Angelman Syndrome is a genetic disorder that affects the nervous system. The features of this condition include intellectual disability, a delay in developmental milestones, and movement disorders. The features occur as a result of the deletion or mutation of the maternal copy of the UBE3A gene located on Chromosome 15q. Though individuals usually inherit one copy of this gene from each parent, only the maternal gene remains active in parts of the brain. This phenomenon is known as genetic imprinting, and is also seen in Prader-Willi syndrome.

In the pattern of mendelian inheritance, X- linked dominant inheritance means that all who inherit the X chromosome will present with the condition. In the case of maternal x-linked inheritance sons and daughters have an equal chance of inheriting the condition as there is a 50% chance of inheriting the defective X chromosome from their mother as opposed to a non affected X chromosome from their father. However in paternal X-linked dominant inheritance, sons will be unaffected as they inherit a Y chromosome from their father while daughters are sure to inherit the defective X-chromosome.

In this case, the affected individuals are all heterozygotes. Therefore, the mutation is autosomal dominant. Also, the mother does not carry the mutation, further confirming the autosomal dominant nature of the disease, which is most probably achondroplasia.

The combination of cholestasis, congenital heart disease (mainly affecting the pulmonary vasculature) and anterior-segment abnormalities (primarily posterior embryotoxon) suggests a diagnosis of Alagille syndrome. Clinical features:The facial features are characteristic and include a prominent forehead, deep-set eyes and a pointed chin. The most common skeletal manifestation is butterfly vertebrae, a clefting abnormality of the vertebrae most often seen in the thoracic spine and described in up to 87% of cases. Radio-ulnar synostosis and short phalanges have also been described in Alagille but less frequently. Note: Pectus excavatum is a feature of Noonan syndrome, one of the differential diagnoses of pulmonary valve disease.

47,XYY syndrome is characterized by an extra copy of the Y chromosome in each of a male’s cells. Although many males with this condition are taller than average, the chromosomal change sometimes causes no unusual physical features. Most males with 47,XYY syndrome have normal production of the male sex hormone testosterone and normal sexual development, and they are usually able to father children.47,XYY syndrome is associated with an increased risk of learning disabilities and delayed development of speech and language skills. Affected boys can have delayed development of motor skills or hypotonia.Other signs and symptoms of this condition include hand tremors or other involuntary movements (motor tics), seizures, and asthma. Males with 47,XYY syndrome have an increased risk of behavioural, social, and emotional difficulties compared with their unaffected peers. These problems include attention-deficit/hyperactivity disorder (ADHD)| depression| anxiety| and autism spectrum disorder.Physical features related to 47,XYY syndrome can include increased belly fat, macrocephaly, macrodontia, flat feet (pes planus), fifth fingers that curve inward (clinodactyly), widely spaced eyes (ocular hypertelorism), and scoliosis. These characteristics vary widely among affected boys and men.

Cystic fibrosis has an autosomal recessive pattern of inheritance, meaning that a person might be a carrier of the disease without developing it. If the unaffected partner is a carrier, then there is a 50% chance of inheritance and another 50% chance of having a child who is a carrier. However, if the partner is not a carrier, the offspring will not develop the disease but the possibility of being a carrier raises up to 100%.

Familial/inherited short stature is the most likely and commonest factor resulting in short stature among the children. Klinefelter syndrome is characterised by tall stature, widely spaces nipples and infertility. Other factors include congenital heart disease, maternal deprivation and diabetes mellitus but these are the rare causes.

DiGeorge syndrome usually presents at a young age with abnormal faces. Chest x-ray is characterised by an absent thymic shadow and recurrent infections due to an abnormal T-cell mediated immune response. Sometimes it presents by convulsions of the new-born due to hypocalcaemia as a result of a malfunctioning parathyroid gland and low levels of PTH.

Neurofibromatosis is a genetic disease caused by the mutation of the neurofibromin gene on Chromosome 17. The diagnostic criteria for Neurofibromatosis type 1 are two or more of the following:-6 or more cafe au lait macules-2 or more cutaneous neurofibroma or one plexiform Neurofibroma-Axillary of groin freckling -Optic pathway glioma -2 or more Lisch nodules (hamartomas of the iris seen on slit lamp examination)-Bony dysplasia (such as sphenoid wing dysplasia, bowing of the long bones, or pseudarthrosis)-First degree relative with neurofibromatosis type 1

Ataxic gait is not a direct association of Down’s syndrome. All other given responses are associated with Down’s syndrome.

The trisomy 18 syndrome, also known as Edwards syndrome, is a common chromosomal disorder due to the presence of an extra chromosome 18, either full, mosaic trisomy, or partial trisomy 18q. The condition is the second most common autosomal trisomy syndrome after trisomy 21.Currently, most cases of trisomy 18 are prenatally diagnosed, based on screening by maternal age, maternal serum marker screening, or detection of sonographic abnormalities (e.g., increased nuchal translucency thickness, growth retardation, choroid plexus cyst, overlapping of fingers, and congenital heart defects ).The main clinical features include prenatal growth deficiency, characteristic craniofacial features (dolichocephaly, short palpebral fissures, micrognathia external anomalies of the ears, and redundant skin at the back of the neck), distinctive hand posture (overriding fingers: index finger overlapping the third and 5th finger overlapping the 4th), nail hypoplasia, short hallux, underdeveloped thumbs, short sternum, and club feet and major malformations (particularly involving the heart).

Klinefelter syndrome is a sex chromosome disorder in boys and men that results from the presence of an extra X chromosome in cells. People typically have 46 chromosomes in each cell, two of which are the sex chromosomes. Females have two X chromosomes (46,XX), and males have one X and one Y chromosome (46,XY). Most often, boys and men with Klinefelter syndrome have the usual X and Y chromosomes, plus one extra X chromosome, for a total of 47 chromosomes (47,XXY).Cri-du-chat (cat’s cry) syndrome, also known as 5p- (5p minus) syndrome, is a chromosomal condition that results when a piece of chromosome 5 is missing.Pierre Robin syndrome is not caused by a single gene defect but is a sequence.Meningomyelocele does not follow usual patterns of inheritance.

The physical features and developmental delay are the key aspects in the given scenario. The child in question shows features of gross motor and social developmental delay and has physical features indicative of Prader-Willi syndrome (hypopigmentation, esotropia, disproportionately small hands and feet, loss of central muscle tone and undescended testes). Children with Prader-Willi syndrome can present with failure to thrive until ,12-18 months, at which point, hyperphagia and obesity become more prominent. Other options:- Although Klinefelter syndrome can present with delayed development, undescended/small testes and reduced muscle power, the presence of small hands/feet, hypopigmentation and failure to thrive are not characteristic features. – Marfan syndrome presents with different physical features (arachnodactyly, cardio-respiratory complications and skin changes, amongst others) than those associated with Prader-Willi syndrome. – DiGeorge can manifest with developmental delay, hypotonia and feeding difficulties. However, this clinical scenario does not report any of the typical facial features, hearing abnormalities or cardiac abnormalities that are typically caused by DiGeorge syndrome. – Russell-Silver syndrome can cause developmental abnormalities, poor muscle tone and power (poor head control and muscle function), feeding difficulties and poor growth during the post-natal period and infancy. However, characteristic facial (small, triangular face, blue sclerae) and skeletal abnormalities (limb asymmetry, finger abnormalities) are not present. Therefore, Prader-Willi syndrome is the most appropriate diagnosis for this patient.Note:Prader-Willi syndrome is an example of genetic imprinting where the phenotype depends on whether the deletion occurs on a gene inherited from the mother or father: In Prader-Willi syndrome, it is the paternal gene that is deleted from the long arm of chromosome 15, while in Angelman syndrome the maternal gene is deleted. Prader-Willi syndrome can occur due to the microdeletion of paternal 15q11-13 (70% of cases) maternal uniparental disomy of chromosome 15.

Cystic fibrosis has an autosomal recessive pattern of inheritance, meaning that a person might be a carrier of the disease without developing it. If the unaffected partner is a carrier, then there is a 50% chance of inheritance and a 50% chance of having a child who is a carrier. However, if the partner is not a carrier, the offspring will not develop the disease but the possibility of being a carrier raises up to 100%.

Lesch-Nyhan syndrome is a condition that occurs almost exclusively in males. This condition is inherited in an X-linked recessive pattern It is characterized by neurological and behavioural abnormalities and the overproduction of uric acid. Uric acid is a waste product of normal chemical processes and is found in blood and urine. Excess uric acid can be released from the blood and build up under the skin and cause gouty arthritis (arthritis caused by an accumulation of uric acid in the joints). Uric acid accumulation can also cause kidney and bladder stones.The nervous system and behavioural disturbances experienced by people with Lesch-Nyhan syndrome include abnormal involuntary muscle movements, such as tensing of various muscles (dystonia), jerking movements (chorea), and flailing of the limbs (ballismus). People with Lesch-Nyhan syndrome usually cannot walk, require assistance sitting, and generally use a wheelchair. Self-injury (including biting and head banging) is the most common and distinctive behavioural problem in individuals with Lesch-Nyhan syndrome.

Chédiak–Higashi syndrome is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Familial adenomatous polyposis can have different inheritance patterns.When familial adenomatous polyposis results from mutations in the APC gene, it is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In most cases, an affected person has one parent with the condition.When familial adenomatous polyposis results from mutations in the MUTYH gene, it is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. Most often, the parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but do not show signs and symptoms of the condition.

Haemophilia is a X-linked recessive disorder. In X-linked recessive inheritance only males are affected. An exception to this seen in examinations are patients with Turner’s syndrome, who are affected due to only having one X chromosome. X-linked recessive disorders are transmitted by heterozygote females (carriers) and male-to-male transmission is not seen. Affected males can only have unaffected sons and carrier daughters.

Prader-Willi Syndrome is a genetic disorder that occurs when a chromosome from paternal chromosome 15q is deleted or unexpressed during the formation of the egg or sperm, or in embryonic development. Individuals usually inherit one copy of this gene from each parent, and in this case on the paternal gene remains active in parts of the brain and other organs. This phenomenon is known as genetic imprinting, and is also seen in Angelman’s syndrome. Symptoms seen in Prader-Willi range from poor muscle tone during infancy to developmental and cognitive delays. Many individuals suffer from hypogonadism that affects fertility in both males and females. In Angelman’s syndrome the maternal chromosome 15q is unexpressed. The condition is also called happy puppet syndrome as affected children present with a happy demeanour, ataxic gait, and flapping movements of the limbs.

Neurofibromatosis type 2, also known as schwannomin, is an autosomal dominant genetic disease caused by mutation of the merlin gene located on chromosome 22. Merlin is a tumour suppressor protein, which is responsible for controlling cell shape, growth and adhesion, and is predominantly found in nervous tissue. Its mutation increases the risk of tumour development especially bilateral vestibular schwannomas, the hallmark of neurofibromatosis 2.

Point mutations are the type of mutations in which only a single nucleotide of the DNA is either deleted, substituted or a new single nucleotide is inserted into the DNA, causing alterations in the original normal DNA sequencing. The examples of point mutations include hemochromatosis, sickle cell disease, and Tay-Sach’s disease. Huntington’s disease is a trinucleotide repeat disorder. Down’s syndrome is characterized by an extra copy of chromosome 21, while Klinefelter syndrome is marked by an extra X chromosome. Fragile X syndrome is also a trinucleotide repeat disorder.

The trisomy 18 syndrome, also known as Edwards syndrome, is a common chromosomal disorder due to the presence of an extra chromosome 18, either full, mosaic trisomy, or partial trisomy 18q. The condition is the second most common autosomal trisomy syndrome after trisomy 21.Currently, most cases of trisomy 18 are prenatally diagnosed, based on screening by maternal age, maternal serum marker screening, or detection of sonographic abnormalities (e.g., increased nuchal translucency thickness, growth retardation, choroid plexus cyst, overlapping of fingers, and congenital heart defects ).The main clinical features represent the clues for the diagnosis in the perinatal period and include prenatal growth deficiency, characteristic craniofacial features (dolichocephaly, short palpebral fissures, micrognathia external anomalies of the ears, and redundant skin at the back of the neck), distinctive hand posture (overriding fingers: index finger overlapping the third and 5th finger overlapping the 4th), nail hypoplasia, short hallux, underdeveloped thumbs, short sternum, and club feet and major malformations (particularly involving the heart).

Types of DNA mutations and their impactpoint mutation:Substitution: One base is incorrectly added during replication and replaces the pair in the corresponding position on the complementary strand as in Sickle cell anaemiaInsertion: One or more extra nucleotides are inserted into replicating DNA, often resulting in a frameshift as in one form of beta-thalassemiaDeletion: One or more nucleotides is skipped during replication or otherwise excised, often resulting in a frameshift as in Cystic fibrosis.Chromosomal mutation:Inversion: One region of a chromosome is flipped and reinserted as in Opitz-Kaveggia syndromeDeletion: A region of a chromosome is lost, resulting in the absence of all the genes in that area as in Cri du chat syndromeDuplication: A region of a chromosome is repeated, resulting in an increase in dosage from the genes in that region as in some cancers and Charcot-Marie toothTranslocation: A region from one chromosome is aberrantly attached to another chromosome as in One form of leukaemiaCopy number variation:Gene amplification: The number of tandem copies of a locus is increased as in Some breast cancersExpanding trinucleotide repeat: The normal number of repeated trinucleotide sequences is expanded as in Fragile X syndrome, Huntington’s disease

Advancing paternal age has been linked with lower quality sperm leading to a reduction in overall fertility and an increase in the occurrence of various medical disorders in the fetus. Advanced paternal age has been implicated as a risk factor for diseases like retinoblastoma, achondroplasia, autism spectrum disorders, schizophrenia, and acute lymphoblastic leukaemia. Down’s syndrome is mostly considered a consequence of advanced maternal age, but advanced paternal age has also been implicated as a risk factor.

In humans, each cell normally contains 23 pairs of chromosomes, for a total of 46. Twenty-two of these pairs, called autosomes, look the same in both males and females. The 23rd pair, the sex chromosomes, differ between males and females. Females have two copies of the X chromosome, while males have one X and one Y chromosome.

Treacher Collins syndrome is a congenital disorder transmitted in an autosomal dominant fashion. The basic abnormality is the TCOF 1 gene mutation, which leads to a multitude of clinical features, of which the most striking is the symmetrical craniofacial deformities. Important clinical features include conductive deafness, coloboma of lower eyelids, cleft palate, antimongoloid (short and downward slanting) palpebral fissures, deformed or absent ears, sleep apnoea, and airway issues. Hirsutism is not a recognized feature of this syndrome.

The most probable diagnosis in this patient is Noonan syndrome.Noonan syndrome is an autosomal dominant condition characterised by short stature, heart defects (mainly pulmonary stenosis) and learning difficulties. An affected foetus can present with a significant increase in the nuchal thickness or a cystic hygroma of the neck. The condition is variable, and an affected parent is often only diagnosed after the diagnosis in the child.

Pierre Robin sequence is a condition present at birth, in which the infant has micrognathia, a tongue that is placed further back than normal (glossoptosis), and cleft palate. This combination of features can lead to difficulty breathing and problems with eating early in life. Pierre Robin sequence may occur isolated or be associated with a variety of other signs and symptoms (described as syndromic). The exact causes of Pierre Robin syndrome are unknown. The most common otic anomaly is otitis media, occurring 80% of the time, followed by auricular anomalies in 75% of cases. Hearing loss, mostly conductive, occurs in 60% of patients, while external auditory canal atresia occurs in only 5% of patients.

Based on the clinical scenario provided, the most probable diagnosis for this patient would be tuberous sclerosis which is an autosomal dominant condition.Among the options provided, only Neurofibromatosis Type 1 is inherited by an autosomal dominant pattern. Other options:- Beckwith-Wiedemann syndrome is an example of an imprinting disorder and results from abnormalities of inheritance or methylation of chromosome 11p15.- Cystic fibrosis is an autosomal recessive condition.- Duchenne Muscular Dystrophy is an example of an X-linked recessive condition.- Hypophosphataemic (Vitamin D resistant) rickets is an X-linked dominant condition.

Although initially thought to affect only boys, girls with DMD also have an estimated 10% chance of inheriting the condition. In girls, DMD may present with all or some clinical manifestations.

Penetrance is defined as the percentage of individuals having a particular mutation or genotype who exhibit clinical signs or phenotype of the associated disorder or genotype.Gaucher disease is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Marfan syndrome is a disorder that affects the connective tissue found throughout the body, Marfan syndrome can affect many systems, often causing abnormalities in the heart, blood vessels, eyes, bones, and joints. The two primary features of Marfan syndrome are vision problems caused by a dislocated lens (ectopia lentis) in one or both eyes and aortic root disease, leading to aneurysmal dilatation, aortic regurgitation and dissection is the main cause of morbidity and mortality in Marfan syndrome.

The property described in the question is heterogeneity.Heterogeneity is when a single phenotype or genetic disorder can be caused by multiple numbers of genetic mutations.Other options:- Pleiotropy occurs when a single gene influences multiple phenotypic traits. The underlying mechanism is that the gene codes for a product that is used by various cells. A classic example of pleiotropy is the human disease PKU (phenylketonuria).- The penetrance of a disease-causing mutation is the proportion of individuals with the mutation who exhibit clinical symptoms. For example, the gene responsible for a particular autosomal dominant disorder has 70% penetrance, then 70% of those with the mutation will develop the disease, while 30% will not.

The most probable diagnosis for this patient would be Edward syndrome.Edward syndrome results from trisomy 18. It is the second most common syndrome after Down syndrome. 60% of cases die within 48 hours, and 90% within the first year due to apnoeas. Cardiovascular abnormalities include atrial septal defect, ventricular septal defect and a persistent ductus arteriosus. There is no association with exophthalmos, but it may occur. Right choroid plexus cysts are found on coronal imaging, and 40–70% at post mortem are shown to have multiple large bilateral choroid plexus cysts (>10 mm). These may not become pathological but usually trigger an anomaly scan. Around 1% of cases may present with only a cyst, but 4% may present with other abnormalities.Other options:- Children with the velocardiofacial syndrome have a classic facial appearance with hypertelorism, a tubular nose, a cleft lip/palate abnormality and cardiac anomalies. – Children with Patau syndrome usually present with midline defects and are less likely to have rocker-bottom feet. – Children with Treacher Collins syndrome present with abnormalities of the branchial arches and pharyngeal pouches.

Neurofibromatosis Type 1 (also known as von Recklinghausen disease) does not present with cataracts.The eye findings in NF1 are Lisch’s nodules, which are pigmentary lesions seen on the iris and constitute one of the major diagnostic features in this condition. Note:Interestingly, in another syndrome closely related to it, Neurofibromatosis type 2 (NF-2), cataracts can occur. Early detection in family members may be made by finding lens opacities (both congenital polar cataracts and posterior lenticular opacities). Other options:- Incontinentia pigmenti is an X-linked dominant disorder with pigmentary skin changes, mental retardation and eye involvement in 40% of cases. – Myotonic dystrophy is a triplet-repeat disorder with neurological symptoms and cataracts. – Lowe syndrome (oculo-cerebro-renal syndrome) is an X-linked recessive condition. Males with this X-linked recessive condition have cataracts, hypotonia, mental retardation, generalised aminoaciduria and renal tubular acidosis with hypophosphatemia. – Wilson disease is an inborn error of copper metabolism. The clinical features include hepatic involvement, progressive neurological features, eye involvement, including Kayser–Fleischer rings and cataracts.

Trisomy 21 (Down’s syndrome)is a genetic disorder characterized by the presence of an extra copy of chromosome 21 in all the body cells, mostly due to non-disjunction during gametogenesis. Robertsonian translocation occurs only in about 2-4% of the cases. A variety of clinical features are found in trisomy 21 due to multi-system involvement but the hallmark is hypotonia, which is present in almost all the cases of trisomy 21. Different types of leukemias are also found in association with down’s syndrome, but they are not the hallmark. Atlantoaxial subluxation is secondary to hypotonia, which induces joint and ligament laxity. Other clinical findings are hypothyroidism, Alzheimer’s disease, Hirschsprung’s disease, and pulmonary hypertension.

Turner’s syndrome is characterised by a webbed neck, short stature, primary amenorrhea and cardiac, renal and muscular defects. Gene analysis shows a single X chromosome in the patients. Downs syndrome has certain cognitive and physical abnormalities, whereas in Klinefelter syndrome there are widely spaced nipples, long arms and infertility and it only occurs in men.

Klinefelter’s syndrome is the most common sex chromosome linked disorder with a karyotype of 47XXY. The incidence of the disease is 1 in 500-1000 male births. Childhood presentation consists of unusual growth spurt along with learning difficulties and delayed speech. The adolescence is marked by abnormal sexual maturation leading to hypogonadism and sub-fertility in adulthood.

Hereditary diseases follow specific inheritance patterns according to the type of gene involved. Mutations in the genes which are on the sex chromosome, chromosome X are called X-linked diseases. X-linked recessive conditions result when both the copies of X-chromosomes are defective, which happens in the case of females since males have only one X- chromosome. Thus, these conditions are more common among males, and examples include colour blindness, haemophilia, Lesch-Nyhan syndrome, and hunter’s syndrome, etc. Hunter’s syndrome is a type of lysosomal storage disease which is also known as mucopolysaccharidosis II. Vitamin D resistant rickets is a X-linked dominant disease. Neurofibromatosis type 1 and 2 are autosomal dominant conditions while Wilson’s disease is autosomal recessive.

Tuberous sclerosis, an autosomal dominant disorder, may present with a variety of symptoms, including seizures, developmental delay, behavioural problems, skin abnormalities, and lung and kidney disease. Hamartomas are often associated.

Cystic fibrosis is a progressive, genetic disease. A defective gene causes a thick, sticky build-up of mucus in the lungs, pancreas, and other organs. In the lungs, the mucus clogs the airways and traps bacteria leading to infections, extensive lung damage, and eventually, respiratory failure. In the pancreas, the mucus prevents the release of digestive enzymes that allow the body to break down food and absorb vital nutrients. Since the digestive enzymes are not being made, the food is not completely digested making them bulky, smelly, and hard to flush away. Finger clubbing is a prominent feature of cystic fibrosis on most patients.

Marfan syndrome is a disorder that affects the connective tissue in many parts of the body. Connective tissue provides strength and flexibility to structures such as bones, ligaments, muscles, blood vessels, and heart valves. The signs and symptoms of Marfan syndrome vary widely in severity, timing of onset, and rate of progression.This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.At least 25 percent of Marfan syndrome cases result from a new mutation in the FBN1 gene. These cases occur in people with no history of the disorder in their family.The two primary features of Marfan syndrome are vision problems caused by a dislocated lens (ectopia lentis) in one or both eyes and defects in the large blood vessel that distributes blood from the heart to the rest of the body (the aorta).Associations include:Tall statureLearning disability (50%)Lens subluxation (usually upwards)Femoral herniaHemivertebraeCardiac problems (Aortic/mitral regurgitation, aneurysms)Joint hypermobilityArachnodactyly

Duchenne muscular dystrophy has an X-linked recessive pattern of inheritance. Since the first son is affected by the disease, it means that the mother is a carrier. The male children will inherit the Y chromosome from their father and the X chromosome from their mother, having 50% chances of inheriting the X chromosome with the affected gene.

Cystinosis is a condition characterized by accumulation of the amino acid cystine (a building block of proteins) within cells. This condition is inherited in an autosomal recessive pattern.Excess cystine damages cells and often forms crystals that can build up and cause problems in many organs and tissues. The kidneys and eyes are especially vulnerable to damage| the muscles, thyroid, pancreas, and testes may also be affected.There are three distinct types of cystinosis. In order of decreasing severity, they are nephropathic cystinosis, intermediate cystinosis, and non-nephropathic or ocular cystinosis.Nephropathic cystinosis begins in infancy, causing poor growth and a particular type of kidney damage (renal Fanconi syndrome) in which certain molecules that should be reabsorbed into the bloodstream are instead eliminated in the urine. The kidney problems lead to the loss of important minerals, salts, fluids, and many other nutrients. The loss of nutrients impairs growth and may result in soft, bowed bones (hypophosphatemic rickets), especially in the legs. The nutrient imbalances in the body lead to increased urination, thirst, dehydration, and abnormally acidic blood (acidosis). By about the age of 2, cystine crystals may be present in the clear covering of the eye (cornea). The build-up of these crystals in the eye causes pain and an increased sensitivity to light (photophobia). Untreated children will experience complete kidney failure by about the age of 10. Other signs and symptoms that may occur in untreated people, especially after adolescence, include muscle deterioration, blindness, inability to swallow, diabetes, thyroid and nervous system problems, and an inability to father children (infertility) in affected men.The signs and symptoms of intermediate cystinosis are the same as nephropathic cystinosis, but they occur at a later age.

Somatropin is a recombinant human growth hormone used to treat growth failure conditions associated with natural growth hormone deficiencies. According to the UK National Institute for Health and Care Excellence, these conditions include, Prader-Willi syndrome, Noonan syndrome, short stature Homeobox (SHOX) gene deficiency, Turner’s syndrome, chronic renal insufficiency and children who are small for gestational age. Treatment of short stature in achondroplasia has not seen any significant changes with somatotropin.

CF is inherited in an autosomal recessive manner.This means that to have CF, a person must have a mutation in both copies of the CFTR gene in each cell. People with CF inherit one mutated copy of the gene from each parent, who is referred to as a carrier.CF carriers can pass their copy of the CFTR gene mutation to their children. Each time two CF carriers have a child together, the chances are: 25 percent (1 in 4) the child will have CF50 percent (1 in 2) the child will be a carrier but will not have CF25 percent (1 in 4) the child will not be a carrier of the gene and will not have CFThis male’s parents are obligate carrier because he has a sibling with CFSo the chances he is a carrier too are 2 in 3The risk of having an affected child is the chance of both himself and his partner being carriers: (2/3 × 1/25 = 2/75) × 1/4 = 1/150.

Most cases of Trisomy 18, also called Edwards syndrome, are not inherited but occur as random events during the formation of eggs and sperm. An error in cell division called nondisjunction results in a reproductive cell with an abnormal number of chromosomes. For example, an egg or sperm cell may gain an extra copy of chromosome 18. If one of these atypical reproductive cells contributes to the genetic makeup of a child, the child will have an extra chromosome 18 in each of the body’s cells.Mosaic trisomy 18 is also not inherited. It occurs as a random event during cell division early in embryonic development. As a result, some of the body’s cells have the usual two copies of chromosome 18, and other cells have three copies of this chromosome.Partial trisomy 18 can be inherited. An unaffected person can carry a rearrangement of genetic material between chromosome 18 and another chromosome. This rearrangement is called a balanced translocation because there is no extra material from chromosome 18. Although they do not have signs of trisomy 18, people who carry this type of balanced translocation are at an increased risk of having children with the condition.Canavan disease is a type of leukodystrophy and a degenerative disorder that causes progressive damage to nerve cells in the brain. It is inherited in an autosomal recessive manner.Cystic Fibrosis is the most common lethal recessive disease of white people, with a carrier frequency of 1:25 and is inherited in an autosomal recessive manner.Galactosaemic is autosomal recessive and due to mutations in the GALT gene.Phenylketonuria is the most common inborn error of metabolism in the UK with an incidence of 1:10,000 and a carrier rate of 1:50.

The autosomal dominant pattern of inheritance involves the presence of at least one of the defected copies of the gene in an individual to develop a specific diseased condition. Examples of this mode of inheritance include myotonic dystrophy, neurofibromatosis, achondroplasia, etc. Still’s disease, also called juvenile idiopathic arthritis, is not a heritable disease. Tay-Sachs disease is an autosomal recessive disease., while spinocerebellar ataxia and Friedreich’s ataxia are caused by trinucleotide repeat expansion.

Cystic fibrosis is an autosomal recessive inherited disorder that affects the lungs or the pancreas. In the case of an affected child whose parents do not have the disorder but carry one copy of the mutated gene, each sibling has a 50% chance of being a carrier of the disease. They can inherit one copy of the gene from each parent. There is a 25 % chance that the child may inherit both mutated genes and be homozygous for the trait.

Ehlers-Danlos Syndrome (EDS) is a group of genetic connective tissue disorders with over 13 clinical subtypes. Hyper-mobility is common to many of these subtypes. Vascular EDS is identified by thin, translucent skin prone to easy bleeding, as well as the risk of early arterial rupture, gastrointestinal perforation and uterine rupture. Those affected have dysmorphic features including a thin nose and lips, sunken cheeks and large eyes. The other features including| atrophic scars, a dominant family history, hyper extensible skin and kyphoscoliosis are not specific to vascular EDS and overlap in many of the subtypes.

Tay-Sachs disease is an autosomal recessive disease. For the brother to present with the disease, both parents must be carriers. Therefore, with each pregnancy the probability that the child would be affected is 1 in 4| the probability that the child would be a carrier is 2 in 4| and the probability that the child would be unaffected is also 1 in 4. Unaffected children have a 2 in 3 chance, or 66%, of becoming a carrier according to the patterns of autosomal recessive inheritance.

Turner syndrome (TS) is one of the most common genetic disorders| occurs with an incidence of I: 2,500 female live births. It results from complete or partial chromosome X monosomy. TS is associated with abnormalities of the X chromosome and characteristic clinical features of short stature, gonadal dysgenesis, sexual developmental deficiencies, cardiac and/or renal defects, webbed neck, low-set ears, skeletal deformities including cubitus valgus, a propensity to ear infections and hearing deficits.

Congenital hypertrophy of the retinal pigment epithelium is one of FAP’s extra-intestinal manifestations. It appears in early childhood and affects an estimated 90% of those with FAP.

A patient with Down’s syndrome is likely to be subfertile rather than infertile.Down’s syndrome:The clinical features of Down’s syndrome include:- Face: upslanting palpebral fissures, epicanthic folds, Brushfield spots in iris, protruding tongue, small ears, and round/flat face- Flat occiput- Single palmar crease, pronounced ‘sandal gap’ in the first interdigital space of the feet.- Hypotonia- Congenital heart defects (40-50%)- Duodenal atresia- Hirschsprung’s diseaseThe cardiac complications in these patients include:- Endocardial cushion defect (40%)- Ventricular septal defect (30%)- Secundum atrial septal defect (10%)- Tetralogy of Fallot (5%)- Isolated patent ductus arteriosus (5%)The complications that occur later in the life of the patient include:- Subfertility: Males are almost always infertile due to impaired spermatogenesis. Females, however, are usually subfertile and have an increased incidence of problems with pregnancy and labour.- Learning difficulties- Short stature- Repeated respiratory infections (+hearing impairment from glue ear)- Acute lymphoblastic leukaemia- Hypothyroidism- Alzheimer’s disease- Atlantoaxial instability

Rett syndrome is a disorder that affects the brain and occurs most commonly in girls. It presents with a period of normal development followed by severe problems with language and communication, learning, coordination, and other brain functions.

Individuals with Down syndrome are at increased risk for a variety of eye and vision disorders. Fortunately, many of these eye problems can be treated, especially if discovered at an early age. The quality of life can be further enhanced by the proper assessment and correction of eye problems. The most common eye findings include:- Refractive errors – Children with Down syndrome are more likely to need glasses than are other children. This may be due to myopia (near-sightedness), hyperopia (far-sightedness), and/or astigmatism. Refractive error may develop early in life or later on.- Strabismus – Between 20% and 60% of individuals with Down syndrome have eyes that are misaligned (strabismus). Esotropia (eyes that drift in) is most common while exotropia(eyes that drift out) occurs less frequently. Strabismus may be treated with glasses, patching and/or eye muscle surgery.- Keratoconus – A cone shaped distortion of the cornea (front layer of the eye), occurs in up to 30% of those with Down syndrome. Keratoconus is usually diagnosed around puberty and should be monitored regularly. Blurred vision, corneal thinning, or corneal haze may result from keratoconus. Keratoconus is worsened by eye rubbing| therefore, eye rubbing should be discouraged.- Cataracts – There is an increased incidence of congenital cataracts (present at birth) as well as acquired cataracts (develop later). Cataracts may progress slowly and should be monitored regularly, with surgical treatment performed when appropriate.- Glaucoma- There is an increased risk of infantile glaucoma (elevated pressure within the eye).- Blepharitis – Inflammation of the eyelids with redness at the edge of the lids and crusting around the lashes may occur and cause a feeling of dryness or burning. Treatment is with eyelid hygiene and topical antibiotics.- Tearing – Excessive tears or watering of the eyes may occur because the drainage channels are blocked or narrow (nasolacrimal duct obstruction). This may require surgical intervention.- Nystagmus – This is an involuntary “back-and-forth” movement or shaking of the eyes. It can affect vision to a mild or severe degree.

These cardiovascular findings are suggestive of coarctation of the aorta, which is common among patients with Turner’s syndrome. Physical features of Turner’s syndrome include a short neck with a webbed appearance, a low hairline at the back of the head, low-set ears, and narrow fingernails and toenails that are turned upward.Atrioventricular septal defect is the most common cardiac anomaly in Down’s syndrome. Structural heart defects at birth (i.e., ventricular septal defect, atrial septal defect, patent ductus arteriosus) are common in Edward’s syndrome. Pulmonary stenosis with or without dysplastic pulmonary valve and hypertrophic cardiomyopathy are common in Noonan’s syndrome. Supravalvar aortic stenosis and peripheral pulmonary stenosis are found in William’s syndrome.

Most cases of Prader-Willi syndrome are not inherited, particularly those caused by a deletion in the paternal chromosome 15 or by maternal uniparental disomy. These genetic changes occur as random events during the formation of reproductive cells (eggs and sperm) or in early embryonic development. Affected people typically have no history of the disorder in their family.Rarely, a genetic change responsible for Prader-Willi syndrome can be inherited. For example, it is possible for a genetic change that abnormally inactivates genes on the paternal chromosome 15 to be passed from one generation to the next.Prader-Willi syndrome is a complex genetic condition that affects many parts of the body. In infancy, this condition is characterized by weak muscle tone (hypotonia), feeding difficulties, poor growth, and delayed development. Beginning in childhood, affected individuals develop an insatiable appetite, which leads to chronic overeating (hyperphagia) and obesity. Some people with Prader-Willi syndrome, particularly those with obesity, also develop type 2 diabetes (the most common form of diabetes).

Tuberous sclerosis is an autosomal dominant neurocutaneous condition associated with increased psychiatric co-morbidity. It results from the mutation of TSC1 or TSC2 tumour suppressor genes. Multiple benign tumours of the brain and other vital organs are characteristic of this disease. Important findings include subependymal nodules, bone cysts, cardiac rhabdomyoma, and learning difficulties. Lisch nodules of the iris occur in neurofibromatosis.

Advanced paternal age is associated with poor quality sperm leading to a reduction in overall fertility along with an increase in the occurrence of various medical disorders in the fetus. Advanced paternal age has been implicated as a risk factor for diseases like retinoblastoma, Marfan’s syndrome, neurofibromatosis, achondroplasia, autism spectrum disorders, schizophrenia, and acute lymphoblastic leukaemia. Down’s syndrome is mostly considered a consequence of advanced maternal age, but advanced paternal age has also been implicated as a risk factor. Turner syndrome is not found to be caused by advanced paternal age.