Multisystem

Question 1

CHARGE syndrome

Answer 1

CHD7 gene mutation defined by a constellation of:

C: coloboma
H: heart defects
A: atresia choanae
R: retarded growth and development
G: genital hypoplasia
E: ear abnormalities and/or deafness

According to updated diagnostic criteria, the most defining features are the 4 Cs:
coloboma
choanal atresia
cranial nerve anomalies (especially olfactory pathway absence)
characteristic ear anomalies (especially semicircular canal dysplasia/aplasia)

Major criteria
coloboma (80%): ranges from defect of iris, retina, choroid, or disc, to microphthalmia or anophthalmia

choanal atresia/stenosis (45%) or cleft palate (25-50%)
cranial nerve anomaly/dysfunction

olfactory (90%): hyposmia/anosmia
facial (40%): facial palsy

vestibulocochlear (95-100%): sensorineural deafness
glossopharyngeal or vagal (60-80%): velopharyngeal incoordination for suck/swallow

characteristic ear anomalies (some or all of the following) (90%)

abnormal auricle: short and wide (lop/cup shaped), absent lobule, truncated helix, prominent antihelix

ossicular malformations

Mondini malformation
absent/hypoplastic semicircular canals

Minor criteria
urogenital abnormalities
kidney
duplex kidney
renal hypoplasia/solitary kidney
penis
hypospadias
penile agenesis
scrotum/testes
bifid scrotum
cryptorchidism
vaginal atresia
uterine atresia
congenital heart disease
tetralogy of Fallot
atrioventricular canal defect
double outlet right ventricle
short stature
cleft palate +/- lip
oesophageal atresia / tracheo-oesophageal fistula (~15%) 2
characteristic facies
developmental delay

Question 2

Tuberous sclerosis features

Answer 2

Characterised by the development of multiple benign tumours of the embryonic ectoderm (e.g. skin, eyes, and nervous system).

H: hamartomas (CNS, retinal and skin)

A: angiofibroma (facial) or adenoma sebaceum

M: mitral regurgitation

A: ash-leaf spots

R: rhabdomyoma (cardiac)

T: tubers (cortical, subcortical)

O: autOsomal dominant (autosomal sounds like starting with letter “O” )

M: mental retardation (intellectual disability)

A: angiomyolipoma (renal)

S: seizures; Shagreen patches 1

Neurological
cortical/subcortical tubers: 50% are in the frontal lobe; high T2 and low T1 with only 10% of tubers showing enhancement; frequently calcify after two years of age

subependymal hamartomas: 88% are associated with calcification, although calcification absent in early childhood

subependymal giant cell astrocytomas (SGCA): tend to have intense enhancement

white matter abnormalities

retinal phakomas

rarer findings

cerebellar atrophy
infarcts (due to occlusive vascular disorders)
cerebral aneurysms
dysgenesis of the corpus callosum
Chiari malformations
microcephaly
arachnoid cysts
chordoma

Abdominal
renal angiomyolipoma (AML)
renal cysts
renal cell carcinoma and oncocytomas: occur at a younger age 1

retroperitoneal lymphangiomyomatosis (LAM)
retroperitoneal cystic lesions
gastrointestinal polyps
pancreatic neuroendocrine tumours
hepatic angiomyolipoma(s)

Thoracic
lymphangioleiomyomatosis (LAM)

multifocal micronodular pneumocyte hyperplasia (MMPH)

cardiac rhabdomyomas: typically regress before birth with spontaneous regression in 70% of children by age 4

thoracic duct and aortic/pulmonary artery aneurysm
myocardial fatty foci 14 / cardiac fat containing lesions 20

Musculoskeletal
sclerotic bone lesions: ~55% (range 40-66%)
hyperostosis of the inner table of the calvaria
periosteal new bone
scoliosis
bone cysts

Skin
Cutaneous lesions are present in ~95% of cases, but are rarely appreciated radiographically

hypopigmented macules (ash leaf spots): seen in 90% of patients 1
facial angiofibromas (Pringle nodules or adenoma sebaceum); seen in 75% of patients

fibrous plaques of the forehead (15-20%)

confetti lesions: variant of leukoderma spots

shagreen patches: seen in 20-30% of patients

periungual angiofibroma (Koenen tumours): 20% of patients

Question 3

Genetics of tuberous sclerosis

Answer 3

Spontaneous mutations account for 50-86% of cases 3, with the remainder inherited as an autosomal dominant condition. In the majority of such cases (80%) the mutation has been narrowed down to two tumour suppressor genes, both part of the mTOR pathway 3,13:

TSC1: encoding hamartin, on chromosome 9q32-34

TSC2: encoding tuberin, on chromosome 16p13.3 (accounts for most cases)

Question 4

Cowden syndrome

Answer 4

Also known as multiple hamartoma syndrome

====
The disease is characterised by:

mucocutaneous lesions: present in >90% of cases

gastrointestinal hamartomatous polyps (small and large bowel)

glycogenic acanthosis

thyroid abnormalities: thyroid adenomas, multinodular goitre

fibrocystic disease of the breast

testicular lipomatosis

=======
In addition to benign hamartoma formation, the syndrome carries a recognised increased risk of cancers such as:

breast cancer: develops in 30-50% of those with the syndrome

thyroid cancer: develops in 5% of those with the syndrome, usually follicular

CNS: dysplastic cerebellar gangliocytoma, occurs when in association with Lhermitte-Duclos disease (LDD)

======
Syndromic associations: group of disease known as PTEN-related diseases, which also includes:

1) Lhermitte-Duclos disease (LDD)
2) Bannayan-Riley-Ruvalcaba syndrome (BRRS)

Question 5

Gardner syndrome

Inheritance?
Features?
Associated cancers?

Answer 5

Polyposis syndrome. Autosomal dominant inheritance in the FAP gene (chromosome 5q) in a majority of patients but with 20% of cases resulting from new mutations. Extracolonic features often precede the diagnosis of colonic polyps.

It is characterised by:

familial adenopolyposis
multiple osteomas: especially of the mandible, skull, and long bones
epidermal cysts
fibromatoses
desmoid tumours of mesentery and anterior abdominal wall

Other abnormalities include:

supernumerary teeth, odontomas and dentigerous cysts
duodenal tumours / ampullary carcinoma
papillary thyroid carcinoma

Question 6

von Hippel-Lindau

Inheritance pattern?
Associated features?

Answer 6

ABDO

due to mutations in the VHL tumour suppressor gene on chromosome 3.
Autosomal dominant inheritance with high expression and penetrance; ~80% of cases occur via this pathway with ~20% arising de novo

HIPPEL
Mnemonic:
H: haemangioblastoma of CNS
I: increased risk of renal cell cancer
P: phaeochromocytoma
P: pancreatic lesions (cyst, cystadenoma, cystadenocarcinoma, neuro-endocrine tumours)
E: eye and ear dysfunction (retinal haemangioblastoma, endolymphatic sac tumours)
L: liver and renal cysts

RENAL (>67% of patients)
- renal cell carcinomas (RCCs): usually clear cell, frequently bilateral, 70% lifetime risk, RCC present at an earlier age (mean = 39 years)
- renal cysts: 75%, often bilateral and multiple, can be simple, complex or cystic renal cell carcinoma
- renal angiomyolipomas

ADRENAL
- phaeochromocytomas: 25-30% of patients
- extra-adrenal phaeochromocytoma / paraganglioma: 15%

PANCREAS (may be the earliest manifestation)
- pancreatic cysts: ~40% of patients
- pancreatic neuroendocrine tumours (pNET) and pancreatic serous cystadenoma: ~12.5% of patients
- pancreatic adenocarcinoma: rare

LIVER
- liver cysts

=========
Urogenital
=========
- epididymal cysts
- papillary cystadenoma of the epididymis: ~35%
- broad ligament cystadenomas

====
CNS
====
- CNS haemangioblastomas: ~70% of patients: cerebellar (~60%; range 44-72%), spinal cord (~30%; most commonly in the cervical and thoracic cord)

• choroid plexus papilloma

=============
Head and neck
=============
- retinal haemangioblastomas
- endolymphatic sac tumours (ELST): bilateral in 30%; considered pathognomonic for vHL

Question 7

Multiple endocrine neoplasia - type 1

+ ?genetics

+associations

Answer 7

PPP or PiParPanc

Autosomal dominant genetic disease

===Pituitary adenoma===
prolactinoma (most common)

===Pancreatic neuroendocrine tumours===
gastrinoma (most common: >50%), followed by insulinoma (4-6%), and glucagonoma (<3%)

===Parathyroid proliferative diseases===
- parathyroid hyperplasia (most common): hyperparathyroidism (80-95%)
- parathyroid adenoma
- parathyroid carcinoma (rare)

Genetics
The abnormality is related to MEN1, a tumour suppressor gene located on chromosome 11q13 which produces menin, a nuclear protein important for the regulation of gene expression.

Associations
Numerous other lesions are encountered with greater frequency in patients with MEN1:

lipomas
angiofibromas
adrenal cortical lesions
adrenal adenomas
adrenocortical hyperplasia
cortisol-secreting adenomas
adrenal carcinomas (rare)
carcinoid tumours
hepatic focal nodular hyperplasia
breast carcinoma
meningiomas

Question 8

Multiple endocrine neoplasia - type 2A

Answer 8

PMP
AD

===Phaeochromocytomas===
50% of patients, often bilateral, and can be extra-adrenal

===Medullary thyroid cancer===
100% of patients, aggressive, and may secrete calcitonin

===Parathyroid hyperplasia===
Only seen in 20% of patients, and often presents with hypercalcaemia and renal calculi

Genetics
A small proportion of individuals have a RET D631 proto-oncogene mutation. RET mutation is different from the RET translocation in papillary thyroid carcinoma. The chromosome locus is 10q11.2. 3

Question 9

Multiple endocrine neoplasia - type 2B

Answer 9

PMMM
AD

===Phaeochromocytoma(s)===
in 50% of patients, often bilateral, and can be extra-adrenal

===Medullary thyroid cancer===
100% of patients; aggressive, and may secrete calcitonin

===Mucosal neuroma(s) / ganglioneuroma(s)===

===Marfanoid habitus===

Question 10

Carney triad vs Carney complex vs Carney-Stratakis syndrome

Answer 10

Carney Complex has Cardiac findings (myxoma).

Associate “T” in GIST with Carney Triad; “X” in MyXoma can be associated with Carney compleX

==CARNEY COMPLEX==
multiple endocrine neoplasia syndrome characterised by:

1. cardiac myxoma
   often multiple, seen in two-thirds of patients with Carney complex
2. skin pigmentation (blue naevi): especially of the face, trunk, lips, and sclera

Multiple other features are also well recognised including:

extracardiac myxoma
breast
testis
thyroid
brain
adrenal gland: primary pigmented nodular adrenocortical disease (PPNAD)
pituitary adenoma
malignant melanotic nerve sheath tumour
testicular tumours
Sertoli cell tumours: most common
osteochondromyxoma

===CARNEY TRIAD===
is a rare syndrome defined by the coexistence of three tumours:

1. extra-adrenal paraganglioma
   initially, only functioning extra-adrenal paragangliomas were included, but subsequent work includes non-functioning extra-adrenal paragangliomas 1
2. gastric gastrointestinal stromal tumours (GIST)
3. pulmonary chondroma

In most cases, only two of the three tumours are present at the time of diagnosis, with the most common combination being GIST and pulmonary chondromas. Although not considered part of the triad, there is an increased incidence of adrenocortical adenoma, phaeochromocytoma, and oesophageal leiomyoma. It typically affects young people, with a female predilection. No underlying genetic mutation has been identified

====
Carney-Stratakis syndrome is a rare autosomal dominant condition comprising of familial paraganglioma and gastrointestinal stromal tumour (GIST).
====

Question 11

Klippel-Trenaunay syndrome

Answer 11

very rare congenital disorder that is characterised by a triad of venous malformations, cutaneous capillary malformations, and limb overgrowth. It is considered an angio-osteo-hypertrophic syndrome.

Clinical presentation
Klippel-Trénaunay syndrome classically comprises a triad of:

cutaneous capillary malformations: port wine naevi

limb overgrowth: bony or soft tissue hypertrophy of an extremity (localised gigantism)

varicose veins or venous malformations of unusual distribution

The diagnosis of Klippel-Trénaunay syndrome is usually made when any two of the three features are present. Patients usually present in infancy. Features are often unilateral and typically affect one limb 2; capillary malformations may be absent in the atypical form 14. It may be diagnosed in utero 11.

Hypertrophy
Enlargement of the extremity consists of bone elongation, circumferential soft-tissue hypertrophy or both. This often manifests as leg-length discrepancy, although any limb may be affected. Hyperostosis frontalis interna has also been associated with Klippel-Trénaunay syndrome 23.

Capillary malformations
This is the most common cutaneous manifestation of Klippel-Trénaunay syndrome. Typically, capillary malformations involve the enlarged limb, although skin changes may be seen on any part of the body. The lower limb is the affected site in ~95% of patients.

Varicose veins
Present in a majority of patients with Klippel-Trénaunay syndrome, commonly located on the lateral aspect of the affected limb/leg 18 (and in some contradiction to common vena-saphena-magna varicosity). There may be persistence of embryonic veins, of which the lateral marginal vein (the vein of Servelle) has been the most typical finding (68-80% of patients) 22.

Venous malformations can occur in both the superficial and deep venous systems. Superficial venous abnormalities range from ectasia of small veins to persistent embryological veins and large venous malformations. Deep venous abnormalities include aneurysmal dilatation, aplasia, hypoplasia, duplications, and venous incompetence.

Visceral manifestations
Rectal and bladder haemorrhage are serious complications of pelvic vascular malformations and have been reported in 1% of cases 10. Vascular malformations can involve the:

gastrointestinal tract (20%)

bleeding is the most common symptom and range from occult bleeding to massive, life-threatening haemorrhages and consumptive coagulopathy

the most frequently reported sites are the distal colon and rectum

upper gastrointestinal bleeding from jejunal haemangiomas may also occur 19

genitourinary tract

involved in more severe cases

the absence of severe limb varicosities or venous malformations does not preclude the presence of pelvic involvement

gross haematuria, which is recurrent and painless, is usually the first clinical sign of bladder involvement and frequently manifests early in life

renal hypertrophy and venous enlargement may occur ipsilaterally to the affected side 15

vascular malformations are often located on the anterior bladder wall and dome

the trigone and bladder neck are rarely involved

genital lesions usually do not cause clinical problems for patients with Klippel-Trénaunay syndrome; however, some patients who report erectile dysfunction have abnormal penile veins

spleen

splenic haemangiomas may occur 7,20

Skeletal manifestations
These are usually secondary to leg-length difference 13:

ipsilateral hip dislocation

scoliosis

The name Klippel-Trénaunay-Weber syndrome is misleading as the current consensus uses two different names to denote two different syndromes. However, they are not always consistently addressed as distinct entities in the literature:

Klippel-Trénaunay syndrome is used in this article, whenever possible

Parkes Weber syndrome with true arteriovenous (AV) shunting

Question 12

Sturg-Weber syndrome

Associations?

Answer 12

Sturge-Weber syndrome, or encephalotrigeminal angiomatosis, is a phakomatosis characterised by facial port wine stains and pial angiomas.

It is part of a wide spectrum of possible phenotypes included in the cerebrofacial arteriovenous metameric syndrome (CAMS).

Associations
- coarctation of aorta
- paragangliomas

Mnemonics
STURGE CAPS
S: seizures, sporadic
T: tram-track gyriform calcification; trigeminal territory port-wine stain
U: unilateral weakness (hemiparesis contralateral to facial naevus)
R: retardation
G: glaucoma, GNAQ gene
E: epilepsy
C: calvarial thickening, choroid plexus enlargement
A: atrophy of ipsilateral cerebral hemisphere
P: pial angiomatosis
S: sinus (paranasal) enlargement

8 Cs
congested veins in pial angiomatosis
cerebral atrophy
cortical tram track calcification
cavernous sinus enlargement
choroid plexus enlargement
calvarial thickening
choroidal haemangioma in the eye
cutaneous port-wine stain

Question 13

PHACE syndrome

Epidemiology?

Answer 13

also known as cutaneous haemangioma–vascular complex syndrome or Pascual-Castroviejo type II syndrome, is a phakomatosis that comprises of:

P: posterior fossa malformations (e.g. Dandy-Walker malformation)

H: haemangiomas

A: arterial anomalies

C: coarctation of the aorta and cardiac anomalies

E: eye (ocular) anomalies

When sternal clefting and/or supraumbilical raphe are also present it is termed PHACES syndrome.

==Epidemiology==
PHACE syndrome is nine times more common in females

================
Clinical presentation
================

Clinical diagnosis of PHACE syndrome requires the presence of a characteristic segmental haemangioma or haemangioma >5 cm on the head (face or scalp) plus 1 major criterion or 2 minor criteria

Major criteria anomalies:

==arterial==

anomaly of major cerebral / cervical arteries (ICA, ACA, MCA, PCA, vertebral, basilar)

dysplasia of the large cerebral arteries (tortuosity, kinking, dolichoectasia)

arterial stenosis or occlusion with or without moyamoya collaterals

absence or moderate-severe hypoplasia of the large cerebral arteries

aberrant origin or course of the large cerebral arteries (except common aortic arch variants such as bovine aortic arch)

persistent carotid-vertebrobasilar anastomosis (persistent trigeminal, hypoglossal, proatlantal, or otic)

==structural brain==

posterior fossa anomalies

Dandy-Walker complex

midbrain/hindbrain hypoplasia/dysplasia

==ocular==

posterior segment anomalies

persistent hyperplastic primary vitreous

persistent fetal vasculature

retinal vascular anomalies

morning glory disc anomaly

optic nerve hypoplasia

peripapillary staphyloma

==cardiovascular==

aortic arch anomalies (except common variants such as bovine arch)

aortic coarctation

aberrant origin of subclavian artery

aortic aneurysm

==ventral or midline==

sternal defects or supraumbilical raphe

============
Minor criteria:

arterial:

intracranial aneurysm

structural brain:

midline anomalies

cortical malformations

ocular:

anterior segment anomalies

sclerocornea

cataract

coloboma

microphthalmia

cardiovascular:

ventricular septal defect

right aortic arch / double aortic arch

systemic venous anomalies

ventral or midline:

hypopituitarism

ectopic thyroid

sternal papule/hamartoma

Question 14

Neurofibromatosis type 1

Criteria + genetics

Answer 14

also known as von Recklinghausen disease, is a multisystem neurocutaneous disorder, the most common phakomatosis, and a RASopathy. Additionally, it is also one of the most common inherited CNS disorders, autosomal dominant disorders, and inherited tumour syndromes.

The NF1 gene locus is on chromosome 17q11.2 and the gene product is neurofibromin, which acts as a tumour suppressor of the Ras/MAPK pathway;

==Clinical presentation==
As is the case with many phakomatoses, NF1 results in a variety of abnormalities of variable severity. To make the clinical diagnosis two or more of the following are required 2:

≥2 neurofibromas or ≥1 plexiform neurofibroma

optic nerve glioma

distinctive osseous lesion (such as sphenoid wing dysplasia or thinning of long bone cortex with or without pseudoarthrosis)

> 6 café au lait spots evident during one year (prepubertal >0.5 cm, postpubertal >1.5 cm in size)

axillary or inguinal freckling

≥2 iris hamartomas (Lisch nodules)

a primary relative with NF1

A mnemonic to help remember these features is CAFE SPOT.

In addition, ~45% (range 30-60%) of patients have learning disabilities, and approximately 1% have hypertension due to renal artery stenosis.

It is important to consider that NF1 has a much earlier age of onset than schwannomatosis and NF2, with approximately 50% of patients meeting the diagnostic criteria for NF1 by the age of 1 year and approximately 97% meeting the criteria by the age of 8 years

Question 15

Neurofibromatosis type 1: Associated neoplasms

Answer 15

phaeochromocytoma

malignant peripheral nerve sheath tumour (MPNST) (~10% of patients)

Wilms tumour

rhabdomyosarcoma

renal angiomyolipoma

glioma
juvenile pilocytic astrocytoma (~20% of patients)
optic nerve glioma
diffuse brainstem glioma
spinal astrocytoma and spinal pilocytic astrocytoma

carcinoid tumour(s)

leiomyoma(s)

leiomyosarcoma

ganglioglioma

leukaemia

Question 16

Neurofibromatosis type 2

+genetics

Answer 16

Neurofibromatosis type 2 (NF2) is a rare autosomal dominant neurocutaneous disorder (phakomatosis) manifesting as a development of multiple CNS tumours. Unlike neurofibromatosis type 1 (NF1), it is not associated with neurofibromas. Instead, patients with this disease have:

intracranial schwannomas: mostly vestibular schwannomas, however sometimes patients may have spinal schwannomas

intracranial and spinal meningiomas

intraspinal-intramedullary ependymomas

======
The NF2 gene is located on the long arm of chromosome 22 (22q12) and encodes the merlin protein (also known as “schwannomin”)

Question 17

Fibrous dysplasia

?Locations
?Associated syndromes

Answer 17

The condition is often an incidental finding and is usually painless. Alternatively, it may present with bony expansion and remodelling or with pain.

Monostotic form
The monostotic form is far more common accounting for 70-80% of cases and is usually asymptomatic until the 2nd to 3rd decade but can be seen throughout adulthood 7. After puberty, the disease can become inactive.

Polyostotic form
The polyostotic form accounts for 20-30% and presents earlier, typically in childhood with about 60% showing symptoms before the age of 10 years 2.

Associations

1. McCune-Albright syndrome: in 2-3% of cases with the polyostotic form
2. isolated endocrinopathy without the full McCune-Albright syndrome precocious puberty in girls

hyperthyroidism, hyperparathyroidism: renal stones, calcinosis, acromegaly, diabetes mellitus, Cushing syndrome: osteoporosis, acne, growth retardation

3. Mazabraud syndrome: soft-tissue myxomas (rare); typically multiple intramuscular lesions in the vicinity of most severely affected bone

=========
Location
=========

ribs: 28%, most common
proximal femur: 23%
tibia
craniofacial bones: 10-25%
humerus

often unilateral and monomelic: one limb
femur: 91%
tibia: 81%
pelvis: 78%
foot: 73%
ribs
skull and facial bones: 50% 9
upper extremities
lumbar spine: 14%
clavicle: 10%
cervical spine: 7%

Question 18

Erdheim-Chester disease

Answer 18

Radiographic features

rare non-Langerhans cell, non-familial multisystemic histiocytosis, with widespread manifestations and of highly variable severity. The most common presenting symptom is bone pain.

Musculoskeletal involvement is most common, with multifocal extraskeletal involvement seen in 30-50% of patients

bilateral, symmetric metaphyseal and diaphyseal sclerosis
increased uptake on Tc-MDP bone scan
cortical thickening

lung

can appear similar to Langerhans cell histiocytosis with predominantly cystic disease, septal thickening and preserved lung volume
chest radiographs will often show interstitial oedema pattern (interlobular septal thickening) with cardiomegaly and pleural effusions that do not respond to diuretics

kidneys and retroperitoneum

often involved
usually asymptomatic
hairy kidney sign: irregular symmetric infiltration of the bilateral perirenal and posterior pararenal spaces
coated aorta sign: periaortic soft tissue
inferior vena cava and pelvic ureters are typically spared, which are useful cross-sectional imaging findings for differentiation of retroperitoneal Erdheim-Chester disease from retroperitoneal fibrosis

skin

retro-orbital tissue

optic nerve oedema
retrobulbar masses that can cause proptosis and motility impairment
retrograde extension along the optic nerve to the hypothalamus may explain the distribution of brain involvement

heart, pericardium and aorta

Intracranial involvement of the dura, brain and pituitary are rare

meninges
dural accumulations may mimic meningiomas, with enhancing soft tissue masses
T2 signal characteristics are somewhat different, as the accumulations in Erdheim-Chester disease are hypointense
brain: usually affecting the hypothalamus intraparenchymal masses in ECD appear non-specific
pituitary infundibulum: presenting with diabetes insipidus

Question 19

Thalassaemia

Description, inheritance etc

Imaging features

Answer 19

autosomal recessive haemoglobinopathy
Thalassaemia is a quantitative problem of globin synthesis, whereas sickle cell disease is a qualitative problem of synthesis of an incorrectly functioning globin.

Protective from malaria

Normal adult haemoglobin is composed of HbA (98%) and HbA2 (2%). HbA contains two α globin chains and two β globin chains, and HbA2 contains two α globin chains and two δ globin chains. They are arranged into a heterotetramer. Thalassaemia patients produce a deficiency of either α or β globin, unlike sickle cell disease, which produces a specific mutant form of β globin.

IMAGING

Skeletal
Ineffective haematopoiesis results in severe anaemia that in turn leads to an increase in erythropoietin. This increase results in an expansion of the bone marrow by a factor of up to 15 to 30.

Conversion of yellow to red marrow occurs and in patients with uncontrolled disease marrow expansion results in an enlargement of the medullary space and thinning of cortical bone

General features
osteoporosis and osteopenia
extramedullary haematopoiesis may appear as lobulated masses covering the anterior or posterior segments of the ribs on chest x-ray; extramedullary haematopoiesis is also more frequently seen in the posterior mediastinum compared to the anterior mediastinum or the pelvis
growth retardation
hair-on-end appearance (classic): unusual in patients after the age of nine in treated patients
widening of the diploic space
thinning of the inner and outer table
the occipital bone is spared, due to a lack of hemopoietic bone marrow

Facial bones
rodent or chipmunk facies due to lateral displacement of the orbits (hypertelorism) with maxillary protrusion and ventral displacement of the incisors
hypopneumatisation of the frontal, maxillary, and sphenoid sinuses, filled with marrow containing bone
the ethmoid sinuses are spared due to lack of red bone marrow
dental malocclusion

Ribs
expansion of the ribs: especially at the costovertebral junctions
rib-within-a-rib appearance, noted particularly in the middle and anterior portions of the ribs

Spine
an initial increase in height to width ratio of vertebral bodies
gradual loss of height and biconcavity secondary to compression fractures
severe degree of medullary expansion can cause compression of the spinal cord in the thoracic region
scoliosis

Extremities
widening/expansion of the metacarpal and metatarsal shafts
premature fusion of the epiphyses
reduce longitudinal growth of long bones (humerus more than femur)
loss of concave shape in the long bones resulting in a convex shape
coarsening of the trabecular bone with cyst-like lucencies leading to a “worm-eaten” appearance
enlargement of nutrient foramina due to the activity of hyperplastic marrow
Erlenmeyer flask deformity
Harris lines

Gastrointestinal/hepatobiliary
cholelithiasis
haemosiderosis
splenomegaly
Lungs
diffusion impairment
air-trapping

Question 20

Sickle cell disease

Answer 20

autosomal recessive condition resulting in the formation of abnormal haemoglobin (a haemoglobinopathy), which manifests as multisystem ischaemia and infarction, as well as haemolytic anaemia.

Extramedullary haematopoiesis: Less common in sickle cell disease than in other haemolytic anaemias. The most common site is liver, followed by spleen, thorax, and adrenals

SKELETAL
==vaso-occlusive crises==

= osteonecrosis

bone infarcts typically involve medullary cavities and epiphyses
the proximal humeri, proximal femora, and vertebral bodies are often affected
in the humeri, serpiginous sclerosis is characteristic of infarction

vertebral infarcts may result in
H-shaped vertebrae
tower vertebra
vanishing vertebra
anterior vertebral vascular notches

= subperiosteal and epidural haemorrhage

= hand-foot syndrome (dactylitis)

= growth disturbance

==chronic anaemia==

marrow hyperplasia

long bones: widening of medullary spaces and thinning of cortical bone

skull: widening of diploic space, thinning of the outer table, hair-on-end appearance

osteopenia and pathological fractures

extramedullary haematopoiesis

red marrow reconversion

==infection==
osteomyelitis

==osteosclerosis==

ABDOMINAL
Splenic infarction and subsequent functional asplenia tend to occur early in the disease. The hepatobiliary and renal systems (sickle cell nephropathy) are also commonly involved.

Splenic
splenomegaly
may occur transiently with the sequestration syndrome, where rapid pooling of blood occurs in the spleen, resulting in intravascular volume depletion, with potential for cardiovascular collapse
autosplenectomy
the slow, tortuous micro-circulation of the spleen renders it susceptible to infarction and subsequent functional asplenia
94% are asplenic by age 5
radiological finding is of a small, calcified spleen
splenic abscesses

Hepatobiliary
hepatic iron deposition secondary to multiple transfusions
hepatomegaly +/- coarsened echotexture with portal hypertension
cholelithiasis +/- choledocholithiasis
multiple liver abscesses

Renal
kidneys are often large early in the disease, with variable echogenicity on ultrasound, but shrink with development of renal failure. Bilateral echogenic pyramids are frequently seen in sickle cell disease
renal papillary necrosis
renal vein thrombosis

Gastrointestinal tract
approximately 40% of patients may develop peptic ulcers due to reduced mucosal resistance and bowel ischaemia
girdle syndrome: acute circumferential abdominal pain of vaso-occlusive aetiology

==CNS==
intracranial ICA stenosis and occlusion results in moyamoya
moyamoya syndrome
cerebral atrophy, most common
cerebral ischaemia
chronic small vessel ischaemia
cortical infarcts
cerebral fat emboli from bone marrow necrosis (starfield pattern)
predilection for aneurysms and subsequent intraparenchymal or subarachnoid haemorrhage
PRES 5
spontaneous epidural haematoma (rare)

Question 21

Multiple pulmonary AVM, brain abscess

?condition

Answer 21

Hereditary haemorrhagic telangiectasia (HHT) aka Osler-Weber-Rendu syndrome

=========
nasal: 90%
=========
telangiectasias of nasal mucosa
complications: recurrent epistaxis

============================
skin and mucosal membranes: 90%
============================
telangiectasias of skin, oral cavity, conjunctivae
complications: recurrent bleeding

==========
liver: 71-79%
===========
typically arteriovenous or portovenous shunts
hepatomegaly, right upper quadrant pain, high-output cardiac failure, portal hypertension, mesenteric angina from steal phenomenon

=======================
gastrointestinal tract: 20-40%
=======================
AVMs or angiodysplasia in the stomach, small bowel or large bowel

===========
pulmonary:
===========
pulmonary arterio-venous malformations (AVMs)
36% of patients with solitary pulmonary AVM have HHT
57% of patients with multiple pulmonary AVMs have HHT
complications
pulmonary haemorrhage, haemoptysis (less common)
complications of shunting (more common): paradoxical emboli (due to right to left shunt, e.g. stroke), septic emboli (e.g. cerebral abscess), hypoxaemia, high-output cardiac failure

===========
CNS: 5-10%
===========
cerebral AVMs, spinal AVMs or cerebral aneurysms
complications: headache, seizures, paraparesis, haemorrhage
one-third of cerebral complications in HHT are due to cerebral AVMs or aneurysms, and two-thirds are due to paradoxical emboli from pulmonary AVMs
increased incidence of capillary telangiectasia and developmental venous anomalies

Question 22

Holt-Oram syndrome

Answer 22

Holt-Oram syndrome (“heart-hand syndrome”) classically has cardiac and bilateral upper extremity anomalies without the gastrointestinal or vertebral anomalies

==congenital heart defects==
atrial septal defect (ASD) (commonest cardiac defect 4)
ventricular septal defect (VSD)

==aortic coarctation==

==upper limb abnormalities==
radial ray anomalies, e.g. radial aplasia, radial hypoplasia, radial fusion
thumb anomalies, e.g thumb aplasia
carpal coalition

==phocomelia==
shortening of the proximal to mid portions of the limbs

==clavicle hypoplasia==

Question 23

Phaeochromocytoma

?associated conditions
?imaging features

Answer 23

The majority of cases are sporadic. In 25% of cases, a phaeochromocytoma is a manifestation of an underlying condition, often familial, including

• multiple endocrine neoplasia type II (MEN2): both MEN IIa and MEN IIb

account for 3% of all phaeochromocytomas
almost never extra-adrenal
almost always bilateral

• von Hippel-Lindau disease
• neurofibromatosis type 1
• Sturge-Weber syndrome
• Carney triad: for extra-adrenal phaeochromocytoma
• tuberous sclerosis
• familial phaeochromocytoma

==IMAGING==

==
CT
==

usually large (4-6 cm), heterogeneous masses with areas of necrosis and cystic change 21,22

density always >10 HU 22

they typically enhance avidly

one-third may wash out similar to an adrenal adenoma, but they tend to have a greater enhancement in an arterial or portal venous contrast phase, however, overlap with some hyperenhancing adenomas

tend to enhance more on the portal venous phase than the arterial phase

110-120 HU of enhancement on the arterial phase suggests phaeochromocytoma, but is not specific; hypervascular metastases could be considered in an appropriate setting

10% (range 7-12%) demonstrate areas of calcification

===
MRI
===

MRI is the most sensitive modality for the identification of phaeochromocytomas and is particularly useful in cases of extra-adrenal location. The overall sensitivity is said to be 98%

T1

slightly hypointense to the remainder of the adrenal

if necrotic and/or haemorrhagic then the signal will be more heterogeneous

T2

some are markedly hyperintense (lightbulb sign)

~1/3 do not have marked T2 hyperintensity

areas of necrosis/haemorrhage/calcification will alter the signal

in/out-of-phase: no signal loss on out-of-phase imaging (phaeochromocytomas rarely contain a significant amount of intracellular lipid)

T1 C+ (Gd)

heterogeneous enhancement

enhancement is prolonged, persisting for as long as 50 minutes

Question 24

Phaeochromocytoma

Locations and rules of 10

Answer 24

They most frequently arise from the chromaffin cells of the adrenal medulla.

Approximately 10% of all phaeochromocytomas are not located in the adrenal glands. Extra-adrenal tumours are more likely to be malignant and metastasise

They can be found along the sympathetic chain as well as in the urinary bladder and organ of Zuckerkandl. Thoracic paragangliomas are rare and only account for 1-2% of all cases of phaeochromocytoma.

~10% are extra-adrenal

~10% are bilateral

~10% are malignant

~10% are found in children

~10% are not associated with hypertension

~10% contain calcification

Question 25

Meckel-Gruber syndrome

Answer 25

renal cystic dysplasia: multiple renal cysts (present in most cases)

occipital encephalocele / holoprosencephaly (~70%)

postaxial polydactyly: usually hexadactyly (~65%)
- polydactyly also associated with trisomy 13

Additional hepatic developmental defects and hepatic fibrosis may occur. A variety of malformations may be associated with this syndrome but most agree that cystic renal dysplasia must be present with at least one of the other two anomalies in the classic “triad”.

====
Pathology
Meckel-Gruber syndrome shares some features with trisomy 13 and is therefore also termed pseudotrisomy 13 1. Karyotyping is recommended if the above triad is seen on antenatal scanning.

Markers
elevated maternal alpha-fetoprotein (MSAFP)

Treatment and prognosis
The condition is almost always fatal at birth either because of pulmonary hypoplasia or neonatal renal failure. Parents can be counselled appropriately that the subsequent risk is 25%.

Question 26

Choanal atresia associated syndromes and conditions

Answer 26

Syndromic associations include

CHARGE syndrome

Crouzon syndrome

DiGeorge syndrome

amniotic band syndrome

fetal alcohol syndrome

Treacher Collins syndrome

Other associations include

intestinal malrotation

craniosynostosis

congenital heart disease

Question 27

Alport syndrome

Answer 27

Alport syndrome is an X-linked dominant disease characterised by progressive sensorineural hearing loss, renal disease and, at times, ocular lesions.

Clinical presentation

haematuria

sensorineural hearing loss: typically high frequency

ocular abnormalities
-anterior lenticonus: most common ocular abnormality; may result in cataracts
-perimacular pigmentary changes
-flecks around the fovea

multiple leiomyomas
-oesophagus
-tracheobronchial tree
-female genitalia
-the presence of calcification is highly suggestive of
esophageal leiomyoma

Pathology
It is the result of a mutation in collagen type IV, which is found in the basement membrane of the glomerulus, the cochlea, and the eye.

Question 28

22q11.2 deletion syndrome, also known as the DiGeorge syndrome

Answer 28

Associations
Mondini malformation
choanal atresia

Clinical presentation
CATCH 22 is the mnemonic to remember the chromosome and all the abnormalities.

​Mnemonic
C: congenital heart disease (particularly conotruncal anomalies)
A: abnormal facies (hypertelorism, low set ears, short philtrum, among others)
T: thymic hypoplasia
C: cleft palate/cellular immune deficiency
H: hypoparathyroidism with hypocalcaemia
22: deletion located on chromosome 22

PRESENTATION
cleft lip +/- palate

congenital heart disease (particularly conotruncal anomalies): often a major part of this syndrome, tetralogy of Fallot, interrupted aortic arch, truncus arteriosus

characteristic facies: elongated face, short philtrum, facial asymmetry, prominent nose

choanal atresia

hypernasal speech

learning disabilities

decreased immunity

malformation of third and fourth pharyngeal pouches that result in the defective development of the parathyroid and thymus which can, in turn, lead to: hypoparathyroidism, hypocalcaemia

Question 29

Solitary fibrous tumour of the thorax

Associations/paraneoplastic conditions

Answer 29

Associations
hypoglycaemia (2-4%): thought to be due to the production of insulin-like growth factor 2 (known as Doege-Potter syndrome)

hypertrophic pulmonary osteoarthropathy (~20%): thought to be due to abnormal production of hyaluronic acid
asbestos exposure is not an association

====
Path= well-circumscribed mass; spindled to ovoid cells arranged around a branching and hyalinized vasculature; variable stromal collagen deposition

Question 30

Castleman disease

Answer 30

The most common presentation of Castleman disease is
an enhancing hypervascular mediastinal mass (70%).

Lymphadenopathy in Castleman disease may show
increased metabolic activity, similar to lymphomas and
metastatic lymphadenopathy.

group of benign lymphoid disorders characterized by abnormally enlarged lymph nodes.
* The etiology of Castleman disease is not known, but
both HIV and human herpesvirus type 8 (HHV-8)
infection have been associated with this condition.
* Depending on the anatomic regions affected, the
disease can be classified as unicentric or multicentric.
In unicentric Castleman disease (UCD), one single
abnormally enlarged lymph node or a single region
of affected lymph nodes is present (neck, chest, or
abdomen). In multicentric Castleman disease (MCD),
multiple anatomic regions of groups of lymph nodes
are involved.
* There are two subtypes of MCD: one associated with
HHV-8; and another form considered idiopathic,
in which affected patients are negative for HHV-8.
Patients with MCD who are positive for HHV-8 and
HIV are typically male (90%) and have a high incidence
of Kaposi sarcoma (60%), lymphoma (10%), and
increased mortality.

Question 31

Retroperitoneal fibrosis aetiology

and other IgG4 patologies

Answer 31

is a condition that has previously been described as chronic periaortitis. It is an uncommon fibrotic reaction in the retroperitoneum that typically presents with ureteric obstruction.

Aetiology

idiopathic: Ormond disease (70% benign)

radiation

medication
-hydralazine
-beta-blockers:non-selective e.g. propranolol, β1-selective e.g. metoprolol
-methyldopa and dopamine agonists e.g. pergolide
-ergot derivatives: ergotamine, methysergide
- NSAIDs

inflammation: pancreatitis, pyelonephritis, immune-mediated (e.g. IgG4-related disease)

malignant: desmoplastic reaction, lymphoma

prolonged exposure to asbestos

retroperitoneal bleeding, e.g. after trauma or medical procedure

IgG4:
central nervous system
IgG4-related hypertrophic pachymeningitis
IgG4-related hypophysitis
chronic subdural haemorrhage

head and neck
sialadenitis/chronic sclerosing sialadenitis (Küttner tumour)
Riedel thyroiditis
IgG4-related orbital disease
pansinusitis

thoracic
interstitial pneumonia/IgG4-related lung disease
fibrosing mediastinitis
IgG4-related cardiovascular disease
IgG4-related coronary disease

abdominopelvic
autoimmune pancreatitis
sclerosing cholangitis
sclerosing mesenteritis
cholecystitis
IgG4-related renal diseases: tubulointerstitial nephritis
retroperitoneal fibrosis
inflammatory aortic aneurysm
​prostatitis
gastrointestinal: colorectal

multisystem
inflammatory pseudotumours, e.g. presenting as paravertebral masses
lymphadenopathy

Question 32

Fibrous dysplasia

associations?

Answer 32

==associations==
McCune-Albright syndrome: in 2-3% of cases with the polyostotic form : precocious puberty, multiple cafe au lait spots, polyostotic fibrous dysplasia

Mazabraud syndrome: soft-tissue myxomas (rare); typically multiple intramuscular lesions in the vicinity of most severely affected bone

=====
Monostotic form
ribs: 28%, most common
proximal femur: 23%
tibia
craniofacial bones: 10-25%
humerus

Polyostotic form
often unilateral and monomelic: one limb
femur: 91%
tibia: 81%
pelvis: 78%
foot: 73%
ribs
skull and facial bones: 50%
upper extremities
lumbar spine: 14%
clavicle: 10%
cervical spine: 7%

Question 33

Gorlin-Goltz syndrome

Answer 33

Also known as the basal cell naevus syndrome, nevoid basal cell carcinoma syndrome, or just Gorlin syndrome, is a rare phakomatosis characterised by multiple odontogenic keratocysts (OKC), multiple basal cell carcinomas (BCC) and other abnormalities.

==============
- multiple basal cell carcinomas, often at puberty and in adolescence

• craniofacial anomalies
  odontogenic keratocysts, often multiple
  frontal bossing
  hypertelorism: 5%
  macrocephaly
  calcified falx cerebri
  calcified tentorium and petroclinoid ligaments
  cleft lip
  ocular defects including:coloboma of the iris, microphthalmia
  bridging of the sella turcica
  high arched palate
  agenesis of the corpus callosum (occurs in ~10% of cases)
• musculoskeletal anomalies
  shortened 4th metacarpal bones
  bifid rib or other rib abnormality (fusion, partial agenesis, etc.)
  palmar and plantar pitting: defects of basal cell maturation
• neoplasms/hamartomas
  medulloblastoma: especially in males (M:F ~3:1)
  calcified ovarian fibroma
  lymphomesenteric cysts
  fetal rhabdomyoma
  cardiac fibroma(s)

Question 34

Cronkhite-Canada syndrome

Answer 34

Cronkhite-Canada syndrome is a type of non-neoplastic, non-hereditary hamartomatous polyposis syndrome characterised by rash, alopecia, and watery diarrhoea.

Question 35

Beckwith- Wiedemann syndrome

Associated cancers?

Answer 35

macroglossia: most common clinical finding
ear pits or creases
omphalocele
localised gigantism / macrosomia
lateralised overgrowth (hemihypertrophy)
cardiac anomalies
pancreatic islet cell hyperplasia
organomegaly: hepatosplenomegaly and nepromegaly

malignancies:
Wilms tumours
hepatoblastoma
neuroblastoma
rhabdomyosarcoma
adrenocortical carcinoma
gonadoblastoma
pancreatoblastoma