1. Imaging of genetic diseases.
Dr/ ABD ALLAH NAZEER. MD.

2. Genetic diseases
Classification:
• 4 groups of genetic diseases
• 1. Disorders with multifactorial inheritance
(polygenic).
• 2. Monogenic (Mendelian) disorders.
• 3. Chromosomal aberrations.
• 4. Environmental
(Drugs, infections).

3. 1. Disorders with multifactorial
inheritance (polygenic).
• Influence of multiple genes + environmental factors
• relatively frequent
• Diabetes mellitus.
• Hypertension.
• Gout.
• Schizophrenia (Psychiatry)
• Congenital heart disease - certain forms.
• Some types of cancer (ovarian, breast, colon).
• Often familial occurrence - probability of disease is in 1st
degree relatives about 5-10%; 2nd degree relatives - 0,5-1%.

4. 2. Monogenic (Mendelian) disorders
Mutation of 1 gene, Mendelian type of inheritance
today about 5000 diseases
Autosomal dominant.
Autosomal recessive.
X-linked.
Autosomal dominant disorders.
Both homozygote's and heterozygote's are affected
usually heterozygote's (inherited from one parent)
both males and females are affected transmission
from one generation to the other 50% of children
are affected.

5. Mutations.
A mutation may be defined as a permanent change in the DNA. Mutations
that affect the germ cells are transputted to the progeny and may give rise
to inherited diseases. Mutations thar aries in somatic cells are important
in the genesis of cancers and some congeital malformations.
Mutations may be classified into three catagories:
Genome mutations – involve loss or gain of whole chromosomes (giving
rise to monosomy or trisomy).
Chromosome mutations – result from rearrangement of genetic material
and give rise to visible structural changes in the chromosome.
Gene mutations – may result in partial or complete deletion of a gene or,
more often, affect a single base. For example, a single nucleotide base
may be substituted by a different base, resulting in a point mutation.

6. Autosomal dominant disorders (neurofibromatosis, tuberous sclerosis,
polycystic kidney disease, familiar polyposis coli, hereditary
spherocytosis, Marfan syndrome, osteogenesis imperfecta,
achondroplasia, familiar hypercholesterolemia).
Autosomal recessive disorders (cystic fibrosis, phenylketonuria,
homocystinuria, hemochromatosis, sickle cell anemia, thalassemias,
alkaptonuria, neurogenic muscular atrophies).
X-linked disorders (glucose-6-phosphate dehydrogenase deficiency),
Hemophilia A (defect of Factor VIII), Hemophilia B (defect of Factor IX).
Biochemical and molecular basis of single-gene disorders.
1) Enzyme defects and their consequences.
2) Defects in receptors and transport systems.
3) Alterations in structure, function or quantity of nonenzyme proteins.
4) Genetically determined adverse reactions to drugs.

7. Disorders associated with defects in structural proteins.
Marfan syndrome: A disorder of the connective tissues of the body, manifested principally
by changes in the skeleton, eyes, and cardiovascular system.
Ehlers-Danlos syndromes: A clinically and genetically heterogeneous group of disorders
that result from some defect in collagen synthesis or structure (other disorders resulting
from mutations affecting collagen synthesis include osteogenesis imperfecta, Alport
syndrome, epidermolysis bullosa)
Disorders associated with defects in receptor proteins.
Familiar hypercholesterolemia
A disease that is the consequence of a mutation in the gene encoding the receptor for low-
density lipoprotein (LDL), which is involved in the transport and metabolism cholesterol. More
than 150 mutations, including insertions, deletions, and missense and nonsense mutations,
involving the LDL receptor gene have been identified. These can be classified into five groups:
Class I mutations - uncommon, they lead to a complete failure of synthesis of the receptor
protein. Class II mutations - common, they encode receptor proteins that accumulate in the
endoplasmic reticulum because they cannot be transported to the Golgi complex. Class III
mutations - affect the LDL-binding domain of the receptor. Class IV mutations - encode
proteins that are synthesized and transported to the cell surface efficiently, they bind LDH
normally, but the bound LDL is not internalized. Class V mutations - encode proteins that are
expressed on the cell surface, can bind LDL, and can be internalized, however, the acid-
dependent dissociation of the receptor and the bound LDL fails to occur.

8. Disorders associated with defects in enzymes.
Lysosomal storage diseases: Lysosomes contain different types of
hydrolytic enzymes, which can cleave various substrates in the acid milieu
and can be secreted. With an inherited deficiency of a functional
lysosomal enzyme, catabolism of its substrate remains incomplete,
leading to the accumulation of the partially degraded insoluble
metabolite within the lysosomes. These organells become large and
numerous giving rise to the lysosomal storage disorders. These disorders
result exclusively from mutations that lead to reduced synthesis of
lysosomal emzymes There are also other defects: Synthesis of a
catalytically inactive proteins that cross-react immunologically with
normal enzymes, so the enzyme level appear to be normal.,.defects in
post-translational processing of enzymes (example is a failure of
mannose-6-phosphate receptor), lack of an enzyme activator or protector
protein, lack of a substrate activator protein, lack of transport protein.
The lysosomal storage disorders can be divided into (1) glycogenoses, (2)
sphingolipidoses (lipidoses), (3) mucopolysaccharidoses, and (4)
mucolipidoses. Examples follow:

9. Disorders associated with defects in enzymes.
Tay-Sachs disease – GM2 gangliosidosis, hexosaminidase -subunit
deficiency,GM2 ganglioside accumulates in heart, liver, spleen etc.,
destruction of neurons, proliferation of microglia and accumulation
of lipids in phagocytes within the brain.
Niemann-Pick disease – types A and B, two related disorders with
lysosomal accumulation of sphingomyelin, deficiency of
sphingomyelinase, 80% of all cases repreents type A – the severe
infantile form with neurologic involvement, visceral accumulation of
sphingomyelin and early death within the first 3 years of life.
Gaucher disease – a cluster of autosomal recessive disorders
resulting from mutations in the gene encoding glucocerebrosidase,
the most common lysosomal storage disorder, accumulation of
glucocerebrosides, types I-III, the glucocere¨brosides accumulate
within phygocytes (Gaucher cells) throughout the body – spleen,
liver, bone marrow, lymph nodes, tonsils thymus etc.

10. Disorders associated with defects in enzymes.
Mucopolysaccharidoses (MPS) – the deficiencies of lysosomal enzymes involved in
the degradation of mucoplysaccharides (glycosaminoglycans), several clinical
variants classified from MPS I (Hurler syndrome) to MPS VII, each resulting from
the deficiency of one specific enzyme, all the MPS except one are autosomal
recessive disorders, the exception (Hynter syndrome) is an X-linked recessive
disorder, involvement of multiple organs including liver, spleen, heart, blood
vessels, joint stiffness, mental retardation.
Glycogen storage diseases – resulting from a hereditary deficiency of one of the
enzymes involved in the synthesis or sequential degradation of glycogen, 3 forms:
hepatic, myopathic, miscellaneous (deficiency of -glucosidase and lack of
branching enzymes, type II – Pompe disease and type IV, death early in life.
Alkaptonuria (Ochronosis) – an autosomal recessive disorder in which the lack of
homogentisic oxidase blocks the metabolism of phenylalanine-tyrosine at the level
of homogentisic acid, homogentisic acid accumulates in the body, it selectively
binds to collagen in connective tissues, tendons, and cartilage, these tissues have
a blue-black pigmentation (ochronosis) most evident in the ears, nose, and cheeks,
the deposits of the pigment in the articular cartilages cause the cartilage to lose
its normal structure and function resulting in osteoarthritis.

11. Disorders associated with defects in proteins that regulate cell growth
Neurofibromatosis: types 1 and 2 – two autosomal dominant disorders,
neurofibromatosis type 1 previously called von Recklinghausen disease,
neurofibromatosis type 2 previously called acoustic neurofibromatosis. Although
there is some overlap in clinical features, these two entities are genetically distinct.
Neurofibromatosis-1: The neurofibromatosis 1 gene (NF-1) has been mapped to
chromosome 17q11.2. It encodes a protein called neurofibromin, which down-
regulates the function of the p21ras oncoprotein. NF-1 therefore belongs to the family
of tumor-suppressor genes. Three major features of disorder – multiple neural tumors
(neurofibromas) dispersed anywhere on or in the body, numerous pigmented skin
lesions, and pigmented iris hamartomas, also called Lisch nodules. A wide range of
associated abnormalities has been reported in these patients – skeletal lesions like
erosive defects, scoliosis, intraosseous cystic lesions, subperiosteal bone cysts,
pseudoarthrosis of the tibia. Patients have also a twofold to fourfold greater risk of
developing other tumors (Wilm´s tumor, rhabdomyosarkoma, meningioma, optic
glioma, pheochromocytoma, chronic myeloid leukemia). There is also tendency for
reduced intelligence. Whem neurofibromas arise within gastrointestinal tract,
intestinal obstruction or bleeding may occur. A frequency about 1 in 3000.

12. Neurofibromatosis-2: an autosomal dominant disorder
in which patients develop a range of tumors – bilateral
acoustic schwannomas, multiple meningiomas, gliomas,
ependymomas of the spinal cord, and/or non-neoplastic
lesions – nodular ingrowth of Schwann´s cells into the
spinal cors, meningiomatosis, glial hamartia. Pigmented
(café au lait) spots like NF-1 are present, but Lisch nodules
are not found. The NF-2 gene, located on chromosome
22q12, is also a tumor-suppressor gene, the product of this
gene called merlin shows structural similarity to a series of
cytoskeletal proteins, but is function remains uncertain. An
frequency about 1 in 45,000.

13. Disorders with multifactorial inheritance.
Down syndrome (trisomy 21): The incidence in newborns is about 1 in 700, the
most common cause is meiotic nondisjunction of genetic material, symptoms:
the mental retardation (IQ of 25 to 50), 40% congenital heart malformations,
atresias of esophagus and small bowel, 10-fold to 20-fold increased risk of
developing acute leukemia, 100% patients after 40 years of age
haveneuropathologic changes.
Edwards syndrome (trisomy 18), Patau syndrome (trisomy 13): like Down sy.,
however, the malformations are much more severe and wide-ranging. These
infants only rarely survive beyond the first year of life.
DiGeorge syndrome (chromosome 22q11 deletion – a small deletion of band
11 on the long arm of chromosome 22): Thymic hypoplasia, congenital heart
defects, abnormalities of the palate, facial dysmorphism, developmental
delay, and variable degrees of T-cell immunodeficiency and hypocalcemia.
The molecular basis of this syndrome is not known. The similar clinical and
cytogenetic feature has velocardiofacial syndrome, which includes facial
dysmorphism (prominet nose, retrognathia), cleft palate, cardiovascular
anomalies, and learning disabilities, the immunodeficiency is less frequent.

14. Disorders with multifactorial inheritance.
Klinefelter syndrome (2 or more X chomosomes and 1 or more Y chromosomes): male
hypogonandism, eunuchoid body habitus, infertility, cryptorchidism, hypospadias, skeletal
changes.
XYY syndrome: Individuals are excessively tall, may be susceptible to severe acne, the
intelligence is in the normal range, only 1-2% of individuals exhibit deviant behavior.
Turner syndrome (complete or partial monosomy of the X chromosome): hypogonandism
with female phenotype, short body, webbing of neck, heart anomalies, infertility,
amenorrhea, pigmented nevi, peripheral lymphedema at birth.
Single-gene disorders with nonclassic inheritance.
Diseases caused by triplet-repeat mutations (fragile X chromosome syndrome): The
mutation which is characterized by a long repeating sequence of three nucleotides CGG. It
is the second most common genetic cause of mental retardation after Down sy. The
affected males are mentally retarded (IQ 20-60) with a long face and large mandibule,
large everted ears, and large testicles (macro-orchidism). 50% of affected females have
mental retardation.
Diseases caused by mutations in mitochondrial genes (leber hereditary optic neuropathy)
Diseases associated with genomic imprinting (Prader-Willi syndrome)
Diseases associated with gonadal mosaicism (germ line mosaicism, gonadal mosaicism)

15. Down syndrome.

16. Short metacarpals in Turner syndrome

17. Most common disorders.
P – Point mutation, or
any insertion/deletion
entirely inside one gene
D – Deletion of a gene
or genes.
C – Whole chromosome
extra, missing, or both.
T – Trinucleotide repeat
disorders: gene is
extended in length.

18. Genetic diseases of the CNS.
Several diseases that directly affect the CNS have a genetic
component: some due to a mutation in a in a single gene, other
are proving to have a more complex mode of inheritance. As our
understanding of the pathogenesis of neurodegenerative disorders
deepens, common themes begin to emerge: Alzheimer brain
plaques and the inclusion bodies found in Parkinson disease
contain at least one common component, while Huntington
disease, fragile X syndrome and spinocerebellar atrophy all are
dynamic mutation diseases in which there is an expansion of a
DNA repeat sequence. Apoptosis is emerging as of the molecular
mechanism invoked in several neurodegenerative diseases , as
are other, specific , intracellular signaling events. The biosynthesis
of myelin and the regulation of cholesterol traffic also figure in
Charcot-Marie-Tooth and Neiman-Pick disease respectively.

19. Diseases:
Adrenoleukodystrophy. Parkinson disease.
Alzheimer disease. Phenylketonuria.
Amyotrophic lateral sclerosis. Prader-Willi syndrome.
Angelman syndrome. Refsum disease.
Ataxia telangiectasia. Rett syndrome.
Charcot-Marie-Tooth syndrome. Spinal muscular atrophy.
Cockayne syndrome. Spinocerebellar ataxia.
Deafness. Tangier disease.
Duchenne muscular dystrophy. Tay-Sachs disease.
Epilepsy. Tuberous sclerosis.
Essential tremor. Von Hippel-Lindau syndrome.
Fragile X syndrome. Williams syndrome.
Friedreich's ataxia Wilson's disease.
Gaucher disease Zellweger syndrome.
Huntington disease.
Lesh-Nyhan syndrome.
Maple syrup urine disease.
Menkes syndrome.
Myotonic dystrophy.
Narcolepsy.
Neurofibromatosis.
Niemann-Pick disease.

53. Background
Recent developments in genetics have significantly improved our
understanding of the role of genetic mutations in certain diseases where
there is a familial component. Genetic testing is offered for a number of
mutations such as Von-Hippel Lindau (VHL), familial paraganglioma-
pheochromocytoma, multiple endocrine neoplasia (MEN) and Birt-Hogg-
Dube. In these individuals, malignancy tends to present at an earlier age in
subsequent generations and often with multi-organ disease. Imaging can
play an important role in surveillance of a these patients and allow earlier
detection and treatment of malignancy as part of a multi-disciplinary
approach.
Multi-organ malignancy often develops at an earlier stage in those with
familial cancer syndromes.
Targeted imaging has an important role in these patients for surveillance
and therefore can affect further management.
Imaging plays a vital role in the early diagnosis of these diseases to
improve outcome.
Imaging of genetic genitourinary disease.

54. Hereditary Renal Cell Carcinoma
The number of conditions known to cause hereditary renal
cell carcinoma is increasing. 4% of renal cancers are
familial in origin. They cause multiple bilateral tumours
and occur at a earlier age than non-hereditary tumours.
The more common syndromes are Von Hippel Lindau
(VHL), hereditary papillary renal carcinoma and Birt-Hogg-
Dube.
Imaging plays an important role in the management of
these tumours through early detection. VHL provides a
paradigm for illustrating how studies of a rare familial
cancer syndrome can produce advances in clinical
medicine and important insights into basic biological
processes.

55. Syndrome Frequency of
carcinoma (%)
Predominant
cell type
Associated
anomalies
Von-Hippel Lindau
(VHL)
28-45 Clear cell Haemangioblastomas,
retinal angiomas,
pancreatic cysts and
islet cell tumours,
phaeochromcytomas
Tuberous Sclerosis
(TS)
1-2 Clear cell CNS tubers,
angiofibromas of skin,
cardiac rhabdomyomas
Hereditary papillary
renal ca
19 Papillary type 1 None
Hereditary
Leiomyoma
Unknown Papillary type 2 Cutaneous and uterine
leiomyomas
Birt-Dogg-Dube
syndrome
8-15 Chromophobe Fibrofolliculomas, lung
cysts, pneumothorax
Hereditary renal
cell oncocytoma
Unknown Oncocytoma Renal dysfunction

56. Von Hippel Lindau (VHL)
VHL is an autosomally dominant cancer syndrome caused by mutations in the
VHL tumour suppressor gene. It is characterised by marked phenotypic
variability. The typical age of onset is 2nd - 3rd decade, but can be earlier. The
prevalence in the population is 1:35000-50000. Male and female predominance
is equal. The commonest causes of death are neurological sequelae or renal cell
carcinoma. There is a 70% life time risk of developing cancer.
Features
Multiple hemangioblastomas of the central nervous system and retinal
angiomas (usually precede RCC).
Clear cell renal cell carcinoma (75% bilateral, multifocal disease)
Pancreatic cysts and islet cell tumors.
Pheochromocytomas (25% lifetime risk)
Endolymphatic sac tumours.
Recommended surveillance
Yearly MRI abdomen (axial T1, T2 and post contrast axial T1).
Three yearly MRI brain and spine or earlier if the patient is symptomatic.
Urinary catecholamines from 6 - 7 years. Imaging with MR, MIBG or PET-CT (if
positive catecholamines).
Annual retinal screen.

57. An axial T2 image through the abdomen showing
bilateral renal cysts in a patient with Von Hippel disease.

58. Bilateral multiple renal tumours in a patient with Von Hippel disease.

59. Cerebellar and spinal hemangioblastomas in Von Hippel Lindau syndrome.

60. Serous cystadenoma in the head of
pancreas which proved cystadenoma. Islet cell tumour of pancreas
in pheochromocytoma.

61. Pancreatic neuroendocrine tumours are solid enhancing
tumours , occurring in 8% of patient with VHL disease.

62. Familial Leiomyomatosis
Autosomal dominant inheritance. Individuals affected show germ line
mutations in the classical tumor suppressor gene encoding fumarate
hydratase (FH).
Features
Multiple cutaneous leiomyomas are uncommon and usually benign. They
may cause pain and paraesthesia and can increase in size over time.
Uterine leiomyomas (fibroids) are associated with infertility, pain and
bleeding. They usually manifest at 20-35 years. In some patients,
leiomyomas may become malignant.
There is predisposition to type 2 papillary renal cell carcinoma which is
very aggressive and metastases can present at early stages. Therefore,
early management of renal tumours is required in these patients.
Recommended surveillance
Imaging from the age of 16, although patients may be screened from an
earlier age in some families.
Annual MRI of abdomen. Include pelvis if the patient is symptomatic
although US can be performed for uterine lesions initially.
If renal lesions, 6 monthly follow-up MRI is advised.

63. A,B & C – the cutaneous leiomyomata were confirmed
histologically. There were no renal lesions in this patient.

64. Subtype
Medullary
Thyroid
Carcinoma
Phaeochromo
cytoma
Parathyroid Disease
MEN 2A 95% 50% 20%-30%
FMTC 100% 0% 0%
MEN 2B 100% 50% Uncommon
The types of MEN 2 syndrome and the frequency of each type of condition.

65. Familial Pheochromocytoma-Paraganglioma syndrome.
Pheochromocytomas occur in MEN 2A and 2B, neurofibromatosis (von Recklinghausen
disease), and VHL disease. In the familial pheochromocytoma-paraganglioma
syndrome, the abnormality is on the SDH (succinate dehydrogenize) gene. There are B,
C and D subunit mutations with the most severely affected individuals being the B
mutation. B mutation cause a higher risk of developing paragangliomas and renal cell
carcinoma. B and D mutations tend to cause extra-adrenal disease.
Features
Pheochromocytomas - avid enhancement on T1W and high signal on T2W. Washout
from pheochromocytomas may be variable depending on the composition (can include
fat). Metastases and extra-adrenal lesions are detected on MIBG.
Paragangliomas - undergo hemorrhage, cystic degeneration and are hypervascular.
Have a typical ‘salt and pepper’ appearance on MR due to slow flow or hemorrhage
and signal voids. They occur in:-
Carotid body, Jugular foramen, Middle ear, Aorto-pulmonary window, Posterior
mediastinum and Para aortic region/retroperitoneum
Recommended surveillance
Annual MRI abdomen from age 7 (RCC and pheochromocytoma).
Urinary catecholamines and metabolites. Can be imaged with CT/MR.
Extra-adrenal lesions detected with MIBG/PET-CT.
Three yearly MRI neck and thorax (paraganglioma). Axial T1 and T2 including fat
saturation with gadolinium if needed.

66. Right jugular foramen lesion in
keeping with a glomus jugulare.
CT scan of the temporal bones
showing a glomus tympanicum

67. A carotid body tumour on angiography. It is an extremely vascular tumour which can metastasize.

68. Birt-Hogg-Dube (BHD) syndrome
Is named after three Canadian physicians. BHD has an autosomal
dominant inheritance caused by a FLCN (folliculin) gene mutation. The
differential diagnosis includes tuberous sclerosis (TS). TS has CNS lesions,
different cutaneous features, leiomyomatosis and angiomyolipomas.
Features
Fibro-folliculomas - skin lesions (hair follicular tumours), trichodiscomas
(early fibrofolliculomas), and acrochordons (skin tags).
Renal cell carcinoma of varying histological types, most commonly
Chromophobe type.
Pulmonary cysts, recurrent spontaneous pneumothoraces and bullous
emphysema. Other differentials are lympangioleiomyomatosis,
Langerhans cell histiocytosis and pneumocystis and lymphocytic
interstitial pneumonia.
Recommended surveillance
Solid enhancing renal tumours - are distinguished from cysts on post-
gadolinium sequences.
CT thorax for well-circumscribed cysts in the lower lobe

69. Axial CT thorax image showing lung cysts in a patient with a patient with Birt-Hogg-Dube (BHD)
syndrome.

70. An enhancing left renal lesion with mixed signal on T2W and solid
appearances of renal cell carcinoma in a patient with BHD.

71. Multiple Endocrine Neoplasia type 2 (MEN 2)
There are 3 categories of MEN 2 (table 2):-
MEN type 2A
MEN type 2B (includes ganglioneuromatosis and marfanoid features)
Familial medullary thyroid carcinoma (FMTC)
All patients are at risk of medullary thyroid carcinoma with differing ages of
onset (MEN 2B - early childhood , FMTC - middle age, MEN 2A – early
adulthood). The RET oncogene is associated with 88% of patients with
familial MTC.
Features
Medullary thyroid carcinoma arises from parafollicular cells. It nearly always
spreads to lymph nodes, lung, liver. It causes elevated calcitonin levels. The
tumour is low attenuation on CT (no radio-iodine uptake).
Surveillance Protocol
Prophylactic thyroidectomy by 5-10 years in FMTC depending on mutation.
Annual calcitonin stimulation test thereafter.
Parathyroid and calcium levels (parathyroid adenomas).
Urinary catecholamines and metabolites (pheochromocytoma).
MRI abdomen if positive catecholamines or features of pheochromocytoma
and MIBG or PET-CT (extra-adrenal disease).

72. A large heterogeneous nodule in the left thyroid lobe, secondary to
a medullary thyroid carcinoma in a patient with MEN 2 disease.

73. Multiple calcified liver metastases and a left
renal calculus in a patient with MEN 2 syndrome.

74. Neurofibromatosis Type 2
Neurofibromatosis type 2 is an autosomal dominant neurocutaneous
condition which is compromised of vestibular schwannomas, spinal tumours,
meningiomas and retinal hamartomas.
Features
Schwannomas – symptoms include hearing loss, tinnitus and loss of balance.
Bilateral tumours often occur and age of onset is 30 years.
Meningiomas – 50% of patients develop meningiomas. They are usually
intracranial but can be spinal. Other neural axis tumours include gliomas and
ependymomas.
Hamartomas – retinal hamartomas and cataracts can cause decreased visual
acuity and diplopia.
Recommended Surveillance
Annual MRI brain and spine from 10-12 years. Imaging until the fourth decade
of life at least.
Hearing evaluation for detecting acoustic schwannomas before presentation
on imaging.
If known to have vestibular schwannomas, followed -up with MR IAMS/brain
and ENT clinic.
Regular ocular screening for retinal lesions.

75. There are multiple meningiomata in this patient with NF2.

76. Pre, post-contrast T1 and dedicated IAM sequences of bilateral acoustic neuroma of NF2.

77. Tuberous sclerosis (TS)
A neuroectodermal disorder characterised by hamartomas of the skin,
brain and viscera (heart, lung, kidney). Prevalence is 1:10000. Clinically
patients have adenoma sebaceum, epilepsy and mental retardation.
Features
Hamartomas – occur on subependymal surface of caudate lobe, foramen
of Munro (foM) protruding into the ventricles.
Astrocytoma – in region of foM, uniform enhancement and extension into
ventricle. Low signal on T1W and high on T2W. May cause hydrocephalus.
Cortical or subcortical tubers – are multiple in 75%. They are hyperintense
lesions on T2W.
Angiomyolipomas – usually bilateral and multiple. The hallmark is fat
content and hypervascularity on angiography. They can lead to
hemorrhage but have very low malignant potential.
Recommended surveillance
No recommended protocol in our trust.
Angiomyolipomas are at risk of bleeding if more than 4cm and can
followed up 6-monthly with MR or yearly if less than 4cm.
Large lesions can be treated with embolisation.

78. Pre and post contrast MR showing subependymal lesions and a mass in the
right anterior lateral ventricle, proved giant astrocytoma in tuberous sclerosis.

79. Bilateral fat containing lesions in both kidneys with typical
features for angiomyolipoma in a patient with MS.

80. Genetic diseases of the musculoskeletal system.
There are a number of diseases that are caused by defects
in gene important for the formation and functions of
muscles, and connective tissues. Defects in fibrillin - a
connective proteins that is important in making tissue
strong yet flexible cause Marfan syndrome, while
diastrophic dysplasia is caused by a defect in a sulfate
transporter found in cartilage.
Diseases:
Achondroplasia, Amyotrophic lateral sclerosis, Charcot-
marie-tooth syndrome, Diastrophic dysplasia, Duchene
muscular dystrophy, Ellis-van Creveld syndrome,
Fibrodysplasia ossificans progressiva, Marfan syndrome
and Myotonic dystrophy.

81. Marfan Disease.

82. Annuloaortic ectasia of Marfan Disease, Reformatted CT images shows
marked dilatation of the Valsalva sinus and the sinotubular junction.

83. Marfan syndrome with aortic dissection and background severe pectus excavatum

84. Marfan syndrome. A. CT demonstration of the left undescended testis, high
scrotal in position (arrow). B.CT image shows funnel chest. A 56-years-old
male with Marfan syndrome. C. CT image shows the dissection of the
descending aorta. D. 3D-CTA shows aneurysmal dilation of the aortic root.

85. Achondroplasia is a congenital genetic disorder and the most common skeletal dysplasia. It has
numerous distinctive radiographic features and is the most common cause of short limb
dwarfism.
Radiograph / CT / MRI: Features on radiographs, CT, and MRI are similar and discussed
together here. Cranial: relatively large cranial vault with small skull base, prominent
forehead with depressed nasal bridge, narrowed foramen magnum
cervico medullary kink, relative elevation of the brainstem resulting in a large suprasellar
cistern and vertically-oriented straight sinus, communicating hydrocephalus (due to venous
obstruction at sigmoid sinus).
Spinal: posterior vertebral scalloping, progressive decrease in interpedicular distance in
lumbar spine, gibbus: thoracolumbar kyphosis with bullet-shaped/hypoplastic vertebra
(not to be confused with Hurler syndrome), short pedicle canal stenosis, laminar thickening,
widening of intervertebral discs , increased angle between sacrum and lumbar spine
Chest: anterior flaring of ribs, anteroposterior narrowing of ribs
Pelvis and hips: horizontal acetabular roof (decreased acetabular angle), small squared
(tombstone) iliac wings, small trident pelvis, champagne glass type pelvic inlet, short
sacroiliac notches
Limbs: metaphyseal flaring 8: can give a trumpet bone type appearance, the femora and
humeri are particularly shortened (rhizomelic shortening), long fibula
they may also appear thickened but in fact normal in absolute terms compared to the
normal adult diameter (thickening is perceived due to reduced length), V-shaped growth
plates
trident hand

86. Achondroplasia

87. Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig disease or
Charcot disease is the most common form of motor neuron disease , resulting
in progressive weakness and eventual death.
Radiographic features
MRI
The earliest MR manifestation is hyperintensity on T2WI in the corticospinal
tracts, seen earliest in the internal capsule, as the fibers are most
concentrated here. Eventually the entire tract from motor strip to the spinal
cord is affected with increased T2 signal and volume loss 3.
Iron deposition in the cortex is demonstrated as loss of signal, most evident on
T2* weighted sequences, it is seen on T2WI in 40-60% (SWI is presumably
more sensitive).
It is important to note that both of these features are present in varying
degrees in normal control patients, and as such an appreciation of what is too
much is essential if MRI is to be of benefit.
MR spectroscopy:
decreased NAA
decreased glutamate
increased choline
increased myoinositol

89. Diastrophic dysplasia (DTD) is a type of short limb skeletal dysplasia (micromelic
dwarfism). In adulthood patients have a stature between 100 and 140 cm.
Radiographic features: Characterised by a micromelic dwarfism with hand deformities
(abducted or hitchhiker’s thumb), multiple flexion contractures, and a scoliosis. The
bones are characterised by crescent-shaped flattened epiphyses, a short, broad
femoral neck, and shortening and metaphyseal widening of the tubular bones. There is
irregular deformity and shortening to the metacarpal bones, metatarsal bones, and
phalanges. Abduction of the great toes and clubfeet may also be observed.
Diastrophic dysplasia.

90. Duchenne muscular dystrophy (DMD) is a recessive X-linked form of muscular
dystrophy, affecting around 1 in 3,600 males, which results in muscle degeneration
and premature death. The disorder is caused by a mutation in the dystrophin gene,
located on the human X chromosome, which codes for the protein dystrophin.
Dystrophin is an important structural component within muscle tissue that provides
structural stability to the dystroglycan complex (DGC) of the cell membrane. While
both sexes can carry the mutation, females rarely exhibit signs of the disease.

91. Myositis ossificans progressiva (MOP), now known as Fibrodysplasia ossificans progressiva
(FOP), is a rare, inherited disorder characterized by progressive fibrosis and ossification of
muscles, tendons, fasciae, aponeurosis and ligaments of multiple sites that is disabling and
ultimately fatal. The process of heterotopic ossification starts between 2 and 5 years old.
Myositis ossificans progressiva.

92. Charcot-Marie-Tooth disease (CMT) also known as Hereditary Motor
and Sensory Neuropathy (HMSN), is the most commonly inherited
neuropathy of lower motor (to a lesser degree sensory) neurons.
The disease is divided into the following types:
CMT type 1
this form of CMT disease is a disorder of peripheral myelination.
repeated cycles of demyelination and remyelination result in a thick
layer of abnormal myelin around the peripheral axons.
these changes cause what is referred to as an onion bulb appearance.
CMT type 2
this primarily is a neuronal (i.e., axonal) disorder, not a demyelinating
disorder. CMT type 2 results in peripheral neuropathy through direct
axonal death and Wallerian degeneration.
CMT type 3 (also known as Dejerine-Sottas disease)
characterized by infantile onset, this condition results in severe
demyelination with delayed motor skills; it is much more severe than
type 1.
CMT X (X-linked CMT) and CMT 4: these are also demyelinating
neuropathies.

93. Charcot-Marie-Tooth syndrome.

94. Myotonic dystrophy (dystrophia myotonica, myotonia atrophica)
is a chronic, slowly progressing, highly variable, inherited multisystemic disease. It is an
autosomal-dominant disease. It is characterized by wasting of the muscles (muscular
dystrophy), cataracts, heart conduction defects, endocrine changes, and myotonia. There
are two main types of myotonic dystrophy. Myotonic dystrophy type 1 (DM1), also called
Steinert disease, has a severe congenital form and an adult-onset form. Myotonic
dystrophy type 2 (DM2), also called proximal myotonic myopathy (PROMM) is rarer than
DM1 and generally manifests with milder signs and symptoms. Myotonic dystrophy can
occur in patients of any age. Both forms of the disease display an autosomal-dominant
pattern of inheritance. Both "DM1" and "DM2" have adult-onset forms.
DTI IN MYOTONIC DYSTROPHY

95. DTI IN MYOTONIC DYSTROPHY.

96. X-linked deafness, also termed incomplete partition type III, is
a rare genetic disorder associated with a mutation in the
POU3F4 gene located on the X chromosome.
Clinical presentation
Male patients present with progressive mixed hearing loss. Female
carriers have normal hearing or only mild hearing loss. Vestibular
function is impaired in affected males, however normal in females.
Radiographic features
X-linked deafness, also termed X-linked deformity, has typical
imaging findings:
bilateral and symmetrical widening of the fundus of the internal
auditory canal; absence of the bony partition between the fundus
and the basal turn of the cochlea's.
carrier females can have mild dilatation of internal auditory canal.
There may also be an abnormal bony modioli, vestibular aqueducts
and facial nerve canals (labyrinthine and tympanic segments).

97. CT show the typical findings of X-linked deafness, with bilateral absence of the
bony partition between the fundus and the basal turn of the cochlea's. On the left
side there is an abnormally enlarged vestibular aqueduct.

98. MRI show the typical findings of X-linked deafness, with bilateral absence of
the bony partition between the fundus and the basal turn of the cochlea's.
On the left side there is an abnormally enlarged vestibular aqueduct.

99. Cystic fibrosis is a genetic disorder that affects the respiratory and digestive
systems. People with cystic fibrosis inherit a defective gene on chromosome 7
called CFTR (cystic fibrosis transmembrane conductance regulator). The cells most
seriously affected by this are the lung cells. This mucus clogs the airways in the
lungs, and increases the risk of infection by bacteria.
Organs Affected By Cystic Fibrosis.

100. Cystic lung fibrosis
with multiple cysts
of variable size.
Bottom images
show the presence
of renal and
hepatic
angiomyolipomas.

101. Genetic Liver Disease
Some liver diseases are inherited, and our specialist physicians have extensive
experience in diagnosing and treating these disorders. In addition, genetic
counseling and screening tests are available to the families and relatives of our
patients.
Hereditary Haemochromatosis – Hereditary haemochromatosis is the most
common adult genetic liver disease and results from excessive iron
accumulation in the body, particularly in the liver. Specific and effective
treatment is available, but lifelong monitoring in particularly important.
Alpha-1-Antitrypsin Deficiency – This inherited liver disease may affect the liver
and /or lungs of children and adults. It is caused by the inability to produce
enough A1AT, a protein which protects cells from injury. Management involves
education, nutrition counseling and close monitoring for any complications.
Liver transplantation may be an option if the disease progresses.
Wilson’s Disease – This is a rare genetic disorder that results from excessive
accumulation of copper in the liver and brain. Oral medications effectively
prevent copper buildup, but liver transplantation may be required in some
cases. Wilson’s disease is a particular clinical and research interest of the
hepatologists at the Yale School of Medicine Liver Center and the Norwalk
Hospital Liver Center

102. Iron deposition from hemochromatosis.

103. Honeycomb Appearance of the Liver in Wilson's disease.

104. Swyer syndrome is a condition that affects sexual development.
Sexual development is usually determined by an individual's
chromosomes; however, in Swyer syndrome, sexual development does not
match the affected individual's chromosomal makeup.
People usually have 46 chromosomes in each cell. Two of the 46
chromosomes, known as X and Y, are called sex chromosomes because
they help determine whether a person will develop male or female sex
characteristics. Girls and women typically have two X chromosomes (46,XX
karyotype), while boys and men usually have one X chromosome and one
Y chromosome (46,XY karyotype). In Swyer syndrome, individuals with one
X chromosome and one Y chromosome in each cell, the pattern typically
found in boys and men, have female reproductive structures.
People with Swyer syndrome have typical female external genitalia. The
uterus and fallopian tubes are normally-formed, but the gonads (ovaries
or testes) are not functional; affected individuals have undeveloped
clumps of tissue called streak gonads. Because of the lack of development
of the gonads, Swyer syndrome is also called 46,XY complete gonadal
dysgenesis. The residual gonadal tissue often becomes cancerous, so it is
usually removed surgically early in life.

105. MRI, rudimentary uterus (in white circle).
MRI, gonadal mass within the
left pelvis (in white circle).
Swyer syndrome

106. Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome. = a disorder that occurs
in females and mainly affects the reproductive system. The cause of MRKH
syndrome is unknown, although it probably results from a combination of
genetic and environmental factors.
●Incidence: 1/5,000
●Symptoms.
Primary amenorrhea
Cyclic abdominal pain due to cyclic endometrial shedding without a patent
drainage pathway
Infertility
Renal malformations
Kallmann syndrome = a genetic disorder with the distinctive features of
hyposmia or anosmia and hypogonadotropic hypogonadism
●Incidence: 1/10,000-86,000 (Male＞female)
●Symptoms.
A condition characterized by delayed or absent puberty and an impaired
sense of smell.
Cryptorchidism, Microphallus in males, primary amenorrhea, Bimanual
synkinesis affects about one-fifth of males with the disorder

107. MRKH syndrome. She married nulliparous presented with complaints of primary
amenorrhea. On examination, the patient’s secondary sexual characteristics
were found to be normal. A.B. MRIs show the absence of uterus and vagina. C.
MR axial image shows both ovaries, which appear normal.

108. Kallman syndrome. She had delay in puberty and anosmia. A. MRI shows the incomplete
aplasia of the uterus. B. Single coronal T2 image through the frontal lobes demonstrates
abnormal anatomy with absence of the olfactory bulbs and olfactory sulcus. C. The normal
anatomy of the region consists of the olfactory bulbs (pink arrows) located in the olfactory
grooves of the anterior cranial fossa. The inferior surface of the frontal lobes usually
consists gyrus rectus (straight gyrus) (R) separated from the medial orbital gyrus (M) by
the olfactory sulcus (green arrow). These are absent in Kallman syndrome.

109. Turner syndrome is a chromosomal condition that affects development in
females. The most common feature of Turner syndrome is short stature, which
becomes evident by about age 5. An early loss of ovarian function (ovarian
hypofunction or premature ovarian failure) is also very common. The ovaries
develop normally at first, but egg cells (oocytes) usually die prematurely and
most ovarian tissue degenerates before birth. Many affected girls do not
undergo puberty unless they receive hormone therapy, and most are unable to
conceive (infertile). A small percentage of females with Turner syndrome retain
normal ovarian function through young adulthood.
About 30 percent of females with Turner syndrome have extra folds of skin on
the neck (webbed neck), a low hairline at the back of the neck, puffiness or
swelling (lymphedema) of the hands and feet, skeletal abnormalities, or kidney
problems. One third to one half of individuals with Turner syndrome are born
with a heart defect, such as a narrowing of the large artery leaving the heart
(coarctation of the aorta) or abnormalities of the valve that connects the aorta
with the heart (the aortic valve). Complications associated with these heart
defects can be life-threatening.
Most girls and women with Turner syndrome have normal intelligence.
Developmental delays, nonverbal learning disabilities, and behavioral problems
are possible, although these characteristics vary among affected individuals.

110. Turner syndrome. MRIs show the incomplete
aplasia of the uterus and absence of ovaries.

111. Hands and foot abnormalities associated with genetic diseases
Ellis-van Creveld syndrome, Fibrodysplasia ossificans progressiva ,
Achondroplasia, Kniest dysplasia, pseudohypoparathyroidism,
Acromegaly, Nail-patella syndrome, Marfan,s syndrome,
Mucopolysaccharidosis, Cartilage-hair hypoplasia.
X-ray and photograph of the hands
of a child with Ellis–van Creveld
syndrome. b Note the polydactyly
with an extra small digit on the
ulnar side. Several other digits are
distorted and the third and fourth
metatarsals on the right side are
fused. There is also curvature of the
fifth metatarsal on the left side.

112. Hands of a patient with fibrodysplasia ossificans progressiva. b The hands like
the rest of the body may show production of new bone adjacent to the skeletal
segments but there is a striking shortening and deformity of the thumbs

113. Hands of a child with Kniest disease. Not the long knobby fingers and the
“squared off epiphyses” for the digits as well as the distal radius and ulna.

114. Almost all forms of the mucopolysaccharidoses show gross distortion of the hand and foot
structure. a Shows a child with Hurler syndrome with hepatosplenic enlargement. Note the
hand flexion deformities. As noted in the X-ray, the metacarpals and phalanges are wide
and the distal radius and ulna have a V-shaped deformity. The child is severely mentally
impaired. b (1) A photograph of a child with Morquio’s syndrome. She is short and grossly
deformed but mentally normal. (2)Her hands and feet show gross digital distortion

115. The hands of children with cartilage–hair hypoplasia show skin and structural
alterations consisting principally of short digits often bent. The metacarpals
are short, and the carpal bone are poorly structured and calcified

116. Tumors.
Benign vs. Malignant:
Benign (hemangioma - nevus flammeus -
port wine stains, lymphangioma - hygroma
colli cysticum, sacrococcygeal teratoma)
Malignant (hematopoietic - malignant
lymphomas, leukemia's; neurogenic
(Neuroblastoma, Ewing sarcoma, primitive
neuroectodermal tumor - PNET, CNS-
medulloblastoma), sarcomas (rhabdo-,
osteosarcoma), kidneys (Wilms' tumour),
thyroid (papillary ca).

117. Thank You.