Genetics and dysmorphology








After reading this chapter you should:




  • be able to explain and provide advice regarding patterns of inheritance



  • be able to diagnose and manage common genetic and dysmorphological conditions



  • be able to discuss the role of pre- and postnatal genetic investigations



  • understand the effects of environmental factors affecting the fetus




Patterns of inheritance


Chromosomal abnormality and mutations


There are many conditions seen in paediatric practice that are the result of a genetic mutation, and these range from structural chromosome changes to single nucleotide alterations. These mutations may result in disease and are referred to as pathogenic mutations whilst others, nonpathogenic mutations, are not implicated in disease causation.


Chromosomal abnormalities can be classified as either numerical or structural.


Numerical abnormalities:





  • polyploid—additional sets of 23 chromosomes as in triploidy



  • aneuploidy—presence or absence of one or more chromosome



  • trisomy—presence of three copies of a chromosome



  • monosomy—presence of only one member of the chromosome pair



Structural abnormalities


Translocations, most inversions and large (microscopic) deletions, duplications or insertions will be visible on karyotype. Chromosome microarray analysis will detect even small changes in copy number (sub-microscopic deletions and duplications) but will fail to detect other rearrangements, such as translocations and inversions, unless there are associated alterations in copy number of nearby sequences. The recognised types of structural abnormalities ( Figure 5.1 ) include:




  • translocation—transfer of material from one chromosome to another



  • balanced translocation—transfer of material between chromosomes but no loss of genetic material



  • reciprocal translocation—chromosome breaks and exchange of material between chromosomes



  • Robertsonian translocation—breaks close to the centromere of acrocentric chromosomes and subsequent fusion with another acrocentric chromosome. This leads to the loss of both short arms of the chromosomes involved but without adverse consequences as the missing regions contain no protein-coding genes



  • insertion—insertion of segment into another position in a chromosome



  • deletion—loss of part of chromosome



  • duplication—duplication of part of a chromosome



  • inversion—section of a chromosome rotated by 180° and reinserted



  • ring chromosome—chromosome break, with the two ends joining together to form a ring. There is loss of chromosomal material.




Fig. 5.1


Diagrammatic representation of chromosomal rearrangements


Sex chromosome abnormalities





  • loss of part or all of one of the sex chromosomes as in Turners syndrome (45X0)



  • duplication of one the sex chromosomes as in Klinefelter syndrome (47 XXY)



Genetic sequence variants (point mutations)





  • alterations of one or several contiguous nucleotides, usually within a gene and often within the coding sequence or nearby, so that RNA splicing is affected.



These alterations can be complex. The simplest categories are:




  • substitutions—replacement of one nucleotide by another



  • insertions—addition of one or more nucleotide



  • deletions—loss of one or more nucleotide



The brief description of the nucleotide alteration within the coding sequence of a gene is preceded by ‘c.’ (for coding) and then followed by the associated change in the amino acid sequence of the relevant protein product, itself preceded by ‘p.’ (for protein). Thus, the commonest pathogenic variant in the CFTR gene, causing cystic fibrosis in homozygotes and formerly known as ΔF508, is now presented as: c.1521_1523delCTT; p.Phe508Del.


Such alterations in DNA sequence are now classified by their pathogenicity as definitely benign (class 1), probably benign (class 2), of uncertain significance (class 3), probably pathogenic (class 4) or definitely pathogenic (class 5). There are multiple factors to be taken into account in deciding whether or not a variant is pathogenic. This is complex and involves bioinformatic analysis according to national and international standards and comparisons with international reference databases. It may also require a comparison with test results on parents, siblings and other members of the family.


Autosomal dominant conditions


The disorder is expressed completely in the heterozygote individual, and all offspring of an affected person will have a 50% chance of inheriting the mutation, giving rise to vertical transmission in the pedigree. Variable expression and incomplete or age-dependent penetrance can complicate recognition of autosomal dominant inheritance.


Autosomal recessive conditions


The disorder is expressed in the affected homozygote individuals and may arise de novo or be recognised if



Conditions with autosomal dominant inheritance





  • achondroplasia



  • hereditary elliptocytosis



  • hereditary spherocytosis



  • Huntington’s disease



  • Marfan syndrome



  • myotonic dystrophy



  • neurofibromatosis NF1 and NF2



  • Noonan syndrome



  • tuberous sclerosis complex



  • von Willebrand disease


there are affected siblings. When both parents are carriers, each of their offspring has a 25% risk of being homozygous affected and a 50% risk of being a heterozygous carrier.

Practice Point – conditions with autosomal recessive inheritance





  • alpha-1 antitrypsin deficiency



  • ataxia telangiectasia



  • beta thalassaemia



  • cystic fibrosis



  • Fanconi anaemia



  • galactosaemia



  • glycogen storage disorders



  • homocystinuria




X chromosome linked conditions


These conditions result from mutations in a gene carried on the X chromosome and therefore males are usually affected as they only have one copy of the gene. Female carriers of X-linked conditions are often unaffected but may show some features of the disease, although usually less severely than an affected male.


Features of this X-linked form of inheritance are:




  • no male-to-male transmission



  • all daughters of an affected male will be carriers



  • half of all daughters of a carrier female will be carriers



X chromosome gene disorders are occasionally separated into X-linked recessive, which tend not to manifest significantly in females, and X-linked dominant in which females are commonly affected. In some of these conditions, males may be so severely affected as to die in utero or in early infancy. The distinction between X-linked recessive and X-linked dominant can help in assessing patterns of inheritance in a family, although the random and variable nature of X chromosome inactivation will often blur the distinction.



Practice Point – conditions with X-linked inheritance





  • Becker muscular dystrophy



  • Duchenne muscular dystrophy



  • Glucose-6-phosphate dehydrogenase deficiency



  • haemophilia A and B



  • hypohidrotic ectodermal dysplasia



  • incontinentia pigmenti



  • Rett syndrome



  • Wiskott-Aldrich syndrome




Mitochondrial mutations


Mitochondrial DNA mutations are transmitted by maternal inheritance and are passed down from mother to child but not from father to child. In most people, all mitochondria contain identical copies of the mitochondrial genome (homoplasmy), but in those with mitochondrial disorders there may be a mix of mitochondria with normal and mutated DNA within each cell (heteroplasmy), especially if the mutation would be lethal if it were present in all copies of the genome (that is, if there were homoplasmy for the mutation).


Imprinting conditions


For most autosomal genes, both alleles are expressed in a cell but, for some, only one allele is expressed and the other is switched off. Whether an allele is expressed or repressed is determined by the sex of the parent contributing that gene and the phenomenon is termed imprinting (see Figure 5.2 ). The terms used are:




  • maternally imprinted gene—the maternally derived allele is inactivated



  • paternally imprinted gene—the paternally derived allele is inactivated



Practice Point – conditions due to genetic imprinting abnormalities





  • Prader-Willi syndrome (PWS)—maternally imprinted factors; syndrome arises when the paternal copy is absent (by deletion or maternal disomy) or defective



  • Angelman syndrome—UBE3A gene, paternally imprinted gene; syndrome arises when the maternal allele is absent or defective



  • Beckwith-Wiedemann syndrome—there is cluster of growth-regulating genes at distal 11p15 that are subject to a complex pattern of imprinting; the condition can arise when the balance of gene activity is disturbed through a variety of mechanisms, including paternal 11p15 duplication, paternal uniparental disomy, or point mutation in one of the imprinting control regions or in a specific gene



  • Silver Russell syndrome—has a number of causes including maternal uniparental disomy for chromosome 7 or for 11p15 (the converse of Beckwith-Wiedemann syndrome, above)



  • pseudohypoparathyroidism type 1a— GNAS1 gene, paternal allele suppressed



  • pseudopseudohypoparathyroidism— GNAS1 gene, maternal allele suppressed





Fig. 5.2


The inheritance of a maternally imprinted gene. Father represented in blue. Mother represented in purple. Only the paternally derived copies are expressed. In the ova, imprinting inactivates all maternally derived copies of the allele.


Common genetic and dysmorphological conditions


The number of conditions which have a clear genetic basis is extensive and ever expanding, and a detailed knowledge of the vast majority is beyond the scope of the AKP exam. Clinical features that may suggest an underlying genetic disorder include:




  • multiple individuals of the same family being affected by the same problem



  • multiple problems in the same individual including congenital abnormalities, growth problems, neuro-developmental problems and unusual tumours



Certain features on their own may raise suspicion of a genetic condition and examples of such features are:




  • eyes—unusual shape, different coloured irises



  • hair—brittle, sparse, white patches



  • tongue—large or small tongue



  • teeth—misshapen, extra, primary oligodontia



  • extremes of stature



  • digits—webbed



  • birthmarks that are unusual



There are, however, a core of conditions which may be seen by the paediatric team due to specific abnormalities such as neurodisability, congenital cardiac abnormalities or specific facial or somatic features. Some of these conditions are presented here to illustrate recognised inheritance patterns and some identifiable clinical features and it would be important for candidates to review as many images as possible for each of these recognised diagnoses. This section will show the diagnosis and the associated phenotypic features, but further details about associated clinical problems and their management will be presented in the chapters indicated.


Confirmation of the clinical suspicion through more detailed investigations should be undertaken by clinical genetics teams who will have access to the most appropriate investigations, the required understanding to interpret the results and the appropriate team members to explain the findings and implications to the patient and their family members.


Down syndrome


Trisomy 21—most arise through nondisjunction


Common phenotypic features




  • eyes—up-slanting, epicanthic folds, Brushfield spots, cataracts



  • midface hypoplasia, small mouth and jaw



  • brachycephaly



  • hand abnormalities—single palmar crease, (short broad) hands, clinodactyly



  • hypotonia and hypermobility



  • intellectual disability common (usually mild-moderate)



  • cardiac abnormalities—AVSD most common then VSD then ASD



Antenatal screening is offered to all pregnant women and is outlined in further detail below. Details of management are to be found in Chapter 27 Neurodevelopmental Medicine


Patau syndrome


Trisomy 13


Common phenotypic features include




  • cleft lip and palate



  • polydactyly



  • eye abnormalities—microphthalmia, anophthalmia, coloboma



  • cardiac anomalies—VSD, ASD



  • CNS defects, including holoprosencephaly and meningomyelocoele



  • death usually within the first 12 months



Edward syndrome


Trisomy 18


Common phenotypic features include




  • significant defects in brain development



  • eye abnormalities—microphthalmia, anophthalmia, coloboma



  • cardiac anomalies—VSD, ASD



  • characteristic hand position at birth (see Figure 5.3 )




    Fig. 5.3


    Characteristic appearance of the hand in Edward syndrome



  • death usually within the first 12 months, but survival has improved over the past few decades



Turner syndrome


45,X (also 45,X0) or 45,X with mosaicism


Common phenotypic features




  • short stature



  • lymphoedema in the neonate



  • low hair line



  • webbing of neck ( Figure 5.4 )



  • wide-spaced nipples



  • shield-shaped chest



  • cubitus valgus



  • cardiac defects—bicuspid aortic valve, coarctation



  • usually intellectually normal


Jun 18, 2022 | Posted by in PEDIATRICS | Comments Off on Genetics and dysmorphology
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