinodactyly and single palmar crease.
Note: Upper limbs are more affected than lower limbs.
CVS: Congenital cardiac defects - mainly VSD or ASD.
GIT: Feeding difficulties, Gastro-esophageal reflux, Renal anomalies, Hypoplastic genitalia, undescended testes in males.
De Morsier Syndrome
Aka Septo-Optic Dysplasia
Some assoc HESX1
most cases are sporadic.
Triad of:
Midline brain abnormalities: including absent septum pellucidum and absent corpus callosum.
Optic nervehypoplasia.
Pituitary dysfunction: Hypopituitarism leading to growth hormone deficiency, diabetes insipidus, hypoglycaemia, hypogonadism, hypospadiasis and undescended testes in males.
Pallister Hall Syndrome
Autosomal Dominant
Hypothalamic hamartoma, polydactyly, bifid epiglottis, imperforate anus, renal abnormality
Neurology: Hypothalamic hamartoblastoma which is usually asymptomatic. Some patients may have neurological symptoms including seizures.
Hands/Feet: Mesoaxial (central) polydactyly - which is a very useful clinical sign. Postaxial polydactyly. Syndactyly, dysplastic nails.
Oral: Bifid epiglottis, laryngeal clefts, natal teeth and multiple oral frenulae.
Endocrine: Panhypopituitarism, adrenal insufficiency which can be life threatening.
GIT: Imperforate anus and other genitourinary defects
Fraser syndrome
AR - FRAS1/FREM2
cryptophthalmos Cutaneous syndactyly Genital malformations + ambiguous genitalia Craniofacial abnormalities Larynx atresia/strenosis Kidney malformations
Cenani-Lenz syndrome
AR
Distal limb development
Syndactyly and/oligodactyly
Facial dysmorphisms
Kidney agenesis /hypodysplasia
Caudal dysplasia syndrome
Hypoplastic lower extremities
Fused iliac wings
Lumbosacral vertebrae anomalies with absent sacral vertebrae in sever cases
Closed neural tube defect - tethered cord and lipoma
Renal agenesis
Zellweger syndrome
Peroxisomal metabolic disorder
(Peroxisomes are subcellular organelles present in all cells except erythrocytes, highest conc on liver and kidney)
- craniofacial dysmorphism and profound neurological abnormalities
- accumulation of VLCFA in membranes of neuronal cells contributes to neurological injury
- autosomal recessive. M=F
- high forehead, large anterior fontanelle, marked separated cranial sutures, hypoplastic supraorbital ridges, upward slant of eyes, epicanthal folds, low and broad nasal bridge, high arch palate, deformed ear lobes
- hepatomegaly (cirrhosis and biliary dysgenesis)
- profound hypotonia, weakness, absent reflexes, severe impairment of hearing and vision, neonatal seizures
- profound developmental delays rarely survive beyond 6 months of age
- glomerulocystic kidney disease, cataracts, pigmentary retinopathy
Klippel-Feil syndrome
The classic triad of a short neck, low hairline and limited range of movement of the neck occurs in less than 50%.
Congenital fusion of the neck leads to limited range of movement. More than 50% of children will have scoliosis.
Crouzon syndrome (craniofacial dysostosis type I)
One of the most common craniosynostosis syndromes
Autosomal dominant
FGFR2 (10q26).
Gain of function mutations
Craniosynostosis: coronal and sagittal sutures are affected commonly.
Facial features: Proptosis (due to shallow orbits), hypertelorism, strabismus, mid face hypoplasia, mandibular prognathism.
Characterised by a tall, flattened forehead (secondary to bicoronal synostosis), proptosis, and midface hypoplasia.
CNS: some patients develop hydrocephalus and hind brain herniation.
Crouzon syndrome with Acanthosis nigricans: About 5% of Crouzon patients have acanthosis nigricans.
***structurally normal hands and feet, as well as normal IQ
Aperts syndrome
Apert syndrome (acrocephalosyndactyly type I)
Autosomal dominant
Mutations in the gene encoding fibroblast growth factor receptor 2 (FGFR2), located on chromosome 10.
Manifests clinically as two noticeable craniofacial defects: bicoronal synostosis and maxillary hypoplasia.
Other facial features include protruding eyes (exorbitism) with a laterally down-sloping slant, hypertelorism (widely separated orbits), low-set ears, and high-arched palate.
Additional features may include strabismus, hearing loss, severe acne, and syndactyly of the hands and feet.
Pfeiffer syndrome (Pfeiffer-type acrocephalosyndactyly type V)
Autosomal dominant, from mutations in FGFR1 and FGFR2.
Features include variable degrees of craniosynostosis, midface hypoplasia, and proptosis.
The presence and extent of syndactyly is variable.
Additional manifestations may include broad thumbs and great toes, radiohumeral synostosis, hydrocephalus, and imperforate anus.
Costello syndrome
HRAS - AD, mostly de novo
Short stature, relative macrocephaly, feeding difficulties, developmental delay
Epicathal folds, flat nasal bridge, full lips, large mouth, excess Palmar skin with deep creases
Increase tumour risk - rhabdomyosarcoma
