Genetic disorders with cardiac features
Many chromosomal disorders and genetic syndromes are characterized by congenital heart disease.
· Incidence is 71/4000.
• Caused by a microdeletion on chromosome 22q11.2. Most children have a de novo microdeletion, but in 715% the condition is inherited from an affected parent.
• Apart from cardiac defects, usually involving the aortic arch, features include subtle dysmorphism (wide and prominent nasal bridge, down-slanting eyes, small mouth), parathyroid aplasia/hypoplasia (hypocalcaemia), thymus aplasia (T-cell deficiency). Short stature is common.
• Consider this condition in all children diagnosed with TOF or aortic arch abnormalities, e.g. interrupted aortic arch (720% will have del(22q11)).
• Also consider in any child with CHD, e.g. VSD, who has hypernasal speech, cleft palate, including submucous cleft palate (may present as nasal regurgitation of milk), hypocalcaemia, asymmetric crying facies, recurrent infections, or learning difficulties, especially speech and language delay.
• Diagnosis will be missed on a routine chromosome analysis; it requires a FISH study.
• Incidence 71/5000 births.
• Variable autosomal dominant multisystem disorder caused by mutation in the FBN1 gene on chromosome 15q. There is a high new mutation rate (730%).
• Features include: tall and slim body build with long limbs; pectus malformation of the sternum; scoliosis; high narrow palate; long fingers (arachnodactyly); joint laxity. Most affected children are myopic and some may develop lens dislocation (a major diagnostic feature).
• Cardiac features: initially, there may be a floppy mitral valve. With time, dilatation of the aortic root (another major diagnostic feature) may occur, leading eventually to ascending aorta aneurysm and aortic dissection. Treatment with Losartan has greatly improved the outlook in terms of stabilizing aortic aneurysms.
If genetic confirmation of the diagnosis is required, this may be possible (in conjunction with a clinical geneticist) by mutation analysis of the FBN1 gene.
·Incidence 71 in 2500 births.
• Autosomal dominant disorder. NS is genetically heterogeneous, with 750% caused by mutation in the PTPN11 gene on chromosome 12q. Mutation in several other genes in the RAS/MAP kinase pathway have been reported in other NS cases and in clinically overlapping disorders of cardio-facio-cutaneous syndrome and Costello syndrome.
• Features: short stature, typical facial features (hypertelorism, ptosis, ear abnormalities), a broad neck, congenital heart disease (especially pulmonary stenosis), cardiomyopathy, chest malformation with pectus carinatum superiorly and pectus excavatum inferiorly, mild developmental delay, and undescended testes.
• If genetic confirmation of the diagnosis is required, this may be possible (in conjunction with a clinical geneticist) for some children by mutation analysis of the PTPN11 gene.
·Incidence is 1/7500 live births.
• Caused by a microdeletion on chromosome 7q11 that encompasses the elastin gene.
• Associated cardiac defect is supravalvular aortic stenosis, often with peripheral pulmonary branch stenosis.
• Facial features include: peri-orbital fullness; full cheeks; anteverted nares; wide mouth with full lips; small widely spaced teeth. Most have mild mental retardation with strengths in language, but poor visuospatial skills.
• The typical behavioural phenotype is that of over-friendliness, short attention span, and anxiety.
• 715% of infants have hypercalcaemia.
• Diagnosis is by FISH study for the 7q11 microdeletion