when they mutate

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WHEN THEY MUTATE Genetic Disorders & Their Manifestations

Dr. Apurva Mishra Prof. R.K. Pandey

OnlineGatha – The Endless Tale

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OnlineGatha – The Endless Tale Published by: OnlineGatha – The Endless Tale Address : Indradeep complex, Sanjay Gandhi Puram, Faizabad Road, Indranagar, Lucknow, 226016 Contact : 0522- 4004150, +91-9936649666 Website : www.onlinegatha.com ISBN - 978-93-85818-12-7 - 700 /PUBLISHER NOTE OnlineGatha is a division of CompAddicts Infotech Pvt. Ltd. Established in the month of January 2014, the site is a step into the online literary world. It works by connecting the hardcopy creations to the online world. Will provide platform to the newcomers to publish their creations and also utilize the existing resources for their further evolution. We can also add a feather to the hat of established writers by adding to their business and their income simultaneously. Now forget about the fussy laws and printing-publishing issues-for we are here, working day and night to make your dream come true.

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FOREWARD (Hony.) Brig. Anil Kohli AWARDEE – PADMASHRI, PADMABHUSHAN, DR. B.C. ROY AWARD, B.D.S, M.D.S. (Lko.), FDS, RCS (Eng.), MICD (USA), FACD (USA), FDS RCPS (Glas.), Endodontist & Dental Surgeon

Diplomat of the International Congress of Oral Implantogists Consultant, Escorts Heart Institute & Research Centre Former Chairman, Commission for Dental Education (APDF) Former President, Dental Council of India Former Hony. Dental Surgeon to the President of India Former Hony. Consultant, Armed Forces Medical Services Former Member, Education Committee, FDI Former Adjunct Professor, Boston & Tufts University (USA) Former Dean, Baba Farid Medical University, Punjab

I am glad to write a Foreward for “When they mutate, Genetic disorders & their Manifestations” authored by Prof. R. K. Pandey, Professor and Head, Department of Paediatric and Preventive Dentistry, King George's Medical University, Lucknow. Dental management of the children with special needs is a challenging yet rewarding experience. Clinicians who manage and treat these special children require a thorough understanding of the nature and effects of various disabilities experienced by these children. This comprehensive textbook, explains in great detail the medical and dental aspects of the various disabilities and

5 conditions seen in children with genetic disorders and its manifestations. The topics included in this book cover the length and breadth of literature available in this field at the time of publication and is collated in a format which is easy to read and understand. I would like to congratulate the author for writing such a great textbook. I am confident that this book will be an excellent source of information and handy reference tool for students and clinicians who treat children with special needs. I wish him good success in all his endeavours. (Hony.) Brig. Anil Kohli DR. SONI’S DENTAL CLINIC 28-29, LALA LAJPAT RAI MARG, LAJPAT NAGAR – III, NEW DELHI – 110 024 TEL.: 29844474, 29844475, 29845500 FAX: 29845555 e-mail: [email protected]

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PREFACE

To know, is to know that you know nothing. That is the meaning of true knowledge. Socrates To accomplish an academic pursuit it requires a conscious effort, to acquire the knowledge, to practice, preach and finally to document what is practiced and preached. The first edition of this book is designed for comprehensive learning and understanding about genetic disorders for the undergraduate and post graduate medical students. It lays emphasis on mutation, types on mutations and clinical manifestations of each genetic disorder. We also tried to enlist few major advanced diagnostic techniques for genetic disorders, with detailed procedure which will provide a deep insight and will enhance the learning of molecular genetic techniques. We hope students and faculties will find this book useful. We would be happy to receive feedback for improvement in subsequent edition. Dr. Apurva Mishra Prof. R.K.Pandey

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Contributors list 1. Dr. Akhilanand Chaurasia M.D.S, Assistant Professor, Dept. of Oral Medicine and Radiology King George’s Medical University, Lucknow 2. Dr. Vandana Singh M.D.S, Lecturer, Dept. of Oral Medicine and Radiology King George’s Medical University, Lucknow 3. Dr. Deepa Meena M.D.S, Lecturer, Dept. of Pedodontics Sri Aurobindo College Of Dentistry, Indore, Madhya Pradesh 4. Dr. Varuni Arora M.D.S, Prosthodontist, Lucknow 5. Dr. Sakshi Bamba M.D.S, Pedodontist, Chandigarh 6. Dr. Heena Chopra Resident, Dept. of Paediatric & preventive dentistry King George’s Medical University, Lucknow 7. Vivek Kumar Gaur Project Fellow, Environmental Biotechnology Division CSIR-IITR, Lucknow

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INDEX 1

Introduction

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Genetic Terminologies

11

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Classification Of Genetic Disorders

18

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Manifestations Of Genetic Diseases

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Advanced Diagnostic Techniques For Genetic Disorders

171

5-1

Next Generation Sequencing

173.

5-2

Rapid Aneuploidy Detection

183

5-3

Fluorescent In-Situ Hybridization

186

5-4

QF-Polymerase Chain Reaction

194

5-5

Multiplex Ligation Dependent Probe Analysis

199

5-6

Comparative Genomic Hybridization Array Bibliography

203

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206

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INTRODUCTION: Genetic disorders are still perceived as an uncommon event in our general population. However the literature reveals that every year an estimated 7.9 million children (6 percent of total births worldwide) are born with a serious birth defect of genetic or partially genetic origin. Additional hundreds of thousands more are born with serious birth defects of post-conception origin, including maternal exposure to environmental agents (teratogens) such as alcohol, rubella, syphilis and iodine deficiency that can harm a developing fetus. The expression of various human traits depends on interaction between genes and environment i.e. genetic vs nongenetic (infections, teratogens) factors. Disorders caused due to mutation in a single gene can be due to influence of the environmental factors eg. cystic fibrosis and sickle cell disorder. Similarly infection with HIV-1 can led to genetic polymorphism. As per data presented by Global Report on Birth Defects (New York ) in 2006, birth defects are a global problem, but their impact is particularly severe in middle- and low income countries where more than 94 percent of the births with serious birth defects and 95 percent of the deaths of these children occur. The proportion of births with birth defects as well as the absolute number of births are much higher in middle and low-income countries than in high-income countries because of sharp differences in maternal health and other significant risk factors, including poverty, a high percentage of older mothers, a greater frequency of consanguineous marriages and the survival advantage against malaria for carriers of sickle cell, thalassemia, and glucose6-phosphate dehydrogenase (G6PD) deficiency genes. According to the data in this report, five common serious birth defects of genetic or partially genetic origin in 2001 were: (1) congenital heart defects ; (2) neural tube defects (3) the hemoglobin disorders ( thalassemia, and sickle cell disease) (4) Down syndrome

10 (trisomy 21) and (5) glucose-6-phosphate dehydrogenase (G6PD) deficiency. Combined, these five conditions account for about 25 percent of all of birth defects of genetic or partially genetic origin.

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GENETIC TERMINOLOGIES:

ALLELES: Alternative forms of a gene found on the same locus on homologous chromosomes in an individual. The term coined by Bateson and Saunders (1902) for characters which are alternative to one another in Mendelian inheritance (Gk. Allelon, one another; morphe, form). Now the term allele is used for two or more alternative forms of a gene resulting in different gene products and thus different phenotypes. In a haploid set of chromosomes there is only one allele at its specific locus. Diploid organisms have 2 alleles at a given locus, i.e. a normal and a mutant allele. A single allele for each gene locus is inherited separately from each parent (e.g., at a locus for eye colour the allele might result in blue or brown eyes). An organism is homozygous for a gene if the alleles are identical, and heterozygous if they are different.

ALLELIC HETEROGENECITY: The causation of a diseased phenotype by variety of different genotype at same locus.

BASE PAIR: Two nitrogenous (purine or pyrimidine) bases (adenine and thymine or guanine and cytosine) held together by weak hydrogen bonds. Two strands of DNA are held together in the shape of a double helix by the bonds between base pairs. The number of base pairs is often used as a measure of length of a DNA segment, eg 500 bp. CHROMOSOME JUMPING: A technique of isolating clones from a genomic library that are not contiguous by skipping a region between known points on the chromosome. Done

12 usually to bypass regions that are difficult or impossible to walk through or regions known not to be of interest.

CHROMOSOMES: The term was proposed by Waldeyer (1888) for the individual threads within a cell nucleus (gk. chroma, colour; soma, body). The self-replicating genetic structures of cells containing the cellular DNA that bears in its nucleotide sequence the linear array of genes. In prokaryotes, chromosomal DNA is circular, and the entire genome is carried on one chromosome. Eukaryotic genomes consist of a number of chromosomes whose DNA is associated with different kinds of proteins. They are collection of genes or the carrier of genetic codes. Human beings have 23 pairs of chromosomes (46) out of which 22 pairs are autosomes and a pair of sex chromosomes. CODON: The term proposed by Crick (1963) for the sequence of nucleotides in DNA or RNA.which is responsible for determining that a specific amino acid shall be inserted into a polypeptide chain. There is more than one codon for most amino acids. It has now been established that the codon is a triplet of nitrogenous bases in DNA or RNA that specifies a single amino acid. CONGENTIAL: Conditions present at birth. DOMINANT: The term which Mendel (1866) introduced for a character which is manifest in all the members of the first filial generation (F1) from a cross between two purebreeding, homozygous strains differing in respect of this character, and which is evident in three quarters of the individuals of the second filial (F2) generation.

FAMILIAL CONDITIONS: Conditions that appears to cluster with in families (genetic or non-genetic).

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GENE EXPRESSION: The process by which a gene's coded information is converted into the structures present and operating in the cell. Expressed genes include those that are transcribed into mRNA and then translated into protein and those that are transcribed into RNA but not translated into protein (e.g., transfer and ribosomal RNAs). The degree of expression is called expressivity.

GENE MAPPING: Determination of the relative positions of genes on a DNA molecule (chromosome or plasmid) and of the distance, in linkage units or physical units, between them.

GENE POOL: All of the alleles available among the reproductive members of a population from which gametes can be drawn.

GENE: A segment of DNA which codes for the synthesis of a polypeptide. Gene is the basic unit of hereditary. The term coined by Johannsen (1909) for the fundamental physical and functional unit of heredity. The word gene was derived from De Vries' term pangen, itself a derivative of the word pangenesis which Darwin (1868) had coined. A gene is an ordered sequence of nucleotides located in a particular position (locus) on a particular chromosome that encodes a specific functional product (the gene product, i.e. a protein or RNA molecule). It includes regions involved in regulation of expression and regions that code for a specific functional product. GENETIC CODE: The sequence of nucleotides, coded in triplets (codons) along the mRNA, that determines the sequence of amino acids in protein synthesis. The DNA sequence of a gene can be used to predict the mRNA sequence, and the genetic code can in turn be used to predict the amino acid sequence.

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GENETIC DRIFT: The random change of the occurance of a particular gene in a population; genetic drift is thought to be one cause of speciation when a group of organisms is separated from its parent population. Ramdom genetic drift: Changes in allelic frequency due to sampling error. Changes in allele frequency that result because the genes appearing in progenies are not a perfectly representative sampling of the parental genes. (eg. in small populations)

GENOTYPE: The term proposed by Johannsen (1909) for the hereditary constitution of an individual, or of particular nuclei within its cells. HEREDITARY: Conditions that can be transmitted from parents to off-springs.

HOMOLOGUS CHROMOSOMES: A pair of chromosomes containing the same linear gene sequences, each derived from one parent. Humans normally have 22 pairs of homologous chromosomes and 2X chromosomes (female) or 1X and 1Y chromosome (male).

KARYOTYPES: A photomicrograph of an individual's chromosomes arranged in a standard format showing the number, size, and shape of each chromosome type; used in low-resolution physical mapping to correlate gross chromosomal abnormalities with the characteristics of specific diseases. LOCUS: The position of a gene on a chromosome or other chromosome markers; also, the DNA at that position. The use of the term locus is sometimes restricted to main regions of DNA that are expressed. MENDEL’S FIRST LAW: The two members of a gene pair segregate from each other during meiosis; each gamete has an equal probability of obtaining either member of the gene pair.

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MENDEL’S

SECOND

LAW:

The law of independent assortment; unlinked or distantly linked segregating gene pairs assort independently at meiosis.

MOSAICISM: Condition in which an individual harbors 2 or more genetically distinct cell lines; results from a genetic change after formation of a zygote, ie postzygotic event. MUTATION: A change in the DNA of a particular gene. The term which De Vries introduced into biological literature for an abrupt change of genotype which is inherited. Any permanent and heritable change in DNA sequence. Types of mutations include point mutations, deletions, insertions, and changes in number and structure of chromosomes.

NUCLEOTIDE: A subunit of DNA or RNA consisting of a nitrogenous base (purine in adenine and guanine, pyrimidine in thymine, or cytosine for DNA and uracil cytosine for RNA), a phosphate molecule, and a sugar molecule (deoxyribose in DNA and ribose in RNA). Depending on the sugar the nucleotides are called deoxyribonucleotides or ribonucleotides. Thousands of nucleotides are linked to form a DNA or RNA molecule. PEDIGREE: A diagram mapping the genetic history of a particular individual or family.

PENETRANCE: Probability of an individual with diseased genotype to exhibit diseases. Term coined by Voigt (1926) for the percentage with which a dominant or homozygous recessive gene expresses itself in the phenotype. Quantitative concept of gene expression. It depends both on genotype and environment. If all individuals of the genotype show the trait, penetrance is 100%. PHENOTYPE: The physical or clinical appearance of an individual determined by a pair of genes at a given locus or genotype. The phenotypic expression may vary as per modifying factors (genetic or non-genetic).

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PLASMID:

Autonomously replicating, extrachromosomal circular DNA molecules, distinct from the normal bacterial genome and nonessential for cell survival under nonselective conditions. Some plasmids are capable of integrating into the host genome and are used as a cloning vector for small pieces of DNA (typically 50 to 5000 base pairs) by insertion into the plasmid. A number of artificially constructed plasmids are used as cloning vectors.

PLEIOTROPHIC GENES: Genes that have more than one discernible effect on phenotype. For eg. Marfan’s syndrome characterized by ocular, cardiovascular and skeletal disorders. POLYGENIC DISORDERS: Genetic disorders resulting from the combined action of alleles of more than one gene (e.g., heart disease, diabetes, and some cancers). Although such disorders are inherited, they depend on the simultaneous pressence of several alleles; thus the hereditary patterns are usually more complex than those of single-gene disorders. PROBABILITY: The expectation of the occurrence of a particular event. Likelihood of the occurrence of any event in the doctrine of chances, or the ratio of the number of favorable chances to the whole number of chances, favourable and unfavourable. PROTEONOMICS: Systematic analysis of protein expression of normal and diseased tissues that involves the separation, identification and characterization of all of the proteins in an organism. RECESSIVE: Mendel (1866) proposed this tterm for a character which was not evident in the first filial generation (F1) of a cross between two pure-breeding strains differing in respect of this character, and which re-appeared in one quarter of the second

17 filial generation (F2). The recessive character is expressed phenotypically in the homozygous or hemizygous state.

SINGLE GENE DISORDER: Hereditary disorder caused by a mutant allele of a single gene (e.g., Duchenne muscular dystrophy, retinoblastoma, sickle cell disease in human beings). TRAIT: An attribute or character of an individual within a species for which heritable differences can be defined.

TRANSCRIPTION: The synthesis of an RNA copy from a sequence of DNA (a gene); the first step in gene expression.

TRANSFORMATION: A process by which the genetic material carried by an individual cell is altered by incorporation of exogenous DNA into its genome. The phenomenon was first described by Griffith (1928) in Diplococcus pneumoniae.

TRANSGENIC: Containing foreign DNA eg. transgenic mice contain foreign (eg. human) DNA sequences in addition to the complete mouse genome. TRANSLOCATION: Transfer of a segment of a chromosome to a non-homologous chromosome. Translocations are usually reciprocal.

VARIABLE EXPRESSIVITY: Two individual with same genotype and different phenotype. The reasons behind variation in expression can be due to influence of modify factors which may be either be environmental or due to influence of other genes.

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CLASSIFICATION OF GENETIC DISORDERS:

1. 2. 3. 4.

Chromosomal Disorders Monogenetic conditions (Single gene disorder) Polygenetic conditions (Multifactorial disorder) Disorder with non-traditional mechanism of expression and inheritance

1. Chromosomal disorders: These can be due to abnormality in number or structure of genes such as:  Duplication  Deletion  Rearrangement  Extra chromosomes Rearrangement of chromosomal disorders can be further divided into:  Balanced rearrangement – an altered state but doesn’t causes diseases  Unbalanced rearrangement – an altered state causing diseases

2. Monogenetic conditions: These follow Mendelian law of inheritance. Monogenetic conditions can be divided into four mode of inheritance:  Autosomal Dominant: Autosomal dominant conditions accounts for presence of only one copy of altered allele at a locus. These are the most common genetic disorders reported in human beings. Individually it’s rare to find each autosomal dominant disorder, thus most affected child are as a result of mating between affected and unaffected parents(de-novo mutation). E.g. Huntingtons disease, Neurofibromatosis 1

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Fig: 1 FIG 1: A pedigree illustrating an autosomal dominant disorder. Affected individuals are depicted by colour. By convention, males are represented by square and females by circle. 

Autosomal Recessive: Autosomal recessive conditions accounts for presence of two copies of an altered allele at a locus to exhibit the dieases. Two unaffected people who each carry one copy of the mutated gene have a 25% chance with each pregnancy of having a child affected by the disorder. E.g. Cystic fibrosis, Sickle cell anemia, Spinal muscular atrophy.

Fig: 2 FIG 2: A pedigree illustrating an autosomal recessive disorder. Affected individuals are depicted by solid colour and heterozygotes by partial shading.

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X- Linked Dominant: X‐linked dominant disorders are caused by mutations in genes on the X chromosome. Only a few disorders have this inheritance pattern. Males are more frequently affected than females, and the chance of passing on an X‐linked dominant disorder differs between men and women. The male progeny of a man with an X‐linked dominant disorder will not be affected, while his female progeny will inherit the condition. A woman with an X‐linked dominant disorder has a 50% chance of having an affected daughter or son with each pregnancy. E.g Hypophosphatemia.



X- Linked Recessive: X‐linked recessive disorders are also caused by mutations in genes on the X chromosome. Males are more frequently affected than females, and the chance of passing on the disorder differs between men and women. The sons of a man with an X‐linked recessive disorder will not be affected, and his daughters will carry one copy of the mutated gene. With each pregnancy, a woman who carries an X‐linked recessive disorder has a 50% chance of having sons who are affected and a 50% chance of having daughters who carry one copy of the mutated gene. E.g Hemophilia A, Duchenne muscular dystrophy, Color blindness.

Fig:3 FIG:3 A pedigree illustrating an X linked recessive disorder. Affected individuals are depicted by solid colour and heterozygous carrier by dots.

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3. Polygenetic Conditions: These are multifactorial disorders, determined by nongenetic or environmental factors. Polygenetic conditions do not follow Mendelian law of inheritance.

4. Non-traditional Mechanism of Expression & Inheritance: Non-traditional mechanism of expression and inheritance occurs due to mutation in mitochondrial genome. It can be due to uniparental disomy i.e. two alleles from same locus inherited from one parent instead from both the parents. Hence it is also known as parent-of-origin effect.

MITOCHONDRIAL INHERITANCE: Majority of genes are enclosed inside the nuclear genome, however there are small number of gene located on mitochondrial DNA (mt DNA). The mtDNA consist of 16.kb of circular DNA and accounts for 1% of total DNA. It encodes protein for aerobic respiration. Each cell having functional mtDNA will be identical (homoplasmy). However mutation in mtDNA will lead to a mix blend of expression (heteroplasmy). The proportion of mitochondrial mutated DNA will determine the phenotypic expression of mutation. More than 85% of mtDNA mutation before there is a phonotypical significant defect in aerobic respiratory chain. To diagnose the disorders due to mutation in mtDNA muscle biopsy is profound over blood sampling to rule out false report, as in mtDNA mutation disorder there may be variation among different body tissues.

MUTATION: Mutation can be defined as alternation or change in genomic material. Mutation can be of two types depending upon the cell line involved:  Somatic

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Germinal At molecular level structural mutation can be majorly divided into following types: 1. Single base pair substitution: It involves substitution of one base pair for anther. Single base pair mutation is also known as point mutation. They can further be divided into :  Missense mutation: Replacement of one amino acid for another. E.g. in Sickle cell anaemia disorder A to T substitution in sixth codon of globin gene.  Non sense mutation: Replacement of an amino acid with stop codon i.e. UAA, UGA, UGA.  Splice site mutation: A single base substitution which creates or destroys an intron-exon splice site. 2. Deletion: These may vary in size from single base pair to mega base pair. E.g. More than 60% of mutations in Duchenne muscular dystrophy are due to deletion in dystrophic gene. 3. Insertion & Duplication: They occur as result of unequal crossing over at meiosis. 4. Frameshift mutation: They can occur either due to deletion or single base pair substitution resulting in misreading of subsequent following codon. 5. Dynamic mutation: These occur when triplet of nucleotide repeated in a gene and the transmission of exact number of repeat is unstable and may increase in further generation. E.g. Fragile X syndrome, Mental retardation. 6. Inversion: It occurs when there is break in two chromosomes, the segments flip over and re-join, resulting in in correct translation.

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MANIFESTATIONS OF GENETIC DISEASES

1.Adiposity, hyperthermia, oligomenorrhea and parotid swelling syndrome : This is also known as AHOP or AOP syndrome. It is caused by a hereditary alteration of some part of the diencephalon. It is thought to be transmitted as sex linked dominant character. Clinical features : The clinical findings are usually limited to females. It consists of adiposity, hyperthermia, oligomenorrhea, parotid swelling and psychic disturbances. The parotid swelling usually begins at the time of puberty and is bilateral. Occasionally the submandibular glands are also involved.

2.AARSKOG SYNDROME (Faciodigitogenital Syndrome) Aarskog–Scott syndrome is a rare disease inherited as autosomal dominant or X-linked and characterized by short stature, facial abnormalities, skeletal and genital anomalies. The Aarskog– Scott syndrome (AAS) is also known as the Aarskog syndrome, faciodigitogenital syndrome, shawl scrotum syndrome and faciogenital dysplasia. Clinical Features: The Aarskog–Scott syndrome is a disorder with short stature, hypertelorism, downslanting palpebral fissures, anteverted nostrils, joint laxity, shawl scrotum, and mental retardation. The physical phenotype varies with age and postpuberal males may have only minor remnant manifestations of the prepuberal phenotype.

24 Growth mild to moderate short stature evident by 1–3 years of age

 delayed adolescent growth spurt  Performance slight (dull normal) to moderate mental                           

deficiency hyperactivity and attention deficit social performance usually good Face, rounded face widow's peak hairline wide-set eyes (hypertelorism) droopy eyelids (blepharoptosis) downslanting eye slits (palpebral fissures) small nose with nostrils tipped forward (anteverted) underdeveloped mid-portion of the face (maxilla) wide groove above the upper lip (broad philtrum) crease below the lower lip delayed eruption of teeth top portion (upper helix) of the ear folded over slightly Hands and feet small, broad hands and feet short fingers and toes (brachydactyly) in-curving of the 5th finger (clinodactyly) mild interdigital webbing, between fingers as well as toes single transverse "simian crease" in palm broad thumbs and big toes Neck, short neck webbing of sides of the neck Chest, mild pectus excavatum (sunken chest) Abdomen, protruding navel inguinal hernias shawl scrotum undescended testicles

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Fig - 4

3) Adrenogenital syndrome :   

It occurs due to hyperplasia or tumors of the renal cortex. Pseudohermaphroditism, sexual precocity and virilizem in women or ferminization in men. Premature eruption of teeth if the disease begins in the early life.

4) Aglossia adactylia syndrome : (Hypoglossia hypodactylia syndrome) The etiology for the condition is unknown. There is no evidence that heredity plays a role in its genesis. There is no sex predilection. There is absence of tongue associated with failure of development of digits. The tongue in most cases is completely absent, or may be present as a small lobule in posterior part of the mouth. But the speech is not severely impaired. The sublingual muscular ridges may be markedly enlarged. Sublingual and submandibular glands may be hypertrophic. The mandible is usually small and poorly developed. Lower incisors have been noted to be missing. Extremities are severely affected, from

26 peromelia to absence of single digit. Both hands and feet are usually involved. Syndactyly has also been reported. Intelligence in these patients is not impaired.

Fig:5

5) Aldrich’s syndrome : (‘Wiskot Aldrich’ syndrome) Wiskott–Aldrich syndrome was linked in 1994[6] to mutations in a gene on the short arm of the X chromosome, which was termed Wiskott-Aldrich syndrome protein gene (WASp). The disease X-linked thrombocytopenia was later discovered to be also due to WASp mutations, but different ones from those that cause full-blown Wiskott–Aldrich syndrome  Inheritance: X-linked recessive  It is characterized by thrombocytopenic purpura,eczema and increased succesptibilty to infection.  Spontaneous bleeding from gingival and palatal petechiae can be seen. Classification: Jin et al. (2004) employ a numerical grading of severity: 0.5: intermittent thrombocytopenia 1.0: thrombocytopenia and small platelets

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2.0: 2.5: 3.0: 4.0:

5.0:

(microthrombocytopenia) microthrombocytopenia plus normally responsive eczema or occasional upper respiratory tract infections microthrombocytopenia plus therapy-responsive but severe eczema or airway infections requiring antibiotics microthrombocytopenia plus both eczema and airway infections requiring antibiotics microthrombocytopenia plus eczema continuously requiring therapy and/or severe or life-threatening infections microthrombocytopenia plus autoimmune disease or malignancy

Fig: 6 Eczematous lesions in infants

6) Amelo-onycho-hypohydrotic syndrome : A rare disorder characterized primarily by tooth and nail abnormalities and reduced sweating ability Clincal features:  Late tooth eruption  Premature tooth eruption  Unusual tooth shape  Everted lower lip  Decreased sweating

28            

Dental staining Enamel anomaly Anodontia Oligodontia Dry skin Fine hair Thin tooth enamel Thickened skin under nails Thin toenails Thin fingernails Hyperconvex nailsSeborrheic dermatitis will be present. In oral features severe hypoplastic hypocalcified enamel seen.

7) Antley-Bixler Syndrome: (Trapezoidocephaly-synostosis syndrome) It is a rare, very severe autosomal recessive congenital disorder characterized by malformations and deformities affecting the majority of the skeleton and other areas of the body. The disorder is suggested to be genetically heterogenous as two distinct gene mutation (FGFR2 & POR gene) are responsible for phenotypic expression of this syndrome. General manifestations: a) b) c) d) e) f) g) h) i) j)

Coronal and lambdoid craniosynostosis Brachycephaly Proptosis Choanal stenosis/atresia Maxillary hypoplasia Humeroraadial synoostosis Camptodactyly (fused interphalangeal joints in the fingers) Multiple contractures Cardiac malformations Nasal/anal atresia

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8) Albright’s Syndrome : (Polyostotic fibrous dysplasia, cutaneous pigmentation and endocrine disorders, Brown spot syndrome). Etiology of the syndrome is obscure. Heredity does not appear to be a factor in the syndrome. The syndrome consists of a classic triad of polyostotic fibrous dysplasia, pigmentation of skin and rarely mucous membrane and endocrine dysfunction.

Fig:7 Oral manifestations – Mandible is more commonly involved. It is enlarged, expanded and distorted. Pigmentation of the lips and buccal mucosa is rarely seen. Radiographic appearance :

Medullary portions of bone are rarefied and present irregular trabeculations. Radiographically the condition presents as a unilocular, multilocular or ground-glass or peau de orange appearance.

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Fig: 8

9. Anderson Syndrome: (Familial Osteodysplasia) It is inherited as an autosomal recessive trait. It is characterized by craniofacial and skeletal anomalies, presence of hyperuricemia and diastolic hypertension. Clincal features : 1. Mandibular prognathism. 2. Hypoplastic. 3. Maxilla and resultant malocclusion.

31 4. The mandible is with wide angle, increased body length, and reduced ramus and body height. 5. Spine abnormalities 6. Collar bone abnormalities 7. Pelvic abnormalities 8. Thigh bone abnormalities 9. Foot abnormalities 10. Skull abnormalities 11. High uric acid level in blood 12. Diastolic hypertension 13. Recurring fractures 14. Abnormal tooth positioning 15. Flat nose 16. Flat cheek bones 17. Kyphosis 18. Large nose 19. Pointy chin 20. Dental decay 21. Curved fifth finger 22. High blood pressure 23. Thick eyebrows

10) Angioosteohypertrophy Syndrome : (Klippel-Trenaunay-Weber syndrome, hypertrophy)

Hemangiectatic

The syndrome consists of unilateral nevus flammeus of the skin arranged segmentally, varices and hypertrophy of the skeletal and soft tissue developing at about the same time. It is transmitted as either an autosomal dominant or recessive trait. Oral manifestations : The soft and hard palate are most frequently involved. Angiomatosis of the tongue and pharynx were also reported. There is asymmetry of face because of bony hypertrophy; resulting in malocclusion and premature eruption of teeth on the involved side.

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11) Ankyloglossum Superius Syndrome : It consists of congenital ankylosis of tongue to the hard palate and anomalies of hands and feet such as hypoplasia or aplasia of digits and syndactyly. Oral manifestations : The tongue is usually attached to the hard palate, but may also be attached to upper alveolar ridge. The tongue is attached usually in the anterior part. The tongue functions like mobility and extrusion beyond the teeth are hindered. The upper central portion of lip is usually hypoplastic and mandible has been described as hypoplastic. Cleft lip and palate has also been recorded.

12) Aortic arch syndrome : (Subclavian artery occlusive syndrome, subclavian steal syndrome, vetebral –basilar artery occlusive syndrome, pulseless diesease)

Aortic arch syndrome problems are most often associated with trauma, blood clots, or malformations that develop before birth. The arteries' defects result in abnormal blood flow to the head, neck, or arms. In children, there are multiple types of aortic arch syndromes, including:   

Congenital absence of a branch of the aorta Isolation of the subclavian arteries Vascular rings

Symptoms vary according to the affected artery, but may include:  Neurological changes such as: o Dizziness o Blurred vision o Weakness  Blood pressure changes  Breathing problems  Numbness of an arm  Reduced pulse

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 

Transient ischemic attacks General features include dizziness, headache, visual disturbance and anginal pain. In oral features there is tropic ulceration and pain while chewing. It results due to deficient blood supply to the muscles of mastication.

13) Apert’s Syndrome (Acrocephalosyndactyly) : It is classified as a branchial arch syndrome, affecting the first branchial (or pharyngeal) arch, the precursor of the maxilla andmandible.

Fig: 8 Apert syndrome characterized by– 1) 2) 3) 4)

is

a

Craniosynostosis A cone shaped calvarium Midface hypoplasia Pharyngeal attenuation

developmental

malformation

34 5) 6) 7)

8)

Ocular manifestations Syndactyly of the hands and feet Mutations of either Ser252Trp or Pro253Arg in fibroblast growth factor receptor 2 (FGFR2) are responsible for nearly all known cases of Apert syndrome. Common dental features of acrocephalosyndactyly are a higharched palate, pseudomandibular prognathism (appearing as mandibular prognathism), a narrow palate, and crowding of the teeth.

Clinical features : a) Face : Face is usually asymmetric. The middle third of the face is underdeveloped and flat, producing a relative prognathism. The nose is usually described as parrot’s beak. Hypertelorism, exophthalmos and strabismus are often reported. b) Skull : The cranium is usually oxycephalic in appearance. The apex of the cranium is located near to or anterior to the bregma. Anterior fontanelle is open in numerous patients.

14) Ascher’s Syndrome: (Laffer-Ascher Syndrome) The etiology is unknown. However hormonal dysfunction, trauma and heredity are suggested as etiological agents. It is characterized by repeated episodes of lip and eyelid edema and occasionally euthyroid goiter. The syndrome generally occurs within the first 20 years of life Oral manifestations : There is a horizontal line running between the inner and outer parts of upper lip. Very rarely lower lip is also enlarged. The enlargement of lip may exist from childhood. The ‘extra lip’ or the tissue is usually seen when the patient smiles or during talking.

35 Microscopic examination of this excessive tissue usually consists of loose areolar tissue and hyperplastic mucous glands.

15) Ataxia Telangiectasia Syndrome: Also referred to as Louis–Bar syndrome is a rare, neurodegenerative, inherited disease causing severe disability. Ataxia refers to poor coordination and telangiectasia to small dilated blood vessels, both of which are hallmarks of the disease. Mutations in the ATM gene cause ataxia-telangiectasia. The ATM gene provides instructions for making a protein that helps control cell division and is involved in DNA repair. It is a neurocutaneous disorder transmitted as an autosomal recessive trait. Clinical features: a) Face: Face is relaxed, dull or sad. Shoulders are drooped and the head is tilted to one side. There are mild athetoid movements around the shoulders. b) Oral manifestations: Telangiectasia of the hard and soft palate has been reported. There is drooling of saliva and speech is slow, slurred and interrupted. Eye movements are slow and halted during lateral and upward gaze. Warning Signs of a Swallowing Problem  Choking or coughing when eating or drinking  Poor weight gain (during ages of expected growth) or weight loss at any age.  Excessive drooling  Mealtimes longer than 40 – 45 minutes, on a regular basis  Foods or drinks previously enjoyed are now refused or difficult  Chewing problems  Increase in the frequency or duration of breathing or respiratory

36  

problems Increase in lung infections

16) Baby Bottle Syndrome : Bottle mouth syndrome; also called as Nursing bottle caries. This syndrome has been attributed to prolonged use of: 1. Nursing bottle containing milk or milk formula, fruit juice or sweet water. 2. Breastfeeding or 3. Sugar or honey, sweetened pacifiers. Clinical features : It presents as a widespread carious destruction of deciduous teeth, most commonly the maxillary incisors, followed by first molars and then the cuspids. But the mandibular incisors are spared, which distinguishes this disease from rampant caries.

Fig: 9

Multiple carious teeth in children

17) Beckwith-Wiedemann Syndrome : Five common features used to define BWS are: macroglossia, macrosomia (birth weight and length greater than the 90th percentile), midline abdominal wall defects (omphalocele/

37 exomphalos, umbilical hernia, diastasis recti), ear creases or ear pits, and neonatal hypoglycemia (low blood sugar after birth). Oral features: 1. 2. 3. 4. 5.

Macroglossia Malocclusion, Anterior open bite Widely spaced teeth likely due to macroglossia Speech problems due to macroglossia

Most children with BWS do not have all of these five features. In addition, some children with BWS have other findings including: nevus flammeus, prominent occiput, midfacehypoplasia, hemihypertrophy, genitourinary anomalies (enlarged kidneys), cardiac anomalies, musculoskeletal abnormalities, and hearing loss. Also, some premature newborns with BWS do not have macroglossia until closer to their anticipated delivery date.

18) Beal syndrome: (Congenital contractual arachnodactyly) It is a rare congenital connective tissue disorder. It is caused by a mutation in FBN2 gene on chromosome 5q23. Contractures of varying degrees at birth, mainly involving the large joints, are present in all affected children. Elbows, knees and fingers are most commonly involved. The contractures may be mild and tend to reduce in severity. Manifestations: a. Cranial deformity b. Bowed long bones c. Muscle hypoplasia d. Mitral valve prolapse e. Arthrogyposis f. Arachnodactyly g. Kyphoscoliosis

38 h.

Abnormal helix of ear (crumpled ear)

19) Behcet’s Syndrome: Behcet’s disease is a systemic vasculitis characterized by recurrent oral and genital ulcers, and ocular inflammation, and which may involve the joints, skin, central nervous system and gastrointestinal tract. It is most common in those of Mediterranean and Eastern origin, although it also affects Caucasians. Genetic susceptibility : The genetic locus most widely studied in Behcet’s disease is the human leukocyte antigen (HLA) complex on chromosome. Clinical features : 1. Recurrent aphthous ulceration –  Oral ulcers  Genital ulcers 2. Skin disease –  Erythema nodosum  Superficial thrombophlebitis  Papulopustular lesions and acneiform nodules  Pathergy is the name give to non-specific hyperreactivity of the skin following minor trauma, which is specific to Behcet’s disease.

Fig: 10 Oral and Occular Ulcers

39

20) Blepharonasal Facial Syndrome: It is inherited as an autosomal dominant trait. It is characterized by joint disorders, craniofacial anomalies and mental retardation. Individual presents with microcephaly, and amtomongoloid slant of palpebral fissures, hypoplastic maxial, protruding lip and mild malocclusion as a result of mid facial hypoplasia.

21) Bloch-Sulzberger Syndrome: Incontinentia pigmenti also known as "Bloch–Siemens syndrome, "Bloch–Sulzbergerdisease, "Bloch–Sulzberger syndrome "melanoblastosis cutis," and "naevus pigmentosus systematicus". It is a genetic disorder that affects the skin, hair, teeth, nails, and central nervous system. It is named due to its microscopic appearance. It is transmitted as a sex-linked dominant trait, and it is lethal in males. More than 95% of reported cases occur in females. The etiology is not known. It is postulated that viral or infectious causes during pregnancy are predisposing factors. a) Oral manifestations : Oral changes are limited to the teeth. They include delayed teeth eruption, pegged or conical shaped crowns of teeth, missing teeth, malformed teeth and additional cusps. Both deciduous and permanent teeth are affected. b) Skin and skin appendages : After 2–3 days of birth, linear or grouped vesicles containing a honey colored serum appear on extremities. By the end of the first month the vesicles may disappear, recur or be replaced by irregularly distributed violaceous papules and inflammatory lesions. Pigmented macules, brownish-gray in color and arranged in a reticulated pattern or in streaks, whorls or

40 patches over trunk and extremities are seen at birth. This pigmentation begins to fade within a few years. It is heavy melanin pigmentation of the epithelium, dropping down into clusters of chromatophores in the upper dermis (incontinence, which gives the disease its name and is considered the hallmark of the syndrome). There is generalized baldness. Rarely finger nails are dystrophic and the breasts asymmetric. During the vesicular stage, microscopic examination reveals dense intraepithelial (or occasionally subepithelial) vesicles containing eosinophils.

22) Bogorad’s Syndrome (Crocodile tears syndrome, Gustatory lacrimation) In this condition the patient exhibits profuse lacrimation when food is eaten; particularly hot and spicy food. It generally follows facial paralysis; either of Bell’s palsy type or the result of herpes zoster, head injury or intracranial operative trauma. Facial nerve has several components – motor, sensory and autonomic – parasympathetic component. The autonomic parasympathetic fi bers arise in superior salivatory nucleus provide secretory and vasodilatory function to submandibular sublingual glands, via chorda tympani and to lacrimal gland the nerve of Wrisberg. If a lesion occurs proximal to geniculate ganglion, then during regeneration, fibers destined to submandibular and sublingual can get interchanged with those destined for lacrimal gland. Thus when gustatory stimuli are evoked, lacrimation is produced.

23) Books Syndrome : (Hyperhidrosis, Premature graying of the hair, and Premolar hypodontia; PHC syndrome). PHC syndrome (P–Premolar aplasia, H–Hyperhidrosis and C– Canities prematura). It is transmitted as an autosomal dominant condition, characterized by:  Premature graying of hair

41        

Premature graying of armpit hair Premature graying of pubic hair Excessive sweating of palms Excessive sweating of soles Missing tricuspid teeth .partial or total absence Missing premolar teeth Excessive sweating Premature gray hair

Clinical features: a) Oral manifestations : All bicuspids may be missing, or only one or two may be aplastic. Because of lack of bicuspids, there is retention of corresponding deciduous teeth. b) Hair : Canities prematura (early, diffuse whitening of the hair) is the most common sign. But pigmentation of skin is never affected. c) Sweating : There can be massive functional hyperhidrosis.

24) Bourneville-Pringle Syndrome : About 50% of these patients demonstrate a hereditary pattern. It is thought to be an irregular autosomal dominant inheritance. It consists of a triad of— 1. Epilepsy 2. Mental Deficiency 3. Aenoma. Oral manifestations : Oral mucosa may show fibrous growth in the anterior gingiva, lip, buccal mucosa, dorsum of tongue and palate. They are usually the color of normal mucosa, but might be bluish, red or yellow, ranging in size from pin-point to that of a small pea. High palatal vault, cleft lip or cleft palate has also been reported. Enamel hypoplasia (pitted enamel hypoplasia)occur in 70% of individuals.

42

25) Branchiootorenal syndrome (BOR SYNDROME): It is an autosomal dominant disorder characterized by sensorineural, conductive, or mixed hearing loss, structural defects of the outer, middle, and inner ear, branchial fistulas or cysts, and renal abnormalities ranging from mild hypoplasia to complete absence. Reduced penetrance and variable expressivity has been observed (Fraser et al., 1978). Melnick et al. (1978) maintained that the BOR syndrome is distinct from the BO syndrome because in the latter condition renal anomaly is absent and deafness is not a constant feature, Cremers and Fikkers-van Noord (1980) concluded that the 2 syndromes are in fact a single entity. Clinical Features: Melnick et al. (1975, 1976) described a family in which the father and 3 of 6 living children (a son and 2 daughters) had mixed hearing loss associated with a Mondini-type cochlear malformation (hypoplasia of cochlear apex shown by tomography) and stapes fixation, cup-shaped, anteverted pinnae, bilateral prehelical pits, bilateral branchial cleft fistulas, and bilateral renal dysplasia with anomalies of the collecting system. The father and affected son also had aplasia of the lacrimal ducts. A fourth child, who died at 5 months of age, was said to have had branchial cleft fistulas and bilateral polycystic kidneys. Conditions in the same nosoembryologic community were discussed. Fitch and Srolovitz (1976) reported a woman with preauricular pits, cervical fistulas, and partial deafness who gave birth to 2 children with preauricular pits and severe renal dysgenesis. Fraser et al. (1978) reported a kind red with the BOR syndrome. Clinical features included preauricular pits, branchial fistulas, sensorineural, conductive, or mixed hearing loss, lacrimal stenosis, and malformed external ears. Radiographic studies showed hypoplastic and malformed external ear canals, ossicles, and cochlea. Radiographic studies of the urinary tract showed

43 minor anomalies, including partially distorted pelvicalyceal systems, narrow pelviureteric junctions, and renal dysplasia. Not all features were expressed in those affected. Fraser et al. (1978) also provided a review of previously reported cases. Carmi et al. (1983) observed a man with the BOR syndrome and crossed renal ectopia who fathered 3 children born with bilateral renal agenesis and the Potter syndrome. Preisch et al. (1985) reported affected father, son, and daughter. The father and daughter showed unilateral tearing with eating, i.e., gustatory lacrimation. Another family reportedly showed the same phenomenon. Gustatory lacrimation, sometimes described as 'crocodile tears,' was noted by Gorlin (1976) to have been observed in over 100 cases but never in multiple members of families. Most cases are unilateral and often follow facial trauma or surgery but can occur as a congenital defect in innervation. Heimler and Lieber (1986) described a large, 4-generation kindred with branchiootorenal syndrome containing 16 individuals with confirmed manifestations of the disorder. Of these, only 4 had abnormalities in all 3 systems, whereas 7 had branchial arch and/or hearing defects but no reported renal abnormalities. However, because only 1 of these individuals had undergone detailed renal evaluation, it is possible that the incidents of renal defects in this kindred was higher than reported. Chitayat et al. (1992) made the diagnosis of BOR syndrome in a woman who had had 2 pregnancies complicated by oligohydramnios due to renal hypoplasia and agenesis. Both babies died neonatally of pulmonary hypoplasia. Histopathology of the temporal bones of the second child showed marked immaturity of the middle ear cleft, ossicles, facial nerve and canal, and cochlear nerve. The mother's renal ultrasound study was normal although intravenous pyelography indicated renal hypoplasia. The mother had a hearing problem first recognized at age 5 when abnormality of the right ossicular mass and antral region was found. A preauricular pit on the right in the mother was pictured.

44 Chen et al. (1995) described 45 individuals with the BOR syndrome, highlighting differences and similarities to findings reported by others. Characteristic temporal bone findings included hypoplasia of the cochlea, which was four-fifths of normal size with only 2 turns, dilation of the vestibular aqueduct, bulbous internal auditory canals, deep posterior fossa, and acutely angled promontories. They pictured a 3-generation family with various manifestations. Graham and Allanson (1999) described a 14-month-old girl with unilateral congenital cholesteatoma (604183) and anomalies of the facial nerve, in addition to the branchial arch, otic, and renal malformations that comprise the BOR syndrome. The mother also had the BOR syndrome and unilateral duplication of the facial nerve. This was said to be the first study of a BOR patient with congenital cholesteatoma and the second family in which cholesteatoma and anomalies of the facial nerve were described in patients with BO/BOR syndrome. In the branchiootorenal syndrome, renal defects, which are estimated to be severe in only 6% of patients, can include collecting system duplication, hypoplasia, cystic dysplasia, hydronephrosis, and agenesis (Izzedine et al., 2004).

26) Burning Mouth Syndrome : (Oral dysesthesia; Glossodynia; Glossopyrosis stomatodynia; Stomatopyrosis) Etiology : Many etiological factors have been suggested which include – a) Local factors– Denture irritation or sensitivity to denture base, candidiasis, bacterial infections, allergies to mercury. b) Systemic factors– Vitamin deficiency, hormonal and immunologic disturbances, iron deficiency and side effects of drugs. c) Psychogenic factors are also considered to play an important role in etiology of burning mouth syndrome.

45

d) Xerostomia : Chemical/ radiation induced, physiological/ psychological causes Clinical features : Patients with the syndrome describe their symptoms as ‘a burning feeling’ and the symptoms may vary from slight to severe. Women are more commonly involved than men in the age group between 40 and 49 years. The tongue is reported to be the most frequent site, followed by alveolar mucosa, lips and cheeks. It can be continuous or intermittent. Associated symptoms include taste disturbances, dry mouth, sleep disturbances, headaches and nonspecific health problems. The burning sensation can be quantified using linear analogue scales such as Visual Analog Scale.

Fig;11 Dry mouth with ulceration

27) Carpenter syndrome: (Acrocephalopolysyndactyly type II) Carpenter syndrome has been associated with mutations in the RAB23 gene,which is located on chromosome 6 in humans. The primary diagnostic factor is a malformation of the skull. The two most common types of craniosynostosis are sagittal and

46 bicoronal. Sagittal craniosynostosis manifests itself by causing a long narrow skull. It is quantitatively determined by measuring the anterior to posterior (front to back) diameter of the skull. An increased A-P diameter indicates a malformed fusion of the sagittal suture. Individuals affected with sagittal craniosynostosis have narrow, prominent foreheads and the back of the head is much larger than normal. The “soft spot” is very small or missing altogether with this particular type of craniosynostosis

Fig: 12 Clincal features: 1. 2. 3. 4. 5.

Acrocephaly Flat nasal bridge Syndactyly fingers/polysyndactyly toes Obesity Reduced height

47

28) Caffey-silverman syndrome : (Infantile cortical hyperostosis; Smyth’s syndrome) It has been suggested that the syndrome is caused by a congenital anomaly of the vessels supplying the periosteum of the involved bones. The hypoxia causes a focal necrosis of the overlying soft tissue resulting in new subperiosteal bone formation. An allergic phenomenon has also been suggested as the basis of disease, with edema and inflammation producing periosteal elevation and subsequent deposition of calcium. Recently attention has been brought to hereditary aspect that it appears to be transmitted as autosomal dominant trait. Clinical features : a) Oral manifestations : Mandible is most frequently affected and is the striking feature. It is manifested as symmetrical swelling of the mandible, usually the angle and ramus areas involved. Few patients also have severe malocclusion. Enamel hypoplasia is not seen despite the febrile component of the disease. b) Face : Because of the swelling, face is so striking that the condition may be diagnosed, especially when mandible is involved. The condition is initiated by tender, deeply placed soft tissue swellings over the face, thorax and extremities. This swelling can be accompanied by redness and increased temperature. Radiographic features : Mandibular involvement is manifested as gross thickening and sclerosis of the cortex due to an actively proliferating periosteum. Changes in other bone are similar.

48

29) Candidiasis endocrinopathy syndrome : The etiology of this syndrome is obscure. It is transmitted as autosomal recessive trait. Clinical features : The syndrome consists of chronic mucocutaneous candidiasis and presence of one or more autoimmune endocrinopathies, particularly hypoparathyroidism and/or Addison’s disease, chronic lymphocytic thyroiditis, pernicious anemia, diabetes mellitus are other immunologically related disorders. The candidal infection usually occurs in the first few years of life and precedes the endocrine problems by up to 13 years. Candidiasis is relatively mild and is usually restricted to oral cavity and finger nails (especially thumb nails). Other mucosal surfaces like esophagus, oropharynx, larynx and vagina can also be involved. There can also be candida induced strictures of oropharynx and esophagus which can cause dysphagia, and hoarseness of voice. A variety of immunologic abnormalities have been reported mainly those affecting the cell mediated immune system. It has been also reported that there is a specific inability to respond to antigens of Candida albicans. Therefore delayed hypersensitivity and/or production of lymphokines can be impaired or absent.

30) Carotid artery syndrome: Carotid artery syndrome or stylohyoid syndrome is caused by the elongated styloid process. It is an uncommon and under diagnosed clinical case. Often it presents with vaguepain in the throat, facial pain, and referred otalgia, difficulty in swallowing. The first mention of elongated styloid process as clinical entity in literature was by Luke in 1870. Very little correlation exists between extent of the ossification and the intensity of the symptoms. Patient may present with vague pain on swallowing, turning the head, or opening the mouth. Other symptoms could be earache, headache, dizziness or syncope. These symptoms are

49 caused may be because of impingement of glossopharyngeal nerve by the calcified ligament a) Deviated styloid process or ossified ligament causing impingement on the internal or external carotid artery exerting pressure. b) There is atypical facial pain.

Fig: 13 Orthopentomograph showing bilateral elongated styloid process.

31) Cerebro-costo-mandibular syndrome : It is an autosomal recessive condition. The disorder is characterized by thoracic deformities, mandibular and facial anomalies. Clinical features : It consists of microcephaly, long trunk, rib anomalies, producing gaps and tracheal cartilage malformation producing a barking cough. Oral features : It includes micrognathia, high arched palate and absence of uvula and soft palate.

50

32). Cerebo-oculo-facial-skeletal syndrome Cerebrooculofacioskeletal Syndrome, COFS Syndrome, Pena Shokeir II Syndrome, Pena Shokeir Syndrome Type II, Cockayne Syndrome type II. Cerebro-oculo-facio-skeletal (COFS) syndrome is a genetic degenerative disorder of the brain and spinal cord that begins before birth. The disorder is characterized by growth failure at birth and little or no neurological development, structural abnormalities of the eye and fixed bending of the spine and joints. Abnormalities of the skull, face, limbs and other parts of the body may also occur. COFS syndrome is inherited as an autosomal recessive genetic trait. COFS is now considered to be part of the spectrum of disorders within Cockayne syndrome. Individuals with cerebro-oculo-facio-skeletal syndrome are usually identified at birth or shortly thereafter, on the basis of their physical appearance and severe psychomotor retardation. However, some may present prenatally (Laugel 2013). The appearance of those affected by the disorder is relatively characteristic and includes the major diagnostic criteria of (1) microcephaly (2) ocular anomalies including cataracts, microphthalmia, optic atrophy, and blepharophimosis (Grizzard et al 1980) (3) dysmorphic facies with a high and broad nasal bridge, large ears, overhanging upper lip, and Micrognathia (4) musculo-skeletal abnormalities including flexion contractures of the limbs (arthrogryposis), scoliosis, hip dysplasia or dislocation, narrow pelvis, short stature, osteoporosis, dysplastic acetabula, and rocker-bottom feet with proximal displacement of the second metatarsals and longitudinal grooves in the soles along the second metatarsal.

51 Infants may also have a short neck, hirsutism, widely spaced nipples, single palmar creases, axial hypotonia, peripheral hypertonia, and renal anomalies. Affected children are usually small at birth due to intrauterine growth retardation; growth progresses poorly in the postnatal period as well (Pena and Shokeir 1974; Preus 1990; Laugel et al 2008). Affected infants may develop seizures including infantile spasms (Harden et al 1991). There is invariably severe motor delay. Few affected infants are capable of more than rolling over, and perhaps sitting, smiling, and learning a few words. Nevertheless, variable progression has led some authors to suggest that there are 2 subtypes of cerebro-oculo-facio-skeletal syndrome (Casteels et al 1991). Vision and hearing are often impaired. The children suffer from feeding difficulties and failure to thrive. In the terminal stages, the children may lose weight despite adequate caloric intake by tube feeding. Repeated respiratory infections eventually lead to death in infancy or early childhood, usually by 6 years, although one well-documented patient died at 11 years of age. At that time, it had become apparent that he resembled children with Cockayne syndrome in appearance and in regard to hypersensitivity to sunlight. CT scan of the brain reveals enlarged ventricles and subarachnoid spaces with white matter hypo-intensity in the infantile period followed by progressive calcification in the basal ganglia, white matter, and sometimes the cortex. Laboratory findings are nonspecific and amino acid survey is normal. Patients may exhibit mild hepatic dysfunction, and liver biopsies may show fatty infiltration or mild cirrhosis (Pena and Shokeir 1974). Some cases have elevated creatine kinase levels in infancy and muscle biopsies show slight sarcomeric disorganization and fibrosis (Lerman-Sagie et al 1987; GershoniBaruch et al 1991). Bone biopsies show necrotic chondrocytes and loss of osteocytes (Hwang et al 1982).

52 The neuropathological findings in cerebro-oculo-facioskeletal syndrome include: (1) Severe microcephaly and mild ventriculomegaly evident from birth; (2) Possible delayed myelination in cerebral structures with otherwise normal myelin structure (3) Swollen, pas-positive ubiquitinated granular glial cells in the white matter which appear shortly after the onset of myelination (4) Subsequent patchy or diffuse loss of myelin with atrophy and gliosis in the white matter (5) Progressive cortical atrophy (6) Parenchymal, pericapillary, and vascular mineralization in the globus pallidus and putamen, cerebral cortex at the depths of sulci, and white matter (7) Rare binucleate purkinje cells (8) Severe degenerative changes in the internal granular and purkinje cell layers of the cerebellum (9) Retinal degeneration with optic nerve atrophy (del bigio et al 1997). At birth and in infancy, the brains have a normal gyral pattern, cortical architecture, and cortical thickness suggesting that basic developmental processes are intact, although partial agenesis of the corpus callosum has been reported in 2 infants with cerebrooculo-facio-skeletal syndrome (Surana et al 1978; Sakai et al 1997). Small brain size with ventriculomegaly at birth suggests that the degenerative process begins in utero.

33) Chediak-higashi syndrome: It is an uncommon genetic disease, which is transmitted as an autosomal recessive trait. There is defect in granule containing cells, such as granulocytes and melanocytes. Abnormal granules also have been observed in renal tubular cells, nerve cells, and fibroblasts. The giant melanosomes in skin and hair result in pigment dilution.

53 Clinical features : Ulcerations of the oral mucosa, severe gingivitis and glossitis are commonly reported. There are recurrent bacterial infections of the skin and respiratory tract. The reason being abnormal granules seen in blood granulocytes results in neutrophils with decreased chemotactic and bactericidal ability, although phagocytosis remains intact. The abnormality in bactericidal activity is thought to be caused by an inefficient use of lysosomal enzymes. Other features : Hypopigmentation will be noted in skin & hair resulting from pigment dilution. Neuropathy and ataxia are prominent features in some patients. Photophobia, nystagmus, generalized lymphadenopathy and hepatosplenomegaly have also been reported. Laboratory findings : Hematologic studies show giant blue-gray granules in the cytoplasm of granulocytes. These granules are hallmark of the syndrome.

34) Cleft palate lateral synechia syndrome: The syndrome was first discussed by Fuhrmann and coworkers. Synechiae are adhesions between anatomic structures. Etiology : The cause is still unknown, but many theories have been proposed. Mathis postulated that the adhesion was remnants of Bucco pharyngeal membrane. Hayward and Avery thought the adhesions developed as a result of contact between epithelium of the palatine shelf and the floor of the mouth. It is inherited as an autosomal dominant trait.

54 Clinical features : Synechiae of oral cavity are fibrous adhesions which originate in the margins of the palatal cleft, and may also be found spanning the palatal cleft, and attach the mandibular alveolar ridge or floor of the mouth. These adhesions restrict the facial growth and there is elevation of floor of mouth and tongue. This in turn could inhibit the fusion of palatal shelves, resulting in cleft. Mandible is often hypoplastic and upper lip is short. Small tongue and often ankyloglossia have been reported. Radiographs demonstrate abnormal temporomandibular joint.

Fig: 14 Cleft lip

55

35) Cleidocranial dysostosis: (Cleidocranial dysplasia / Mutational dysostosis) It is an autosomal dominant hereditary congenital disorder. Etiology: It occurs due to mutations in the CBFA1 gene (also called Runx2), located on the short arm of chromosome 6, which encodes transcription factor required for osteoblast differentiation. The RUNX2 gene provides instructions for making a protein that is involved in bone and cartilage development and maintenance. This protein is a transcription factor, which means it attaches (binds) to specific regions of DNA and helps control the activity of particular genes. Researchers believe that the RUNX2 protein acts as a "master switch," regulating a number of other genes involved in the development of cells that build bones (osteoblasts). These genetic changes reduce or eliminate the activity of the protein produced from one copy of theRUNX2 gene in each cell, decreasing the total amount of functional RUNX2 protein. This shortage of functional RUNX2 protein interferes with normal bone and cartilage development, resulting in the signs and symptoms of cleidocranial dysplasia. Clinical features: 1. Painless swelling in the area of the clavicles at 2–3 years of age 2. Clavicles (collarbones) can be partly missing leaving only the medial part of the bone. 3. Prognathic mandible due to hypoplasia of maxilla 4. Short, tapered fingers and broad thumbs 5. An abnormal curvature of the spine (scoliosis)

56 6. Bones and joints are underdeveloped. 7. People are shorter and their frames are smaller than their siblings who do not have the condition. 8. Multiple unerupted supernumerary tooth 9. Missing gonial angle in radiograph 10. Failure of eruption of permanent teeth. 11. Bossing (bulging) of the forehead. 12. Open skull sutures, large fontanelles 13. Hypertelorism.

Fig: 15

Pic courtesy Dr. Vandana Singh

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36) Cockayne syndrome : (Weber-Cockayne syndrome, Neill-Dingwall syndrome) It iis a rare autosomal recessive condition and is associated with a group of disorders called leukodystrophies (conditions characterized by degradation of white matter). The underlying disorder is a defect in a DNA repair mechanism. Clinical features: It consists of primordial dwarfism, flexion deformities, kyphosis, hyperostosis of skull bones, sensitivity to sunlight and various eye anomalies such as atrophy, retinal degeneration and cataract. The child appears prematurely senile, with sunken eyes, prognathic mandible and carious teeth.

37) Coffin-lowry syndrome: Coffin–Lowry syndrome is a genetic disorder that is Xlinked dominant and which causes severe mental problems sometimes associated with abnormalities of growth, cardiac abnormalities, kyphoscoliosis, as well as auditory and visual abnormalities. The syndrome is caused by mutations in the RPS6KA3 gene.This gene is located on the short arm of the X chromosome. a) Oral features : 1. 2. 3. 4. 5. 6. 7. 8.

Mouth usually held open Full thick lips with pouty lower lip Relative mandibular prognathism due to Hypoplastic maxilla Malocclusion with overjet and/or overbite Hypodontia of lower permanent teeth Increased incidence of periodontal disease Hypoplastic teeth

b) General features :  Square forehead/bitemporal narrowing

58      

Prominent ears Cardiac abnormalities affect 15% of the patients. Progressive kyphoscoliosis affects 1 in 2 patients. Patients may also have an underdeveloped upper jaw bone, abnormally prominent brows, or widely spaced eyes. Auditory abnormalities are frequent and often present. Vision abnormalities are not often present.

38) Cornelia de lange syndrome : (Bushy Syndrome , Amsterdam dwarfism)

Cornelia de Lange Syndrome (CdLS) is a genetic disorder present from birth, but not always diagnosed at birth. It causes a range of physical, cognitive and medical challenges and affects both genders equally. a) Oral features : 1. Micrognathia 2. Down turned, thin lips cleft palate in 20% 3. Delayed tooth eruption and widely spaced microdontia often severe dental behavior problems.

Fig: 16

teeth

59 c) General features : 

Low birth weight (usually under 5 pounds/2.5 kilograms)



Delayed growth and small stature



Developmental delay



Limb differences (missing limbs or portions of limbs)



Small head size (microcephaly)



Thick eyebrows, which typically meet at midline (synophrys)



Long eyelashes Short upturned nose and thin downturned lips



Long philtrum



Excessive body hair



Small hands and feet



Small widely spaced teeth



Low-set ears



Hearing impairments



Vision abnormalities (e.g., ptosis, nystagmus, high myopia, hypertropia)



Partial joining of the second and third toes



Incurved 5th fingers (clinodactyly)



Gastroesophageal reflux



Seizures



Heart defects (e.g., pulmonary stenosis, VSD, ASD, coarctation of the aorta)

60

Fig: 17 Photograph depicting anodontia and abnormailities in feet. (Pic courtesy Dr. Deepa Meena)

Fig: 18 Radiograph showing absence of multiple teeth (Pic courtesy Dr. Deepa Meena)

39) Costen’s syndrome : It is a symptom complex originally described by Costen in 1934. It was proposed that the signs and symptoms of the syndrome arose because of loss of posterior teeth, resulting in over closure and altered temporomandibular joint function. The pain resulted from pressure on the chorda tympani or auriculotemporal

61 nerves. However, subsequent investigators have failed to support this evidence. Clinical features : Patients complain of continuous or intermittent heating impairment. Other complaints include stuffy sensation in the ears especially at meal time, tinnitus, sometimes accompanied by a snapping noise when chewing, otalgia, dizziness and head ache about the vertex, occiput and behind the ears. Burning sensation in the throat, tongue and side of nose are also reported.

40) Cowden syndrome : (Multiple hamartoma syndrome) It is an autosomal dominant disease characterized by facial trichilemmomas associated with gastro-intestinal tract, central nervous system, thyroid and muco-skeletal abnormalities. The characteristic hamartomas of Cowden syndrome are small, noncancerous growths that are most commonly found on the skin and mucous membranes (such as the lining of the mouth and nose), but can also occur in the intestinal tract and other parts of the body. They are largely benign. However, people with Cowden syndrome have an increased risk of developing several types of cancer, including cancers of the breast, thyroid, and uterus. Etiology: Mutations in the PTEN gene cause Cowden syndrome. PTEN is a tumor suppressor gene, which means it helps control the growth and division of cells. Inherited mutations in the PTEN gene have been found in about 80 percent of people with Cowden syndrome. These mutations prevent the PTEN protein from effectively regulating cell survival and division, which can lead to the formation of tumors. Cowden syndrome is one of several inherited diseases caused by mutations in the PTEN gene.

62 Clinical features: 1. Papillomatous lesion as well as pebbly lesions will occur on of lip, gingiva, palate and pharynx.

Fig: 19 Multiple fibromas over body Intraoral fibroma 2. Fibromas at various sites in oral cavity. 3. Hematoma of skin, gastro-intestinal tract, breast and thyroid. 4. Lichenoid and pappillomatous lesions of perioral, perinasal, and periorbital areas of ear and neck.

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41) Crest syndrome :     

C – Calcinosis cutis R – Raynaud’s phenomenon E – Esophageal dysfunction S – Sclerodactyly T – Telangiectasia

Systemic sclerosis is characterized by progressive fibrosis of skin and multiple organs, and by vascular insufficiency through abnormalities in arterioles and capillaries. This form of disease is sometimes not as severe as the systemic sclerosis. Calcinosis cutis is a disorder characterized by intermittent vasospastic episodes triggered by cold or emotional stimuli, resulting in ischemia of the fingers, toes or both. Clinically it is characterized by a typical triphasic color response, which consists of pallor, cyanosis and rubor in the same order of occurrence, involving the affected extremity.

42) Cri-du-chat syndrome : Cri du chat syndrome, also known as chromosome 5p deletion syndrome, 5p- (said minus) syndrome or Lejeune’s syndrome, is a rare genetic disorder due to a missing part (deletion) of chromosome 5. Its name is a French term (cat-cry or call of the cat) referring to the characteristic cat-like cry of affected children. Oral features : 1. 2. 3. 4.

Micrognathia Malocclusion Cleft Lip and palate

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Fig: 20

Difference in creases

General features : 1. 2. 3. 4. 5. 6. 7. 8. 9.

Cat-like cry Microcephaly Round face Epicanthal folds Low set ears Severe psychomotor problems Mental retardation Hypotonia Hypertelorism

65 10. Majority die in early childhood 11. Some survive to adulthood (IQ