Chromosomal Diseases Flashcards
Klinefelter’s Syndrome
Klinefelter’s syndrome is associated with karyotype 47, XXY
Features often taller than average lack of secondary sexual characteristics small, firm testes infertile gynaecomastia - increased incidence of breast cancer elevated gonadotrophin levels
Diagnosis is by chromosomal analysis
NB: Mitral valve prolapse is found in approximately 55% of patients with Kilinefelter’s syndrome.
NB Klinefelter’s vs Kallmans
Klinefelter’s = LH and FSH RAISED
Kallman’s = LH and FSH LOW/NORMAL
KLI = TRI - chromosomal (47XXY)
Turner’s Syndrome
Turner’s syndrome is a chromosomal disorder affecting around 1 in 2,500 females. It is caused by either the presence of only one sex chromosome (X) or a deletion of the short arm of one of the X chromosomes. Turner’s syndrome is denoted as 45,XO or 45,X
Features
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)
There is also an increased incidence of autoimmune disease (especially autoimmune thyroiditis) and Crohn’s disease
Turner’s Syndrome -Diagnosis: Example Question
You are asked to review a 22 year old female with a heart murmur. Her height is 4ft 7 inches and she reports having always been short for her year. She has been diagnosed with autoimmune hypothyroidism, for which she is taking levothyroxine replacement and is also taking ‘hormone replacement to protect her bones’ after her GP noted she had not started her periods by 19 years old.
On examination, you note short 4th metacarpals on both hands and lymphoedematous in her hands and feet. Auscultation of her precordium reveals an ejection systolic murmur at the left infraclavicular region. Her body mass index is 22.4 kg/m². The patients blood tests are as follows:
Hb 12.3 g/dl
Platelets 380 * 109/l
WBC 6.5 * 109/l
Na+ 144 mmol/l K+ 4.8 mmol/l Urea 7.2 mmol/l Creatinine 110 µmol/l Adjusted calcium 2.40 mmol/l Phosphate 1.1 mmol/l PTH 9 mg/dl (8.5-10.2mg/dl)
What is the underlying unifying diagnosis?
> TURNER’S SYNDROME
Turner's syndrome Pseudohypoparathyroidism Pseudopseudohypoparathyroidism Noonan syndrome Down's syndrome
A syndromic presentation appears most likely in this patient. An acute infective endocarditis is unlikely for someone who is systemically well, a regurgitant murmur would also be more likely. The symptoms cannot be attributed to delayed puberty, defined as onset of puberty outside 95% of normal population and typically before 18 years old. The combination of primary amennorhea, short stature, lymphoedema, shortened 4th metacarpal, autoimmune predisposition and an ejection systolic murmur suggestive of aortic coarctation should infer a diagnosis of Turner’s syndrome, a disorder caused by loss of a X chromosome.
Noonan syndrome, an autosomal dominant disorder, is a reasonable differential in a patient with short stature, lymphoedema and cardiac problems. However, patients with Noonan syndrome typically presents with learning difficulties, facial dysmorphisms and webbed neck. While valvular abnormalities are less common, hypertrophic cardiomyopathy is more commonly present.
Similar to Noonan syndrome, Down’s syndrome, caused by trisomy 21, also classically presents with facial dysmorphisms such as upslanting palpebral fissures, low set ears and epicanthic folds. Cognitive impairment and learning difficulties are also common. However, similar to our patient, short stature, thyroid dysfunction and cardiac problems, predominantly ASD, VSD and PDA are frequently associated.
Pseudohypoparathyroidism is caused by normal parathyroid hormone release but end organ resistance to hormonal effects, resulting classically in round facies and shortened fourth and fifth metacarpals. The patient is commonly obese with possible learning difficulties.
Pseudopseudohypoparathyroidism presents with the phenotype of pseudohypoparathyroidism but with normal calcium chemistry.
WAGR Syndrome
W = Wilm's tumour A = Aniridia G = Genitourinary malformations R = mental Retardation
Aniridia is an eye disorder characterized by a complete or partial absence of the colored part of the eye (the iris). These iris abnormalities may cause the pupils to be abnormal or misshapen. Aniridia can cause reduction in the sharpness of vision (visual acuity) and increased sensitivity to light (photophobia).
Downs Syndrome - Genetics and Epidemiology
Age 20 = 1 in 1500 risk 30 = 1 in 800 risk 35 = 1 in 270 risk 40 = 1 in 100 risk 45 = 1 in 50 or greater
Non-dysjuction mutation = 94% cases
Robertsonian translocation = 5% cases
Mosaicism = 1% cases
Risk of Reccurrence
1 in 100 if mother <35
10-15% if mother is translocation carrier, 2.5% is father is translocation carrier
If this translocation is trisomy 21 the risk of having another baby with Downs is higher
Downs Syndrome
Clinical Features: Face: - upslanting palpebral fissures - epicanthic folds - brushfield spots in iris - protruding tongue - small ears and round/flat face Flat occiput Single palmar crease Pronounced 'sandal gap' between big and 1st toe Hypotonia Congenital heart defects (40-50%) Duodenal atresia Hirschsprung's disease
Complications: Cardiac: - Endocardial cushion defect (40%) = most common cardiac defect in Downs, also known as Atrioventricular Septal Canal defect - VSD (30%) - Secundum ASD (10%) - Tetralogy of Fallot (5%) - Isolated PDA (5%)
Later Complications: - Subfertility M = almost always infertile due to impaired spermatogenesis F = usually subfertile and have increased incidence of problems with pregnancy and labour - Learning difficulties - Short stature - Repeated respiratory infections - Hearing impairment from glue ear - ALL - Hypothyroidism - Alzheimers - Atlantoaxial instability
DiGeorge Syndrome
DiGeorge syndrome:
Underlying defect = 22q11.2 deletion, failure to develop 3rd and 4th pharyngeal pouches
Common features include congenital heart disease (e.g. tetralogy of Fallot), learning difficulties, hypocalcaemia, recurrent viral/fungal diseases, cleft palate
