What is the characteristic triad of features in McCune-Albright Syndrome?
- Polyostotic fibrous dysplasia
- Cafe-au-lait skin pigmentation
- Autonomous endocrine hyperfunction
What does the gene involved in McCune-Albright syndrome encode for?
Alpha subunit of a G-protein
What is the proposed mechanism for the phenotype resulting from the mutation of the G protein in McCune-Albright syndrome?
- Mutation in G protein --> inactivation of intrinsic GTPase activity --> prevents inactivation of Gs alpha subunit once activated --> continuous stimulation of AC even in absence of ligand binding to receptor --> increased intracellular cAMP and continual stimulation of downstream cAMP signalling cascades
How does the pattern of inheritance of McCune-Albright syndrome result in the variable phenotype?
- Post zygotic somatic mutation
- -- All daughter cells of embryonic cell inwhich mutation occurs contain mutation
- -- the earlier in embryogenesis that the mutation occurs the more widespread the involvement
What is the most common endocrine features of McCune-Albright syndrome?
What is the cause of precocious puberty in McCune-Albright syndrome and what are the ramifications for growth?
- result of gonadotropin independent autonomous ovarian or testicular function
- results in sexual precocity, increased growth velocity and advanced skeletal maturity
What are the endocrine features of McCune-Albright syndrome?
- ACTH-independent Cushings syndrome (growth failure and HTN in infancy)
- Hyperthyroidism (autonomous hyperfunctioning nodules)
- Growth hormone excess (from somatotroph adenomas in the pituitary)
What are the non-endocrine features of McCune-Albright syndrome?
- Fibrous dysplasia - most commonly affecting long bones, ribs ans skull
- Cafe-au-lait spots - large melanotic macules which do not cross the midline
- Hypophosphataemia - decreased reabsorption of phosphate in the renal tubule
- Hepatic abnormalities
Which genetic mutations are associated with Rubinstein-Taybi syndrome?
- CBP (CREBBP) - CREB binding protein - Chr 16p13
- EP300 - EA1 binding protein p300 - Chr 22q13
What are the characteristic facial abnormalities seen in Rubeinstein-Taybi syndrome?
- Hypoplastic maxilla with narrow palate
- prominent beaked nose
- low set ears
- large anterior fontanelle
- small mouth
What are the digital abnormalities seen in Rubenstein-Taybi syndrome?
- Broad great toes
- Broad thumbs with radial angulation
- Broad fingers
- Persistent foetal finger pads
What are the features of Rubenstien-Taybi syndrome?
- Characteristic facial and digital abnormalities
- Strabismus, congenital glaucoma, retinal abnormalities
- Delayed osseous maturation
- Cardiac abnormalities
- Capillary nevus of forehead or nape
What does is IPEX an acronym for?
What triad of disorders does IPEX syndrome typically present with?
- Life threatening chronic diarrhoea due to an autoimmune enteropathy
- Autoimmune endocrinopathy (neonatal type 1 diabetes or thyroiditis)
- Dermatitis, usually eczematous
What is the genetic basis of IPEX?
- Caused by mutations in the gene for the transcription factor Foxp3 - located on Chr xp11.23
- Foxp3 is a member of the forkhead box P (FOXP) family of transcription factors
- - fundamental to the function of the subset of T lymphocytes know as regulatory T cells
What are the gastrointestinal manifestations of IPEX?
- Autoimmune enteropathy - chronic intractable diarrhoea with failure to thrive
- Protein losing enteropathy
- Severe food allergy
- Autoimmune hepatitis
What are the common skin findings in IPEX?
- Dermatitis - eczematous rash
- Diffuse erythema
- alopecia universalis
- Psoriasiform rashes
- Painful fissurary chelitis
- Pemphigoid nodularis
What are other features can be present in IPEX?
- Haematologic disorders - Coombs positive haemolytic anaemia, autoimmune thrombocytopenia, autoimmune neutropenia
- Exaggerated response to infection
- Renal disease - interstitial nephritis
- Developmental delay
- Pulmonary disease - infection related, interstitial lung disease, ABPA
What are the features of Aicardi syndrome?
- Myoclonic seizures
- Agenesis of corpus callosum
- Lacunar chorioretinopathy
- Developmental delay
What are the characteristic features of EEG in Aicardi syndrome?
Periodic asynchronous discharges from left and right hemispheres
What are the characteristics of Alagille Syndrome?
- Paucity of intrahepatic bile ducts - cholestasis and conjugated hyperbilirubinaemia
- Peripheral pulmonary artery stenosis
- Butterfly vertebrae
- Posterior embryotoxon
- Characteristic facies
What are the facial features of Alagille syndrome?
- Broad forehead
- Deep set, widely spaced eyes
- Long straight nose
- Underdeveloped mandible
What genes are involved in Alagille syndrome?
- NOTCH2 or JAG1
- Autosomal dominent inheritence
What are the clinical features of Angelman's syndrome?
- Puppet like gait, ataxia
- Paroxysms of laughter
- Characteristic facies
- Cerebral atrophy
- Absent speech
What are the facial features of Angelman's syndrome?
- Deep set eyes
- Large mouth with prognathia
- Wide spaced teeth
- Tongue protrusion
What is the genetic basis for Angelman syndrome?
- Deletion on Chromosome 15 encoding UBE3A, involved in ubiquitin pathway.
- Maternal UBE3A gene is expressed and paternal gene is silenced - imprinting
- Uniparental disomy accounts for some rare cases
What are the features of Apert syndrome?
- Irregular craniosynostosis
- Midface hypoplasia
- Symmetrical syndactyly of hands and feet - 2nd-4th digits