Syndromes

Question 1

What is Morquio syndrome?

Answer 1

-MPS IV
-Characterised by short trunk, dwarfism, fine corneal
deposits and skeletal dysplasia
-The chest can be barrel shaped
with flared ribs
-Results in restrictive chest wall abnormality confirmed by the high RV and low TLC

Question 2

Stickler

Answer 2

◾autosomal dominant, gene mutation causing defect in collagens type II, IX or XI
◾midface hypoplasia, Pierre-Robin sequence
◾severe myopia, glaucoma, cataracts, retinal detachment
◾hearing loss (SNHL)
◾hypermobile joints leading to early arthritis

Question 3

Waardenburg

Answer 3

ADD
Associated with SNHL
White forelock 
Broad nasal root
Heterochromia iridis
Assymetry of the face (can be subtle)
Hypertrichosis of median eyebrow (monobrow)

NOT associated with congenital cardiac disease

DDX: Horner’s syndrome

Question 4

Congenital rubella

Answer 4

Add
Associated with SNHL
Blueberry muffin rash

Question 5

Pendred

Answer 5

Autosomal recessive. Congenital bilateral, non-progressive SNHL (severe à profound) and goitre with occasional hypothyroidism. Dilation of vestibular aqueduct bilat +/- cochlear hypoplasia. Abnormal perchlorate discharge test or goitre.
SNHL

Question 6

Usher

Answer 6

autosomal recessive. Three subtypes (I, II, III) depending on genes affected: congenital bilateral sensorineural hearing loss; retinitis pigmentosa leading to gradual visual loss; variable vestibular function impairment
SNHL

Question 7

Von hippel lindau

Answer 7

add

AD
haemangioblastoma risk

Question 8

Sturge weber

Answer 8

add

large facial port wine stain with intracranial AVM
Hallmark is leptomeningeal angiomas

Question 9

klippel-trenaunay-weber

Answer 9

add

Large complex vascular lesion under skin (on top looks like port wine stain with soft tissue overgrowth) can cause hemihypertrophy - management for this are compression garments

NOT the same as Sturge weber

Question 10

osler-weber-rendu

Answer 10

add

AD

Question 11

NF1

Answer 11

Add
Autosomal dominant
Defect in neurofibromin gene (RAS pathway)

Criteria:
Lisch nodules (eye) at least 2
Optic gliomas (NOT astrocytoma) - can cause papilloedema and impact on pituitary causing precocious puberty or other
Cafe au lait at least 6
neurofibromas- at least 2 typical or 1 plexiform
Sphenoid dysplasia 
Long bone deformities
axilla/inguinal freckilin
1st degree releative

Focally degenerative myelin (hyperintensity in deep grey and white matter) –> increased signal of the brainstem, thalami, globus pallidus –> tend to resolve with time

Question 12

Tuberus sclerosis

Answer 12

Add
Autosomal dominant
2 known loci
high spontaneous mutation rate
Cardiac rhabdomyoma
renal angiolipoma
angiofibroma (aka sebaceous adenoma)
Ungal fibroma
LAM (lungs, usually women)
ash leaf spots
Shagreen patches (orange, bumpy)
cortical tubers
subependymal nodules
SEGA
retinal hamartomas

Question 13

Ataxia telangectasia

Answer 13

• AR
• Primary def of T and B cells
• Mutations in ATM gene –> normally encodes a DNA repair gene –> unable to repair DNA –> cell cycle arrests –> Cerebellar degeneration
• Multiple telangectasias- face, eyes, mouth
• Cerebellar degeneration
• Raised AFP, low IgA, low IgG and low IgE
• can get bleeds in brain
• Associated increased risk of ALL

To remember: 5A's
ATM gene
Ataxia (cerebellar defects)
spider Angiomas (telangiectasia)
IgA deficiency
ALL

Symptoms:
-ataxia onset in childhood
-telangiectasias onset in childhood
-recurrent sinopulmonary infections
ears, sinuses, lungs (treat with antibiotics and IVIG)

Physical exam:

• multiple telangiectasias, most commonly on face and ears, also on conjunctival sclera (see above photo)
• ocular movement abnormalities (strabismus, nystagmus)
• cerebellar ataxia
• dysmetria
• dysdiadochokinesia
• hypotonia

Variable rate progression –> wheel chair eventually
-death early adulthood

Question 14

Incontinentia pigmenti

Answer 14

Add

Ectoderm and neuroectoderm affected

Blasko distribution of blisters and vesicles which resolve leaving a swirling brown pattern in same distribution. Can be warty, pigmented, hypopigmented
Whorled or linear appearance.

Dental- small, missing, delayed or deformed teeth
Nails- dystrophic
Hair- alopecia
Eyes- anophthalmia, cataracts, retina vascular issues
Brain- seizures, learning difficulties, ataxia
NO renal issues

X-linked dominant - affects females only

Question 15

McCune albright

Answer 15

Large, irregular cafe au lait spots on back and buttocks called ‘coast of maine’
associated with gonadotropic independent precocious puberty- classically with an ovarian cyst

Question 16

Horner syndrome

Answer 16

Suspect if a child has had cardiac surgery in the question!

Can present with assymetry of the eyes–> sunken eye (enophthalmos), paler iris, smaller pupil

Question 17

IPEX syndrome

Answer 17

ADD

Is a known cause of INTESTINAL FAILURE

Question 18

Bloom syndrome

Answer 18

• AR
• rare
• Mutation in BLM gene which makes recQhelicases (caretakers of genome)

Dysmorphic:

• high-pitched voice
• including a long, narrow face; a small lower jaw; and prominent nose and ears.
• learning disabilities, an increased risk of diabetes, chronic obstructive pulmonary disease (COPD), and mild immune system abnormalities
• aspermia in men
• Very short stature, photosensitive rash (butterfly rash, and sun exposed)and marked increase in cancer –> particularly skin and leukemia
• telangiectasias (including eyes)
• Hypo/hyper pigmented skin

Question 19

Blueberry muffin Syndrome

Answer 19

-Due to the presence of clusters of blood-producing cells in the skin (extramedullary erythropoiesis), or bleeding into the skin (purpura) or spreading cancer (metastases).

Tumours such as:

Congenital LEUKAEMIA cutis (AML)
Langherhans cell histiocytosis
Neuroblastoma
Congenital rhabdomyosarcoma

Blood disorders such as:

Haemolytic disease of the newborn – rhesus or ABO incompatibility
Hereditary spherocytosis
Twin-twin transfusion syndrome

Congenital infections such as: TORCH

Rubella
Toxoplasmosis
Cytomegalovirus
Herpes simplex
Coxsackie virus
Parvovirus
Epstein Barr virus
Syphilis

Question 20

Meier-Gorlin syndrome

Answer 20

• AR
• Several genes including ORC1
• form of primordial dwarfism as IUGR
• is characterised by short stature, microcephally, micrognathia, under-developed or absent patella and small ears.

Facies:

• ears may be low-set or rotated backward.
• small mouth (microstomia)
• micrognathia
• full lips, and a narrow nose with a high nasal bridge

Question 21

Miller syndrome

Answer 21

• AR
• Defect in DHODH gene

-Characterised by malar hypoplasia, micrognathia, cleft lip and cleft palate and downward slanting eyes

• small cupped ears, Conductive hearing loss
• skeletal abnormalities
• GU abnormalities sometimes
• normal intellect

Question 22

Auriculo-condylar syndrome

Answer 22

• AD
• GNAI3 or PLCB4 gene
• is characterised by ear malformations (such as less folds in the external ear, narrow ear canals and pre- and post-auricular ear tags) micrognathia and malfunction of the temporomandibular joint.
• “question mark” shaped ears
• Other features can include facial asymmetry, prominent cheeks, microstomia and cleft palate

Question 23

DiGeorge syndrome (velocardial facial syndrome)

Answer 23

22q11 microdeletion

CATCH 22

C- cardiac (conal truncal and aortic arch defects) esp truncus arteriosus

A-abnormal facies ( low set rotated ears, hypertelorism, micrognathia, high nasal bridge)

T- Thymic hypoplasia (variable. 1% have complete aplasia with SCID)

C- Cleft palate (full or submucosal)

H- hypocalcemia (abnormal parathyroid glands)

22- chromosome 22

Question 24

Osteogenesis imperfecta

Answer 24

◾structural or quantitative defects in type 1 collagen (primary component of the extracellular matrix of bone and skin) - leads to osteoporosis
◾classic OI is autosomal dominant
◾triad: fragile bones, blue sclerae, early deafness
◾type I (mild): blue sclerae, recurrent fractures in childhood and presenile hearing loss
◾type II (perinatal lethal): stillborn or death in the 1st year of life; extreme fragility of skeleton and other connective tissues, multiple intrauterine fractures of long bones; sclerae are dark blue-grey
◾type III (progressive deforming): fractures from minimal trauma, heal with deformity, “popcorn” appearance of metaphyses due to disorganisation of bone matrix, rib cage flaring, scoliosis, vertebral compression, extreme short stature
◾type IV (moderately severe)
◾type V (hyperplastic callus)
◾type VI (mineralisation defect)
◾type VII, type VIII (recessive)

Question 25

Marfan syndrome

Answer 25

◾autosomal dominant, mutations in gene encoding ECM protein fibrillin-1 (on 15q21) ◾30% are sporadic, new mutations often associated with advanced paternal age ◾1/5000 – 1/10000 births ◾skeletal: disproportionate overgrowth of long bones; anterior chest wall deformity; arm span >1.05 times height; reduced upper to lower segment ratio; arachynodactyly - wrist sign, thumb sign; thoracolumbar scoliosis ◾cardiovascular: AV valve prolapse/regurgitation - heart failure; ventricular arrhythmia, AF, SVT; aortic aneurysm and dissection ◾ocular: lens dislocation (occurs in 60-70% of patients); early and severe myopia; retinal detachment; early cataract ◾pulmonary: pneumothorax (15% of patients); pectus excavatum/scoliosis - restrictive lung disease

Question 26

Hunter syndrome

Answer 26

◾mucopolysaccharidosis II - deficiency of iduronate-2-sulfatase ◾X-linked, Xq28 - IDS gene, 80% point mutations, major deletions and rearrangements in the rest ◾exclusively males, reported in females due to lyonisation ◾wide clinical manifestation due to marked molecular heterogeneity ◾coarse facial features, short stature, dysostosis multiplex, joint stiffness, mental retardation manifest between 2 to 4 years of age ◾grouped skin papules, extensive Mongolian blue spot

Question 27

Achondroplasia

Answer 27

◾manifests at birth with short limbs, long narrow trunk, large head with midfacial hypoplasia and prominent forehead (prototype chondrodysplasia) ◾limb shortening greatest in proximal segments, fingers often display trident configuration ◾infants usually display delayed motor milestones, often not walking alone until 18-24 months; related to hypotonia and mechanical difficulties ◾spinal canal is stenotic - infants can experience compression at level of foramen magnum à hypotonia, FTT, quadraparesis, central/obstructive apnoea, sudden death ◾mutations at FGFR3 codon 380 - mutation maps to transmembrane domain of receptor - inhibits linear bone growth (fibroblast growth factor receptor 3) ◾autosomal dominant, but most cases are sporadic

Question 28

Congenital CMV

Answer 28

the most common infectious cause of SNHL. Congenital CMV is the most common intrauterine infection in humans as well as the leading infectious cause of sensorineural deafness. 40,000 infants in the United States are born each year with congenital CMV; 90 percent are asymptomatic.Among the 10 percent who are symptomatic, approximately 60 percent develop SNHL ADD

Question 29

Bardet biedl syndrome

Answer 29

It is an autosomal recessive disorder. Mutations in at least 15 genes have been described. Mutations involving the nephronophthisis (NPHP) genes are well characterised and cause childhood endstage renal disease and retinitis pigmentosa Bardet-Biedl syndrome is the next most common syndromic form of RETINITIS PIGMENTOSA, and is associated with polydactyly, obesity (MAY LOOK like PRADER WILLI), renal abnormalities, and mental retardation. Other features can include micro-orchidism, polyuria and polydipsia.

Question 30

Usher syndrome

Answer 30

Most common syndromic cause of Retinitis pigmentosa - Usher patients have congenital or early-onset hearing impairment followed by development of RP (similar retinopathy pattern to Bardet Biedl syndrome) - It doesn’t cause obesity (differs from BBS)

Question 31

Alagille syndrome

Answer 31

- Bile duct hypoplasia. - AD - JAG1 and NOTCH2 - Alagille Syndrome (arteriohepatic dysplasia) is the most common syndrome with intrahepatic bile duct paucity. - Facial characteristics: broad forehead, deep set /widely spaced eyes, long straight nose, underdeveloped mandible. - Ocular abnormalities: posterior embryotoxon. - Cardiac Abnormalities: Usually peripheral PS, sometimes Tetralogy of Fallot. - Vertebral arch defects: butterfly vertebrae. Tubulointerstitial nephropathy. - DEKA def secondary to biliary atresia --> can develop bone demineralisation and Rickets - Prolonged survival but can suffer significant morbidity from Neuro effects of Vit E deficiency - increased risk of hepatic failure and hepatocellular carcinoma.

Question 32

Albright hereditary osteodystrophy

Answer 32

- This condition is associated with genetic imprinting. It is thought to be inherited in an autosomal dominant pattern, and seems to be associated with a Gs alpha subunit deficiency - Short 4th/5th metacarpal, round face - Low Vit D - Pseudohypoparathyroidism - resistance to PTH ``` -Hypogonadism Brachydactyly syndrome Choroid plexus calcification Hypoplasia of dental enamel Full cheeks Hypocalcemic tetany ```