Syndromes

Question 1

What is Turner’s Syndrome?

Answer 1

Chromosomal disorder (45XO or 45X)
~1 in 2,500 females.

Presence of only one sex chromosome (X) or a deletion of the short arm of one of the X chromosomes.

Short stature
Shield chest, widely spaced nipples
Webbed neck
Bicuspid aortic valve (15%)
Coarctation of the aorta (5-10%)
Primary amenorrhoea
Cystic hygroma (often diagnosed prenatally)
High-arched palate
Short fourth metacarpal
Multiple pigmented naevi
Lymphoedema in neonates (especially feet)

Increased incidence of autoimmune disease (especially autoimmune thyroiditis) and Crohn’s disease

Turner’s syndrome is XO, and therefore only affects girls. Treatment is with growth hormone, and to initiate puberty. Once satisfactory growth and development has been achieved, this is stopped and oestrogen treatment is started. Progesterone is added at the time of puberty to induce withdrawal bleeds.

Physical features:
Lymphoedema and rocker bottom feet at birth
Short stature
Webbed neck
Broad chest
Less common: multiple naevi, poorly developed nails, ptosis, low hairline

Endocrine features (relating to gonadal dysgenesis):
Amenorrhoea
Dlayed or absent puberty
Infertility

Associated problems:
Cardiac anomalies (most frequently coarctation of the aorta)
Kidney defects
Diabetes mellitus
Skeletal problems
Strabismus, hyperopia
Inc. incidence of autoimmune conditions
Hypertension with age
Some increase in ADHD, and visuospatial problems, but often of normal intellect

Question 2

What is McCune Albright syndrome?

Answer 2

Rare genetic disorder: bones, skin, and endocrine tissues. Severity can be very variable due to mosaicism.

2 of the following 3 are necessary for diagnosis:
Polyostotic fibrous dysplasia
Cafe-au-lait skin pigmentation
Autonomous endocrine hyperfunction

Endocrine hyperfunction may include hyperthyroidism, acromegaly, Cushing syndrome, & gonadotropin-independent precocious puberty.

Polyostotic fibrous dysplasia may cause joint stiffness, joint or bone pain, multiple fractures, gait abnormalities, and bony deformities.

Short stature and precocious puberty are features

Question 3

What is Patau syndrome

Answer 3

Trisomy 13

Microcephalic, small eyes
Cleft lip/palate
Polydactyly
Scalp lesions

Question 4

What is Edward’s syndrome

Answer 4

Trisomy 18
- Over 90% die as embryos or foetuses
- Poor prognosis in live-born infants due to multiple organ defects
- 80-90% female babies
- associated with increased maternal age

Features
Single umbilical artery
Intrauterine growth retardation
Microcephaly, low set ears
Micropthalmia
Micrognathia
Overlapping fingers, clenched fist
Rocker bottom feet
>90% have cardiac defects (most commonly VSD)
Pulmonary hypoplasia
GI abnormalities are common (including omphalocele, ileal atresia, oesophageal atresia, prune belly)
Renal abnormalities
Low IQ

Question 5

What is Fragile X syndrome?

Answer 5

Trinucleotide repeat disorder

Fragile X is a genetic syndrome characterised by mental retardation, an elongated face, large protruding ears, and large testicles. They tend to be shy, avoid eye contact, and have difficulties reading facial expressions. They often display stereotypic movements such as hand flapping.

The speech of affected individuals of often abnormal. Of note are abnormalities of fluency (flow). Such speech is often referred to as cluttered.

It is caused by a mutation of the FMR1 gene which is an important gene for neural development and functioning. The gene is located at Xq27. In people with fragile X there is extensive trinucleotide repeats at this gene (CGG). As with other trinucleotide repeat disorders (Huntington’s, myotonic dystrophy, Friedreich’s ataxia, and spinocerebellar ataxia) the greater number of repeats the more severe the condition.

Females as well as males are affected. This is through the process of X-inactivation, where one X in each female cell inactivates itself.

Males:
learning difficulties
large low set ears, long thin face, high arched palate
macroorchidism
hypotonia
autism is more common
mitral valve prolapse

Females (one fragile chromosome + one normal X chromosome) range from normal to mild

Learning difficulties
Macrocephaly
Long face
Large ears
Macro-orchidism

Fragile X is a genetic syndrome characterised by mental retardation, an elongated face, large protruding ears, and large testicles (post-puberty). Children tend to be shy, avoid eye contact, and have difficulties reading facial expressions. They often display stereotypic movements such as hand flapping.

It is caused by a mutation of the FMR1 gene which is an important gene for neural development and functioning. The gene is located at Xq27. In people with fragile X, there is extensive trinucleotide repeats at this gene (CGG). As with other trinucleotide repeat disorders (Huntington’s, myotonic dystrophy, Friedreich’s ataxia, and spinocerebellar ataxia) the greater number of repeats the more severe the condition.

Question 6

What is Noonan syndrome?

Answer 6

Webbed neck
Pectus excavatum
Short stature
Pulmonary stenosis

Question 7

What is Pierre Robin syndrome?

Answer 7

Micrognathia
Posterior displacement of the tongue (may result in upper airway obstruction)
Cleft palate

Many similarities with Treacher-Collins syndrome.
Treacher-Collins syndrome is autosomal dominant so there is usually a family history of similar problems

Question 8

What is Prader-Willi syndrome?

Answer 8

Hypotonia
Hypogonadism
Obesity

Question 9

What is William’s syndrome?

Answer 9

Short stature
Learning difficulties
Friendly, extrovert personality
Transient neonatal hypercalcaemia
Supravalvular aortic stenosis

Question 10

How is Fragile X diagnosed?

Answer 10

Can be made antenatally by chorionic villus sampling or amniocentesis

analysis of the number of CGG repeats using restriction endonuclease digestion and Southern blot analysis

Question 11

What is type 1 neurofibromatosis?

Answer 11

Autosomal dominant (chromosome 17)
50% of cases are due to a spontaneous mutation.

Equal in both sexes and is more common in Caucasians.

Characterised by developmental changes in the skin, bones, and nervous system.

Highly variable in different people, and can appear at any age, showing differing penetration and mosaicism.

The prevalence in the UK is 1: 2,500-3,000.

In addition to the early skin features, other common features include scoliosis, learning disabilities, visual problems, and epilepsy.

Question 12

What is type 2 neurofibromatosis?

Answer 12

Autosomal dominant - chromosome 22
50% of cases are due to a spontaneous mutation.
Affects skin, nervous system, skeleton
Equal in both sexes and is more common in Caucasians.

Presents with CNS tumours, most typically bilateral acoustic neuromas.

Question 13

What is the diagnostic criteria for type 1 neurofibromatosis?

Answer 13

Minimum of 2 of 7 criteria:

1. > 6 cafe au lait spots or hyperpigmented macules. >5mm in children <10 years, >15mm in children >10.
2. Axillary or inguinal freckles
3. > 2 typical neurofibromas or one plexiform neurofibroma
4. Optic nerve glioma
5. > 2 Iris hamartomas (called Lisch nodules, seen on slit lamp only)
6. Sphenoid dysplasia, or long bone abnormalities
7. First degree relative with NF1

Question 14

What is Wiskott-Aldrich syndrome?

Answer 14

X-linked recessive
Causes a combined B- and T-cell defect

Recurrent infections are common
Eczema
Thrombocytopenia
Splenomegaly
Bloody diarrhoea
Potential for malignancies is increased, particularly lymphomas and acute lymphoblastic leukaemia

IgG may be increased, decreased, or in normal range.

Question 15

What cardiovascular anomalies occur in Williams syndrome?

Answer 15

Cardiovascular abnormalities are seen in 80% of patients with Williams syndrome

Hypertension monitoring is lifelong and starts from a young age (elastin insuffiency –> systemic arteriopathy)

Supravalvular aortic stenosis is the most common abnormality
Pulmonary artery stenosis is the second most common

Further associations:
Coronary artery abnormalities
Valvular and septal defects
Mitral valve regurgitation and prolapse

Sudden death:
Sudden cardiac death is 25-100 fold increased in children with Williams syndrome compared to other children

Question 16

What is Angelmann syndrome?

Answer 16

Maternal microdeletion chromosome 15

Microcephaly
Developmental delay
Seizures
Jerky hand movements

Question 17

What is Prader-Willi syndrome?

Answer 17

Absence of Prader-Willi gene on long arm of chromosome 15 - may be due to microdeletion of paternal 15q11-13 (70% of cases), maternal uniparental disomy of chromosome 15

Genetic imprinting: phenotype depends on whether the deletion occurs on a gene inherited from the mother or father:
- Prader-Willi syndrome if gene deleted from father
- Angelman syndrome if gene deleted from mother

hypotonia during infancy
dysmorphic features
short stature
hypogonadism and infertility
learning difficulties
childhood obesity
behavioural problems in adolescence

Question 18

What is Alagille’s syndrome?

Answer 18

Autosomal dominant with variable expression. microdeletion of the 20p12 gene corresponding to JAG1.

mainly affects the liver, causing paucity of bile ducts and cholestasis. It can also cause congenital heart problems, butterfly hemi-vertebrae, and distinct facial features (broad forehead, deep-set eyes, pointed chin, and elongated nose.)

Serious complications include:
Malabsorption and growth problems
Portal hypertension
Liver failure

Pauity of bile ducts
- most babies present with cholestatic jaundice.
hepatosplenomegaly
pruritus
xanthomas
fat-soluble vitamin deficiencies (ADEK)
coagulopathies
rickets

Cardiac problems include:
Tetralogy of Fallot
Patent ductus arteriosus (PDA)
Atrial septal defect (ASD)
Ventricular septal defect (VSD)
Pulmonary atresia (PA)

Hemivertebrae are associated with Alagille’s

Question 19

What is Rett syndrome?

Answer 19

Rare neurodevelopmental disorder (approx 1:10,000 female births). Almost exclusively affects females but cases of males have been described.

Likely to have a genetic basis (although most cases are sporadic). It is associated with mutations in the MECP2 gene (Xq28). Case reports indicate complete concordance in monozygotic twins.

Typically have a normal period of development until 6-18 months. Thereafter children develop problems with language (loss of previously acquired speech), purposeful hand movements replaced with stereotypic movements (hand wringing movements are a classic sign), ataxia, and psychomotor retardation. Other stereotypical movements may occur such as licking or biting the fingers and tapping or slapping. Head circumference is normal at birth but growth begins to decelerate between 6-12 months resulting in microcephaly. All language skills are lost, both receptive and expressive and social skills plateau at developmental levels between 6-12 months.

Seizures associated in 75% of those affected and abnormal EEG findings are seen in almost all children.

Breathing problems are also seen with episodes of hyperventilation, apnea, and breath holding.

Children may live for well over a decade after the onset of the disorder but after 10 years many patients are wheelchair bound with virtually no language ability.

Additional features include seizures, breath holding and hyperventilation, sleep difficulties and issues with locomotion.

Question 20

What is Treacher- Collins syndrome (TCS)?

Answer 20

Autosomal dominant, congenital disorder
TCOF1 gene mutations

Most distinctive feature is bilateral and symmetrical craniofacial deformities:
- Short and downward slanting palpebral fissures
- Coloboma
- Micrognathia
- Hypoplastic facial bones
- Zygoma hypoplasia causing depressed cheekbones
- Malformed or absent ears
- Conductive hearing loss
- Cleft palate
- High arched palate
- Dental anomalies

Associated findings:
- Airway problems
- Sleep apnea
- Impaired feeding
- Normal intelligence

Question 21

What is Shwachman-Diamond syndrome?

Answer 21

Autosomal recessive
2nd most common cause of exocrine pancreatic insufficiency in children (1st is CF)

Features:
Exocrine pancreatic insufficiency
Bone marrow dysfunction
Short stature
Skeletal abnormalities

Pancreatic enzyme replacement is lifelong.

Question 22

What is Marfan’s syndrome?

Answer 22

Autosomal dominant connective tissue disorder.
Defect in the fibrillin-1 gene on chromosome 15
Affects around 1 in 3,000 people. Equal sex ratio

Features
Tall stature with arm span to height ratio > 1.05
High-arched palate
Arachnodactyly
Pectus excavatum
Pes planus
Scoliosis of > 20 degrees
Repeated pneumothoraces
Dural ectasia (ballooning of the dural sac at the lumbosacral level)
Associated with hemivertebrae
Associated with femoral hernia
50% - learning disability

Heart: dilation of the aortic sinuses (seen in 90%) which may lead to aortic aneurysm, aortic dissection, aortic regurgitation, mitral valve prolapse (75%),

Life expectancy used to be ~40-50 years, significantly improved with regular echocardiography monitoring + beta-blocker/ACEIs. Aortic dissection + other cardiovascular problems remain leading cause of death.

Question 23

What is Sturge-Weber syndrome?

Answer 23

One of the phakomatoses

Features: port-wine stains of the face, glaucoma, seizures, intellectual disability, and ipsilateral leptomeningeal angioma (cerebral malformations and tumors).

Question 24

What is Goldenhar syndrome?

Answer 24

rare congenital defect characterized by incomplete development of the ear, nose, soft palate, lip and mandible on usually one side of the body. Common clinical manifestations include limbal dermoids, preauricular skin tags and strabismus. It is associated with anomalous development of the first branchial arch and second branchial arch.

Question 25

What is DiGeorge syndrome?

Answer 25

Most common microdeletion syndrome, due to 22q11 deletion. Sporadic in 90%, 10% inherited autosomal dominant. UK incidence 1 in 4000. 90% of diagnosis can be made following karyotyping + FISH studies for the deletion.

Embryonic defect of 3rd and 4th branchial arches

Long face, hypocalcaemia, cardiac defects (especially ToF), and immune deficiencies.

Long face
Micrognathia
Hypertelorism
Narrow palpebral fissures
Short philtrum
Cleft palate
Small teeth
Low-set, abnormal ears

Short stature
Low or borderline IQ (nearly all)
Congenital heart disease (nearly half)
Hypocalcemia (hypoparathyroidism)
Hearing loss (conductive & sensorineural)
Renal anomalies
Immune disorders (T-cell deficiency due to thymic hypoplasia/aplasia)
Autoimmune conditions
Behavioural problems
Psychiatric problems, including higher risk of schizophrenia

Memory aid: CATCH-22 (not for use as a diagnostic term):
Cardiac defects
Abnormal facial features
Thymic aplasia/hypoplasia
Cleft palate
Hypocalcemia/Hypoparathyroidism
22- Due to 22q11 deletion

Question 26

What is CHARGE syndrome?

Answer 26

Coloboma - 80%
Heart defect - 58%
Atresia of choanae - 100%- causes congenital stridor
Mental retardation - 94%
Growth deficiency - 87%
Genital hypoplasia in males - 75%
Ear anomalies - 88%

Question 27

What is Alport syndrome?

Answer 27

genetic condition characterized by kidney disease, hearing loss, and eye abnormalities.

Progressive loss of kidney function. Almost all affected individuals have blood in their urine (haematuria), which indicates abnormal functioning of the kidneys. Many people with Alport syndrome also develop high levels of protein in their urine (proteinuria). The kidneys become less able to function as this condition progresses, resulting in end-stage renal disease (ESRD).

Question 28

What is Young syndrome?

Answer 28

Similar to Kartanager’s and also called: azoospermia sinopulmonary infections, sinusitis-infertility syndrome and Barry-Perkins-Young syndrome

Rare - combination of syndromes such as bronchiectasis, rhinosinusitis and reduced male fertility.

Lung function usually normal but the mucus is abnormally viscous. Reduced fertility (obstructive azoospermia) due to functional obstruction of sperm transport down the genital tract at the epididymis, where the sperm is found in viscous, lipid-rich fluid. The syndrome was named after Donald Young, the urologist who first made observations of the clinical signs of the syndrome in 1972.Possible causes include genetics, and exposure to mercury during childhood, but the cause is unknown.