child who has features of a genetic disorder, e.g. at risk for a genetic condition for which at risk for a genetic condition with pediatric onset for which Inappropriate situations for genetic testing in a child \200 An asymptomatic child is at risk for a genetic condition that usually has onset in adult li fe for which preventive or effective therapeutic measures are not available, e.g. Huntingto n \200\231s disease. Testing for Practice does vary, but we recommend that testing be defer red until the child is old enough to seek testing in their own right, or at least to take p art in the discussion about testing. Parents sometimes request testing of young children wi thout having necessarily thought through the dif \201 culties this may lead to later on. W e suggest referral to clinical genetics if parents remain keen to perform carrier test. Gen etic testing of children for the should not be performed unless testing is necessary to pre vent substantial harm to the family member. carrier status, e.g. siblings of a child with cystic \201 brosis. bene \201 t of another family member 25_McClure_25.indd 932 11/14/2012 3:33:35 PM CHROMOSOME TESTS 933 Chromosome tests Karyotype analysis A standard chromosome analysis involves a G-banded kary otype viewed by a cytogeneticist using a light microscope. Using this approach, the maxi- m um resolution is 75 \200\22310Mb. One of the major advantages of a chromo- some analysis is that it is a genomic survey, i.e. it looks in outline at the whole genome. The normal male karyotype is 46, XY. The normal female karyotype is 46, XX. Fluorescence in situ hybridiza tion (FISH) Targeted studies are possible at higher resolution using speci \201 c FISH pro bes. Using FISH, it is possible to see the submicroscopic deletions re- sponsible for Willi ams syndrome (7q) and Angelman syndrome (15q), but only if the clinician speci \201 cally requests this. Molecular kayotyping using microarrays Microarray analysis is an ever improving technology which enables much higher resolution DNA analysis than is possible with light microscopy. I t has recently started to be used in clinical practice and has been especially valuable to clinical geneticists in identifying patients with chromosomal ab- normalities previously no t diagnosable by standard techniques. However, it is a specialist tool and is not routinely in use in pediatric settings. There are two main types of array: Targeted arrays These analyze selected regions of the genome, e.g. known syndromes and sub- telomeric regions. Genome-wide arrays These give genome-wide coverage at varying degrees of resolution ranging from 1Mb to 100kb, i.e. 10 \200\223100 times greater resolution than conventional light mi croscopy. It is important to appreciate that at high levels of reso- lution there is consid erable normal variation in the human genome. Copy number variation is routinely identi \201 ed both in pathological states and as normal family variants. Differentiating between the pathological and non- pathological variation is not within the compass of the non-speci alist. 25_McClure_25.indd 933 11/14/2012 3:33:35 PM CHAPTER 25 Genetics 934 Molecular genetic analysis The human genome contains 73,000,000,000 DNA base pairs and 725, 000 genes. In genetic disorders, the pathology may range from a whole extra chromosome, e.g . Down syndrome, to a single DNA base pair alteration, e.g. achondroplasia. Molecular genet ic tests are highly speci \201 c tests that only reveal information about one very speci \201 c gene analysis, generally selected because of a strong clinical diagnosis, e.g. achon droplasia. \200 commonly occurring mutation, analysis is simple and If there is a comparatively inexpensive, e.g. cystic \201 brosis and the CF29 kit tests f or the 29 most common mutations in the Caucasian population, and achondroplasia in which tw o common mutations, G1138A and G1138C in the FGFR3 gene, account for 798% of mutations in c hildren with achondroplasia). If the and takes 72 \200\2236 weeks for most tests. Such test s, based on information obtained from other family members, should involve a clinical genet icist. If the Genetic testing in this situation can be laborious, expensive (often 7 1000) , and only a small proportion may be available as diagnostic tests. In the UK, reporting ti mes are being reduced for these tests and now routinely take about 6 \200\2238wks, even for a very large challenging gene, e.g. FBN1 in Marfan syndrome and TSC1 and TSC2 in tuberous sclerosis. Consult a clinical geneticist about whether genetic testing is appropriate in th ese circumstances. mutation in a family is known, analysis is usually straightforward mutation is unknown, an entire gene may have to be sequenced. 25_McClure_25.indd 934 11/14/2012 3:33:36 PM PRACTICAL ISSUES RELATING TO GENETIC TESTING 935 Practical issues relating to genetic testing Counseling the family before testing Diagnosti c testing Think carefully about the potential impact of the diagnosis you may make with a g enetic test. Some genetic conditions are relentlessly progressive and life-limiting, e.g. D MD. Others imply lifelong impairment of a child \200\231s ability to learn and communicate, e.g. Angelman syndrome, fragile X syn- drome. If you make a genetic diagnosis, it is likel y to remain a permanent aspect of that child \200\231s life. There may be some treatable el ements to the condition, but it is unlikely to be transient or curable. The diagnosis may h ave implications for other family members. The family should preferably be counseled by a c linical geneticist, before a genetic test is performed. Ensure that the parents understand what you are testing for and why. Explain how long it may take to obtain a result and make careful arrange- ments for communicating the result. Predictive testing The circumstances in which this may be appropriate can be complex and ca n vary for different disorders. This should be arranged through a clinical geneticist. 25_McClure_25.indd 935 11/14/2012 3:33:36 PM CHAPTER 25 Genetics 936 Down syndrome Incidence 71 in 600 \200\223700 live births (incidence increases with advanci ng maternal age). Cause The great majority (795%) of babies with Down syndrome have trisomy 21, usually due t o non-disjunction during maternal oogenesis. 72% are the result of a Robertsonian transloca tion. 72% are mosaic, with a normal cell line as well as the trisomy 21 cell line. Clinical features \200 \200 \200 Usually presents at birth. Generalized hypotonia and marked head lag. Facial features: epic anthic folds, a \202 at facial pro \201 le, protruding tongue. Later Brush \201 eld \200\231s spots apparent in the iris (whitish spots). Flat occiput (brachycephaly) and shor t neck. Typical limb features: short broad hands (brachydactyly), short incurved little \201 ngers (clinodactyly), single transverse palmar crease, and a wide \200\230sandal \200 \231 gap between the \201 rst and second toes. Mildly short stature. Intellectual impairm ent becomes apparent. IQ scores range from 25 to 70. Social skills often exceed other intel lectual skills. small low-set ears, up-slanting eyes, prominent \200 \200 Associated conditions 7 \200 40 \200\22350% have congenital heart disease, most commonly a trio- ventricular septal defect (AVSD), ASD, VSD, Fallot tetralogy. GI problems include: du odenal atresia, anal atresia, HSD. Increased risk of infection. Developmental hip dysplasia . Eczema. Deafness: Cataracts. Leukemia (1%). Acquired hypothyroidism. \200 \200 \200 \200 \200 \200 \200 both sensorineural and conductive. Diagnosis If there is clinical suspicion of Down syndrome, a senior pediatrician should dis cuss their concerns with the parents. The diagnosis is con \201 rmed by a chromosome analy sis showing an additional chromosome 21. Most cytogenetics laboratories are able to offer a rapid analysis, e.g. interphase FISH, in order to establish the diagnosis quickly. 25_McClure_25.indd 936 11/14/2012 3:33:36 PM DOWN SYNDROME 937 Management \200 \200 Refer for a detailed cardiac assessment, hip US, and audiology. Genetic counseling by a cli nical geneticist should be offered. It is not necessary to undertake parental chromosome an alysis if the cause is non-disjunctional trisomy 21 or mosaic trisomy 21, but this is very important if the karyotype shows a translocation. Putting the parents in contact with a sup port organization, such as the Down Association, is often helpful (M www.downs-syndrome.org .uk and M www.ndss.org). Long-term follow-up should ideally be by a multidisciplinary team led by a pediatrician with special expertise, such as a developmental pediatrician, working in a child development center. Physiotherapy to improve tone and posture is often required . Routinely test TFT annually. Refer for audiology and ophthalmic assessment 1 \200\2232-ye arly. Almost all children with Down syndrome are now educated in mainstream schools with ap propriate educational support. \200 \200 Prognosis If deaths from congenital cardiac disease are excluded, life expectancy is well i nto adult life, although somewhat shortened as almost all develop Alzheimer disease by age 40yrs. Majority of adults can live semi-indepen- dently with supervision. 25_McClure_25.indd 937 11/14/2012 3:33:36 PM CHAPTER 25 Genetics 938 Common chromosomal disorders Down syndrome See b p.936 Klinefelter syndrome (47, XXY) \200 71/600 \200\2231/800 boys. \200 \200 Affects Majority caused by non-disjunction during maternal oogenesis. Boys with Klinefelter syndrome enter puberty normally, but by mid-puberty the testes begin to involute and the b oys develop hypergonadotrophic hypogonadism with decreased testosterone production (often t all and may develop feminine body build). Testes are small in adult life and men with Kline felter syndrome are generally infertile (azoospermia). Gynaecomastia develops at puberty in (cid:2)50%. Boys with Klinefelter syndrome typically have an IQ 715 points lower than thei r siblings. Many boys with Klinefelter syndrome remain undiagnosed throughout childhood, wi th the diagnosis only coming to light during investigation of infertility. Diagnosis is by chromosome analysis. Patau syndrome (trisomy 13) \200 7 \200 75% caused by non-disjunction during maternal oo genesis; 720% 71/6000 births. Incidence is Robertsonian translocation; 75% result from mosaicism. Trisomy 13 is usually diagnosed by a ntenatal US scan, since the majority of affected babies have multiple congenital anomalies. Typical malformations include: microphthalmia; cleft lip/palate; congenital heart disease (e.g. ASD or VSD); renal anomalies (e.g. fused kidneys); postaxial polydactyly; together wi th severe/profound mental retardation. If there is clinical suspicion of trisomy 13, a seni or pediatrician should discuss their concerns with the parents. The diagnosis is con \201 rmed by a chromosome analysis (additional chromosome 13). Most cytogenetics laboratories ar e able to offer a rapid analysis, e.g. interphase FISH, to con \201 rm the diagnosis quick ly. holoprosencephaly; SGA; microcephalic; Edwards \200\231 syndrome (trisomy 18) \200 \200 \200 71/8000 births. Incidence is Majority caused by non-disjunction during maternal oogenesis. Babies with tris omy 18 are usually SGA (mean birth weight 2240g) with an OFC <3rd centile. Other common fea tures include: congenital heart disease, usually VSD +/ \200\223 valve dysplasia; short ste rnum; overriding \201 ngers; \200\230rocker-bottom \200\231 feet. There is a strong fema le excess. Median life expectancy is 74 days, although some affected babies live for severa l months. If there is clinical suspicion of trisomy 18, a senior pediatrician should discus s their concerns with the parents. Initial rapid interphase FISH testing followed by formal chromosome analysis (additional chromosome 18). Turner syndrome (45, X) See b p.948 25_McClure_25.indd 938 11/14/2012 3:33:36 PM COMMON CHROMOSOMAL DISORDERS 939 25_McClure_25.indd 939 11/14/2012 3:33:36 PM CHAPTER 25 Genetics 940 Genetic disorders with cardiac features Many chromosomal disorders and genetic syndromes ar e characterized by congenital heart disease. Deletion 22q11 syndrome/velocardiofacial syndrome/Di George syndrome 71/4000. \200 \200 Incidence is Caused by a microdeletion on chromosome 22q11.2. Most children have a de novo microdeletion, but in 715% the condition is inherited from an affected parent. Apart from c ardiac defects, usually involving the aortic arch, features include subtle dysmorphism (wid e and prominent nasal bridge, down-slanting eyes, small mouth), parathyroid aplasia/hypopla sia (hypocalcaemia), thymus aplasia (T-cell de \201 ciency). Short stature is common. Cons ider this condition in all children diagnosed with TOF or aortic arch abnormalities, e.g. i nterrupted aortic arch (720% will have del(22q11)). Also consider in any child with CHD, e. g. VSD, who has hypernasal speech, cleft palate, including submucous cleft palate (may pres ent as nasal regurgitation of milk), hypocalcaemia, asymmetric crying facies, recurrent inf ections, or learning dif \201 culties, especially speech and language delay. Diagnosis wil l be missed on a routine chromosome analysis; it requires a FISH study. Marfan syndrome (MFS) \200 \200 71/5000 births. Incidence Variable autosomal dominant multisystem disorder caused by mutation in the FBN1 g ene on chromosome 15q. There is a high new mutation rate (730%). Features include: malforma tion of the sternum; scoliosis; high narrow palate; long \201 ngers (arachnodactyly); joi nt laxity. Most affected children are myopic and some may develop lens dislocation (a major diagnostic feature). Cardiac features: time, dilatation of the aortic root (another major diagnostic feature) may occur, leading eventually to ascending aorta aneurysm and aortic di ssection. Treatment with Losartan has greatly improved the outlook in terms of stabilizing aortic aneurysms. If genetic con \201 rmation of the diagnosis is required, this may be po ssible (in conjunction with a clinical geneticist) by mutation analysis of the FBN1 gene. tall and slim body build with long limbs; pectus initially, there may be a \202 oppy mitral valve. With 25_McClure_25.indd 940 11/14/2012 3:33:36 PM GENETIC DISORDERS WITH CARDIAC FEATURES 941 Noonan syndrome (NS) 71 in 2500 births. \200 \200 Incidence Autosomal dominant disorder. NS is genetically heterogeneous, with 750% caused by mutation in the PTPN11 gene on chromosome 12q. Mutation in several other genes in the RAS/ MAP kinase pathway have been reported in other NS cases and in clinically overlapping disor ders of cardio-facio-cutaneous syndrome and Costello syndrome. Features: ear abnormalities) , a broad neck, congenital heart disease (especially pulmonary stenosis), cardiomyopathy, c hest malformation with pectus carinatum superiorly and pectus excavatum inferiorly, mild de velopmental delay, and undescended testes. If genetic con \201 rmation of the diagnosis is required, this may be possible (in conjunction with a clinical geneticist) for some childr en by mutation analysis of the PTPN11 gene. short stature, typical facial features (hypertelorism, ptosis, Williams syndrome (WS) \200 Incidence is 1/7500 live births. \200 Caused by a microdele tion on chromosome 7q11 that encompasses the elastin gene. Associated cardiac defect is sup ravalvular aortic stenosis, often with peripheral pulmonary branch stenosis. Facial feature s include: peri-orbital fullness; full cheeks; anteverted nares; wide mouth with full lips; small widely spaced teeth. Most have mild mental retardation with strengths in language, b ut poor visuospatial skills. The typical behavioral phenotype is that of over-friendliness, short attention span, and anxiety. 7 \200 15% of infants have hypercalcaemia. \200 \200 Diagnosis is by FISH study for the 7q11 microdeletion For further information including gro wth charts see: syndrome.org/ M www.williams- 25_McClure_25.indd 941 11/14/2012 3:33:36 PM CHAPTER 25 Genetics 942 Genetic testing in cognitive impairment Amongst children with severe mental retardation, a high proportion will have a genetic cause. This can be elucidated in 750% of children, with chromosomal disorders being the largest group. Referral to clinical genet- ics should be c onsidered for all children with unexplained severe global developmental delay/mental retard ation. The referring pediatrician may undertake some basic diagnostic genetic testing, including the following: \200 Chromosome with unexplained developmental delay. Speci \201 c FISH tests for submicroscopi c microdeletions, e.g. Williams, 22q11 syndrome, can also be requested. Fragile disability, but remains a rare disorder. As it is often dif \201 cult to diagnose on clinical grounds , genetic testing should be offered to all children with developmental delay. Creatine dela yed motor milestones and/or global delay. Thyroid for congenital hypothyroidism on the newb orn blood spot screen. If this result was normal (need con \201 rmation), repeat investiga tion is not required unless there are clinical signs suggestive of hypothyroidism. Amino an d organic acids: inborn errors of metabolism are individually rare, but may present with no n-speci \201 c features, e.g. developmental delay and/or FTT. Plasma and urine samples sho uld be arranged if there is developmental regression, episodic decompensation, parental con sanguinity, a family history, or physical examination \201 ndings consistent with a metab olic disorder, e.g. microcephaly, macrocephaly, hepato-splenomegaly. \200\230Non-speci \201 c \200\231 abnormalities are more common than true diagnoses. Urine glycosaminoglycans (mucopolysaccharidoses): consider if developmental regression, glue ear, coarse features, macrocephaly. Ophthalmological eye signs (e.g. nystagmus), neurological signs, microcephaly . Audiology regarding hearing. Consider congenital infection: in children with intrauterine growth retardation, microcephaly, and eye/hearing signs. Requires comparison of maternal b ooking and current maternal serology. Useful for children up to 718 months of age. analysis: investigation with the highest yield for children X analysis: this is the commonest cause of inherited learning kinase in boys: DMD may present with speech delay and function tests: children born in the UK should have been tested opinion: especially if there is concern regarding vision, assessment: especially if there is speech delay or concern See M www.phgfoundation.org/pages/work.htm. 25_McClure_25.indd 942 11/14/2012 3:33:36 PM GENETIC TESTING IN COGNITIVE IMPAIRMENT 943 Angelman syndrome (AS) 71/40 000. \200 \200 Incidence AS is caused by impaired or absent function of the maternally imprinted UBE3A gen e on chromosome 15q11.13. A distinctive neurobehavioural condition with severe developmenta l delay, profound speech impairment, an ataxic wide-based gait, and a speci \201 c behavio ral phenotype (excitable personality, hand- \202 apping, and inappropriately happy affect) . Seizures are common. The genetics of AS are complex. Refer to a clinical geneticist. Fragile X syndrome (FRAXA) \200 71/5500 males. It is the most common inherited cause of Incidence mental retardation. Caused by a full expansion (>200 repeats) in the (CGG) in the FRAXA gene on chromosome Xq27.3. Boys with fragile X syndrome typically have global develo pmental delay often with gaze avoidance, stereotyped repetitive behaviors such as hand- \202 apping and resistance to change of routines. Up to 50% of girls with a full FRAXA expa nsion will have learning and behavioral dif \201 culties that are similar to, but less sev ere, than those seen in affected boys. Genetic counseling is very complex and there will be genetic implications for relatives. Referral to a clinical geneticist is recommended. n triplet repeat Prader \200\223Willi syndrome See b p.949 Rett syndrome \200 \200 71/10 000 female births. Affects Caused by mutation in the syndrome appear normal in the \201 rst 6 months of life . A severe neurodevelopmental disorder. Almost exclusively affects girls. Presents after ag e 1yr usually with developmental regression and loss of purposeful hand movements. May deve lop seizures, scoliosis, erratic breathing with episodes of breath-holding and hyperventila tion, and stereotypic hand-wringing. MECP2 gene on Xq28. Girls with Rett Smith \200\223Magenis syndrome \200 \200 \200 Affects at least 1/25,000 children. Usually caused by a Typical features include a broad fa ce with midface hypoplasia, brachydactyly, obesity, developmental delay/learning disability with behavioral disturbance, especially of sleep (night-time waking and daytime somnolence ). The diagnosis may be missed on a routine chromosome analysis and may require FISH for th e 17p11.2 microdeletion. de novo microdeletion on chromosome 17p11.2. Williams syndrome See b p.941 25_McClure_25.indd 943 11/14/2012 3:33:36 PM CHAPTER 25 Genetics 944 Genetic disorders with neuromuscular features The majority of severe neuromuscular disorder s affecting infants and children have a genetic basis. In addition to accurate assessment a nd ex- amination of the child, a detailed family history and examination of parents may som etimes be very helpful in establishing the diagnosis. Congenital myotonic dystrophy See also b pp.136 \200\223137, 546. \200 Caused by a triplet repeat expansion (CTG) on chromosome 19q. Congenitally affected infants usually have a huge expansion of the triplet repeat with >1000 repeats. Occurs in affected babies born to women who also have myotonic dystrophy (an AD disorder with onset usually i n adult life), even when mild or undiagnosed. Typically, there is polyhydramnios and at del ivery the baby is \202 oppy and may require prolonged ventilatory support. Diagnosis is u sually possible by careful examination of the mother (percussion myotonia) (also enquire if mother sleeps with eyes open) and analysis of a DNA sample from the infant. Neonatal morta lity is muscle weakness. Many have associated moderate intellectual impairment. n in the myotonin gene 720%. Survivors have static or slowly progressive Duchenne muscular dystrophy See also b p.546. \200 71/3500 male births: DMD is the most common and severe Affects form of childhood muscular dystrophy. Caused by mutations (deletions, duplications, and point mutations) in the dystrophin gene on chromosome Xq28. Presents with developmenta l delay, especially late walking and speech delay. In the early phase of the disease, boys have dif \201 culty rising from the \202 oor (Gower \200\231s maneuver sign where the ch ild climbs up his thighs with his hands to get up off the \202 oor). Later there is early loss of ambulation (mean age 79 years). Affected boys develop a progressive cardiomyopathy . 730% of boys with DMD have a mild learning disability that is not progressive. Serum CK i s grossly elevated, usually >10 times normal levels. Diagnosis is often possible by genetic testing, avoiding the need for muscle biopsy. DMD follows X-linked recessive inheritance a nd expert genetic counseling is an essential part of management. Death from cardiorespirato ry failure or infection usually occurs in the late teens or early 20s. 25_McClure_25.indd 944 11/14/2012 3:33:37 PM GENETIC DISORDERS WITH NEUROMUSCULAR FEATURES 945 Spinal muscular atrophy See also b p.540. \200 An AR disorder caused by bi-allelic mutation in the 5q13. 795% of infants with type 1 SMA a re homozygously deleted for exon 7 of the SMN1 gene. In severe cases, babies usually feed n ormally for the \201 rst few weeks with the earliest sign often being of a tiring infant who does not \201 nish his feed. Clinical examination may show fasciculations of the tong ue, an important clinical indicator. Develop symmetrical proximal muscle weakness as a cons equence of degeneration of the anterior horn cells of the spinal cord. Intelligence is unaf fected. Several types: \200 SMN gene on Type 1 SMA (severe) sit or walk. Usually die from respiratory failure by age 6 \200\22312mt hs. Type 2 SMA (intermediate) \200\224 but not to walk unaided. Survival into adult life is usual. Type 3 SMA (mild) \200\224 onset of proximal muscle weakness after age 2yrs. Abilit y to walk independently initially; survival into adult life. \200\224onset in \201 rst few months of life. Never able to onset before age 18mths. Able to sit, Diagnosis can be made by molecular genetic testing. 25_McClure_25.indd 945 11/14/2012 3:33:37 PM CHAPTER 25 Genetics 946 Genetic disorders with dermatological features Sometimes it is the cutaneous features that are the key to diagnosis of a genetic disorder (see also b Chapter 22). Ehlers \200\223Danlos syndrome (EDS) See b p.838. \200 Incidence \200 There are numerou s types of EDS. Classical EDS is autosomal dominant and caused by mutation in the COL5A1 an d COL5A2 genes. All forms of EDS are characterized by skin fragility, unsightly bruising an d scarring, musculoskeletal discomfort, and susceptibility to osteoarthritis. The skin is s oft and hyperextensible with easy bruising and thin, atrophic \200\230cigarette paper \200 \231 scars, joint hypermobility, varicose veins, and a risk of premature delivery in affect ed fetuses. Hypermobile EDS is a common and usually mild autosomal dominant disorder charac terized by soft skin with hypermobility of large and small joints. 71/5000 births. Neuro \201 bromatosis type 1 See also b pp.531, 662. \200 \200 \200 71/4000. NF1 has a prevalence of AD condition caused by mutation in the For a clinical diagnosis of NF1, the patient should have two or more of the following features: \200 \200 NF1 gene on 17q11.2. caf -au-lait spots ((cid:2)0.5cm in children); 6 or more 2 or more neuro \201 bromata of any type (dermal neuro \201 bromata are small l umps in the skin that appear in adolescence) or 1 or more plexiform neuro \201 bromata; fr eckling in the axilla, neck, or groin; optic glioma (tumor in the optic pathway); 2 or more Lisch nodules (benign iris hamartomas); a distinctive bony lesion, e.g. sphenoid wing dysp lasia, or dysplasia or thinning of the long bone cortex, e.g. pseudoarthrosis; a \201 rst -degree relative with NF1. \200 \200 \200 NF1 is a highly variable disorder with a small risk of serious complications, e.g. scoliosi s, pressure effects of tumors or malignant change, (e.g. neural crest tumors), hypertension . Regular surveillance, e.g. annual review, is recommended to try and detect these early. X-linked hypohidrotic ectodermal dysplasia \200 The condition follows X-linked recessive inheritance and is caused by mutation in the EDA-1 gene. Boys have reduced/absent sweating that may cause dangerous hyperpyrexia in infancy. Carrier females may be mildly affected. 25_McClure_25.indd 946 11/14/2012 3:33:37 PM GENETIC DISORDERS WITH DERMATOLOGICAL FEATURES 947 Tuberous sclerosis complex See also b pp.372, 530. \200 \200 71/10 000 individuals. Affects A highly variable autosomal dominant multisystem disorder caused by mutation in the TSC1 gene on 9q or the TSC2 gene on 16p. Characterized by hamartomas in the brain, skin, a nd other organs. Commonly presents with infantile spasms. Seizures and mental retardation a re often associated. Hypomelanotic macules ( \200\230ash-leaf \200\231 spots) occur in indi viduals by the age of 5yrs. A Wood \200\231s light (UV) may be needed to visualize these. A ngio \201 bromata occur in later childhood in a butter \202 y distribution over the nose and cheeks. Other cutaneous features include forehead \201 brous plaque, shagreen patches , ungual \201 bromata, and dental pits. 50% of individuals with TSC have normal intellige nce, but children who develop infantile spasms and severe epilepsy in the \201 rst year o f life often have learning disability. Thorough clinical evaluation, e.g. cranial MRI, eye exam, renal US, is indicated to make the diagnosis prior to genetic testing. Expert genetic advice, with careful evaluation of the parents, is important. 760% of cases arise as a res ult of new mutations. Genetic testing is possible by mutation analysis of TSC1 and TSC2, bu t it is helpful to establish a clear clinical diagnosis before embarking on genetic testing . \200 795% of affected Incontinentia pigmenti \200 Rare X-linked dominant disorder caused by mutation in the gene on Xq28 (780% carry a common deletion). Affected male pregnancies almost invariably miscarry. Girls present in the neon atal period with blistering lesions, cropping circumferentially on the trunk and in a linea r distribution on the limbs. Ultimately, lesions regress by late childhood/adult life to le ave atrophic streaky areas of pigmentation or hypopigmentation (often most noticeable on th e back of the calves). The child remains well and continues to feed. There is often a marke d eosinophilia in the blood. NEMO 7 \200 50% have associated abnormalities of dentition, eye (cataracts), or CNS (seizures, microcephaly). Genetic testing is possible; deletion in the NEMO gene. No sp eci \201 c treatment available. 780% of affected individuals carry a large 25_McClure_25.indd 947 11/14/2012 3:33:37 PM CHAPTER 25 Genetics 948 Genetic disorders of growth Assessment of growth plays an important role in deciding whethe r a child may have an underlying genetic disorder. Measurements <0.4th centile or >99.6th c entile nearly always merit further assessment, unless there is a clear explanation. Measure ments between the 0.4th and 2nd centiles or 98th and 99.6th need to be interpreted in conte xt and may be clinically signi \201 cant. If in doubt, discuss with a senior colleague. Intrauterine growth retardation (IUGR) Silver \200\223Russell syndrome \200 7 \200 10% o f children have maternal UPD7. \200 Incidence is unclear (1/3000 \200\223100 000 births). Equal sex ratio. Genetically heterogeneous condition characterized by intrauterine and postnatal growth reta rdation with short stature and FTT. Typically, babies have disproportionately large head (O FC usually 3rd \200\22325th centile), triangular facies, down-turned mouth, some asymmetry of limbs. About 30 \200\22350% of cases will show hypomethylation of the paternal chromosom e at the IC1 (imprinting center) on 11p15.5. Cornelia de Lange syndrome \200 \200 71/50,000 live births. Rare; incidence Intrauterine and postnatal growth impairment, limb anomalies, microcephaly, hirsutism, and distinctive facial features (neat arched eyebrows, short upturned nose, thi n lips with down-turned corners of the mouth). Approximately 60% of affected children have mutations in the gene NIPBL on chromosome 5p13. Short stature Turner syndrome See also b p.469. \200 \200 71/2500 females. Affects Most girls have a single X chromosome (45, X), usually due to non- disjunction. As well as short stature, the typical phenotype includes: broad neck; ptosis; wide carrying an gle at elbows (cubitas valgus); widely spaced hypoplastic nipples; low posterior hairline, excessive pigmented naevi. Puf \201 ness of the hands and feet is a common neonatal \201 nding. Associated abnormalities include: congenital heart disease (15 \200\22350%), especi ally coarctation of the aorta and VSD; structural renal anomalies (730%), e.g. horseshoe ki dney or unilateral renal agenesis; hypoplastic \200\230streak \200\231 ovaries (p amenorrh oea and infertility). The phenotype can be very subtle and is easily missed, and so a chrom osome analysis is usually offered to all girls with unexplained short stature. Tall stature Marfan syndrome See b p.940. 25_McClure_25.indd 948 11/14/2012 3:33:37 PM GENETIC DISORDERS OF GROWTH 949 Obesity Bardet \200\223Biedl syndrome (BBS) \200 \200 Rare condition; incidence in the UK population <1/100 000. Genetically heterogeneous with a t least 8 genes identi \201 ed to date. In the majority of families inheritance is autosom al recessive. Features include: cognitive impairment; renal defects. pigmentary retinopathy; postaxial polydactyly; obesity; Prader \200\223Willi syndrome (PWS) \200 71/10 000 individuals. \200 Affects Caused by disruption to the paternally derived imprinted domain on 15q11 \200\22313 . Babies are \202 oppy with feeding dif \201 culties and may fail to thrive in infancy. There is rapid weight gain between the ages of 1 and 6yrs. Older children have truncal obes ity, mild/moderate learning dif \201 culties, and short stature. Typically children have a n insatiable appetite with food-foraging and other behavioral problems. Diagnosis is by mol ecular genetic analysis ( SNRPN methylation assay). Overgrowth Beckwith \200\223Wiedemann syndrome \200 71/14,000. \200 Incidence Genetic basis is complex; it is caused by disruption of the imprinted region on c hromosome 11p15. Usually presents in the perinatal period with macrosomia. Birth weight is usually >97th centile and length is usually > +2SD. Polyhydramnios or preterm delivery comm only occur. There may be associated congenital anomalies: exomphalos/umbilical hernia; dysm orphic features (e.g. ear lobe creases, port wine stain, macroglossia (large tongue)); visc eromegaly; hemihypertrophy. Neonates are at risk for severe hypoglycaemia and should be mon itored closely. Macrosomia continues through early childhood and then becomes less dramatic with increasing age. Some children with BWS are at increased risk for Wilms \200\231 tumor . 750% diagnosis can be con \201 rmed by molecular genetic testing. In Uniparental disomy 11p15 analysis requires blood testing of child and both parents. \200 Sotos syndrome \200 Incidence \200 Due to mutation or deletion in the Most are isolated de novo mutations but familial cases do occur. 71/15 000 children. NSD1 gene on chromosome 5q35. Characterized by prenatal overgrowth (birth weight 74200g in males; 74000g in females), whi ch persists in childhood, especially through the pre-school years. Final adult height is of ten in the upper normal range. OFC is also increased and bone age is advanced. Affected chi ldren typi- cally have a tall skull with a prominent broad forehead and pointed chin. Devel opmental delay is almost always present, but varies from mild to severe. Some children have seizures. 25_McClure_25.indd 949 11/14/2012 3:33:37 PM 2 5 _ M c C l u r e _ 2 5 . 9 5 0 i n d d 9 S e e T a b e M i s c e l l a n e o u s 5 Table 25.1 Miscellaneous genetic conditions 0 C H A P T E R Syndrome Features Inheritance Chromosome Gene l Achondroplasia Short limbs, large head, \200\230trident \200\231 hand, \202 at midface, lumbar lordosis AD 4p16 FGFR3 2 5 1 2 5 G e n e t i c s Apert Craniostenosis, beaked nose, cleft palate, severe syndactyly ( \200\230mitten hand \200\231 ), d IQ Coloboma, congenital Heart disease, choanal Atresia, Retarded growth (short stature ), hypoGenitalism, external Ear abnormality and deafness AD 10q26 FGFR2 . CHARGE (see b pp.373, 846) AD (usually de novo) 8q12 CHD7 g e n e t i c 5p- (Cri du chat) Hypoplastic larynx (cat-like cry), small stature, microcephaly, micrognathia, low-set ears, hypertelorism, d IQ Craniostenosis, brachycephaly, prominent forehead, proptosis, beaked n ose Hypoplastic thumbs 9 radius, ASD, VSD Sloping forehead, OFC << 0.4th centile (< 4SD), m oderate mental retardation Sporadic 5p deletion (5p \200\223) FGFR2 Crouzon AD 10q26 TBX5 Holt \200\223Oram AD 12q MCPH1-7 c o n d i t i o n s Primary AR microcephaly AR Various DHCR7 Smith \200\223Lemli \200\223 Opitz (SLO) Ptosis, anteverted nostrils, narrow frontal region, hypospadias, toe syndactyly, d IQ Large head, small thorax, short limbs, lethal AR 11q12 \200\22313 Thanatophoric dysplasia Sporadic 4p16 FGFR3 Treacher \200\223Collins Malar hypoplasia, micrognathia, down-slanting eyes, ear malformations, deafness, lower eyel id coloboma AD 5q32 TCOF1 Zellweger Prominent forehead, large fontanelles, \202 at facies, hypotonia, stippled epiphyses, nys tagmus, hepatomegaly AR Various PEX1-14 1 1 / 1 4 / 2 0 1 2 3 : 3 3 : 3 7 P M 2 5 _ M c C l u r e _ 2 5 . i n d d 9 S e e T a b e M i s c e l l a n e o u s 5 Table 25.2 Miscellaneous congenital malformations 1 Condition Features Cause l Amniotic bands Congenital facial clefts, limb constrictions, amputations, syndactyly or talipes Annular amniotic bands 2 5 2 Diabetic embryopathy Macrosomia, organomegaly (particularly heart and liver), polycythaemia, caudal regression s yndrome (sacral and femoral agenesis or hypoplasia), transient hypertrophic cardiomyopathy, neural tube defects Maternal diabetes mellitus . M I S C E L L A N E O U S Fetal compression syndrome Joint contractions/dislocation, talipes, micrognathia, cleft palate, skull deformity In utero compression, e.g. maternal pelvic abnormality c o n g e n i t a l Fetal alcohol syndrome IUGR, hirsutism, microcephaly, mid-face hypoplasia, short palpebral \201 ssures, long smo oth philtrum, d IQ, low weight for height. Excessive maternal alcohol ingestion in pregnancy 2 \200\2233x increase in major malformations, growth retardation, midface hypoplasia, d IQ. Maternal valproate causes a 10x increased incidence of neural tube defects Fetal anticonvulsant syndrome Maternal anticonvulsant therapy in pregnancy C O N G E N T A L M A L F O R M A T O N S Goldenhar syndrome Asymmetric facial hypoplasia, eye coloboma/dermoid, ear hypoplasia, preauri- cular skin tag s, vertebral defects, cardiac defects (Fallot \200\231s tetralogy, VSD) Unknown. Usually sporadic m a l f o r m a t i o n s Klippel \200\223Feil syndrome Cervical vertebral fusion, low hair line, webbed neck, torticollis, kyphoscoliosis, deafnes s Usually sporadic I Moebius syndrome Immobile face, strabismus, limb defects, syndactyly Unknown, usually sporadic Pierre \200\223Robin sequence(see b p.847) Potter \200\231s sequence Micrognathia, glossoptosis, cleft palate Unknown (need to exclude del22q11). Usually sporadic Depressed nasal bridge, crumpled low set ears, talipes equinovarus, joint contractures, lun g hypoplasia and respiratory failure. Lethal Severe oligohydramnios due to renal or urethral abnormalities I VATER association(see b pp.373, 848) Vertebral defects, Anal atresia, Tracheo-oEsophageal \201 stula, Renal defects. (VACTERL = additional cardiac and radial limb defects) Unknown. Usually sporadic 1 1 / 1 4 9 5 1 / 2 0 1 2 3 : 3 3 : 3 8 P M This page intentionally left blank 953 Chapter 26 Inherited metabolic disease General principles 954 Metabolic syndromes: neurological 956 Metabolic syndromes: metabolic acidosis 958 Metabolic syndromes: storage dysmorphism 959 Metabolic syndromes: hepatic syn dromes 960 Metabolic syndromes: cardiac syndromes 962 Urea cycle disorders 964 Disorders of amino acid metabolism 965 Disorders of organic acid metabolism 966 Disorders of carbohydra te metabolism 967 Disorders of lipoprotein metabolism 967 Lysosomal storage diseases 968 Di sorders of fatty acid oxidation 970 Mitochondrial disorders 971 Peroxisomal disorders 972 D isorders of nucleotide metabolism 973 Disorders of porphyrin metabolism 974 Disorders of me tal metabolism and transportation 976 26_McClure_26.indd 953 11/14/2012 3:34:53 PM CHAPTER 26 Inherited metabolic disease 954 General principles Inherited metabolic disease (IMD) may present at any age and the signs a nd symptoms may result from: \200 \200 \200 s \200 