Multiple congenital anomalies Flashcards
AARSKOG SYNDROME
Responsible gene:
Protein:
Cytogenetic locus:
Inheritance:
Clinical Features and Diagnostic Criteria:
Clinical Tests:
Molecular Tests:
Disease Mechanism:
Treatment/Prognosis:
Responsible gene: FGD1
Protein: Rho/Racguanine nucleotide exchange factor
Cytogenetic locus: Xp11.22
Inheritance: XLR (some AR, AD cases reported)
Clinical Features and Diagnostic Criteria: hypertelorism, shawl scrotum, brachydactyly, short stature, cryptorchidism, cervical vertebral abnormalities, ID (30%), milder manifestations in females
Clinical Tests: xray
Molecular Tests:FGD1sequencing (7-20%)
Disease Mechanism: unclear, FGD1/Rho GTPaseCdc42 implicated in cytoskeletal organization, and potentially in skeletal formation and morphogenesis
Treatment/Prognosis: orchiopexy, growth hormone trials have not been successful
BARDET-BIEDL SYNDROME
Responsible genes:
Proteins:
Cytogenetic loci:
Inheritance:
Clinical Features and Diagnostic Criteria:
Clinical Tests:
Molecular Tests:
Disease Mechanism:
Treatment/Prognosis:
Note: 19 genes cause BBS, example of locus heterogeneity
Responsible genes: BBS1, BBS10 (multiple additional genes id’ed)
Proteins: BBS1 protein, BBS10 protein
Cytogenetic loci: 11q13, 12q21.2
Inheritance: AR (though 10% BBS thought to be tri-allelic)
Clinical Features and Diagnostic Criteria: cone-rod dystrophy, truncal obesity, postaxial polydactyly, cognitive impairment, male hypogonadotrophichypogonadism, complex female genitourinary malformations, and renal dysfunction. Night blindness by age 7-8 yrs, legally blind by age 15.5 yrs. A majority have significant learning difficulties, only a minority have severe impairment. Renal disease is a major cause of morbidity and mortality.
Clinical Tests: atypical pigmentary retinal dystrophy with early macular involvement, renal anomalies on US
Molecular Tests:Targeted mutation analysis: p.M390R BBS1 (18%-32% of BBS) and C91fsX95BBS10 (10% of BBS).
Disease Mechanism: Defects in cilia or intraflagellartransport (IFT)
Treatment/Prognosis: visual aids and educational programs for the visually impaired; diet, exercise, and behavioral therapies for obesity; surgery to remove accessory digits; surgical repair of hydrocolpos, vaginal atresia, or hypospadias; HRT for hypogonadism.
**CHARGE SYNDROME
Responsible gene:
Protein:
Cytogenetic locus:
Inheritance:
Clinical Features and Diagnostic Criteria:
Clinical Tests:
Molecular Tests:
Disease Mechanism:
Treatment/Prognosis:
Responsible gene: CHD7
Protein: Chromodomain-helicase-DNA-binding protein7
Cytogenetic locus: 8q12.1
Inheritance: AD
Clinical Features and Diagnostic Criteria: 4/7: eye coloboma, heart anomaly (conotruncaldefects, arch abnormalities), choanal atresia, growth and mental retardation, genitourinary malformations (microphallus), ear anomalies (ossicular malformations, Mondinidefect of the cochlea) and/or deafness. Facial palsy, cleft palate, TE fistula, and dysphagia are commonly associated. 20-25% mortality in the first year
Clinical Tests: echocardiogram, audiology evaluation, temporal bone CT, renal ultrasound
Molecular Tests:CHD7 sequencing (60-65%)
Disease Mechanism: Haploinsufficiency. This class of proteins is thought to have pivotal roles in early embryonic development by affecting chromatin structure and gene expression
Treatment/Prognosis: Assess for airway compromise, swallowing problems, typical surgical correction of heart and GI malformations
CHARGE> CHD7> EAR> AD> Haplo
COFFIN-LOWRY SYNDROME
Responsible gene:
Protein:
Cytogenetic locus:
Inheritance:
Clinical Features and Diagnostic Criteria:
Clinical Tests:
Molecular Tests:
Disease Mechanism:
Treatment/Prognosis:
Responsible gene: RPS6KA3
Protein: Ribosomal protein S6 kinase alpha-3
Cytogenetic locus: Xp22.2-p22.1
Inheritance: XLD
Clinical Features and Diagnostic Criteria: severe to profound ID in males, short, soft fleshy hands, tapering fingers with small terminal phalanges, males <3% in height, microcephaly, stimulus induced drop episodes, kyphoscoliosis, characteristic facial features in older males, normal to profound ID in females.
Clinical Tests: x-ray: thickened skull, anterior vertebrae beaking, metacarpal pseudoepiphyses
Molecular Tests:RPS6KA3 sequencing (35-40%)
Disease Mechanism: unclear, RPS6KA3 is a member of the Ras signaling cascade and participates in cellular events such as proliferation and differentiation
Treatment/Prognosis: Medication for drop episodes, Rispieridonefor self-injurious behavior, annual cardiac exam with echo every 5-10 years.
CL> XLD> RAS signalling
CORNELIA DE LANGE SYNDROME
Responsible gene:
Protein:
Cytogenetic loci:
Inheritance:
Clinical Features and Diagnostic Criteria:
Clinical Tests:
Molecular Tests:
Disease Mechanism:
Responsible gene: NIPBL, SMC1A, SMC3, HDAC8, RAD21
Protein: Nipped-B-like protein, Structural maintenance of chromosomes protein 1A and 3, histone deacetylase 8, RAD21
Cytogenetic loci: 5p13.1, Xp11.22-p11.21, 10q25.2, Xq13.1, 8q24.11
Inheritance: AD (NIPBLand SMC3), XLR (SMC1L1)
Clinical Features and Diagnostic Criteria: pre/postnatal growth retardation, low anterior hairline and synophrys, diaphragmatic hernia, upper limb anomalies (hypoplastic middle phalanx of the index finger, hypoplastic thenareminence), ptosis, nystagmus, mod-severe ID, pulmonary valve stenosis and/or VSD
Clinical Tests: non are diagnostic
Molecular Tests:NIPBL sequencing (~50%), SMC1L1sequencing (4%), SMC3(<1%)
Disease Mechanism: Unknown, the majority of mutations are truncating, likely leading to protein haploinsufficiency
Treatment/Prognosis: Treat individual medical and developmental issues
CRI-DU-CHAT (5p MINUS SYNDROME)
Responsible gene(s):
Protein(s):
Cytogenetic locus:
Inheritance:
Clinical Features and Diagnostic Criteria:
Molecular Tests:
Disease Mechanism:
Responsible gene(s): RPS14?, microRNA 145 and 146a?
Protein(s):
Cytogenetic locus: 5p15.2
Inheritance: 12% due to unequal segregation of a translocation or recombination involving a pericentric inversion in one of the parents, 85% sporadic de novo deletions (80% are on the paternal chromosome)
Clinical Features and Diagnostic Criteria: Cat-like cry (abnormal laryngeal development), slow growth, microcephaly, ID, hypotonia, strabismus, characteristic facial features. Cat-like cry only when deletion limited to band 5p15.32
Molecular Tests:Most are visible, a few are submicroscopic and diagnosed by FISH for the critical region.
Disease Mechanism: A study of 50 patients with deletions ranging from 5p15.2 to 5p13 and found no correlation with size of deletion and degree of mental impairment
Treatment/Prognosis: Supportive care
GREIG CEPHALOPOLYSYNDACTYLY
Responsible gene:
Protein:
Cytogenetic locus:
Inheritance:
Clinical Features and Diagnostic Criteria:
Clinical Tests:
Molecular Tests:
Disease Mechanism:
Treatment/Prognosis:
Responsible gene: GLI3
Protein: Zinc finger protein GLI3
Cytogenetic locus: 7p13
Inheritance: AD
Clinical Features and Diagnostic Criteria: Major findings: macrocephaly, ocular hypertelorism, preaxial polydactyly, cutaneous syndactyly. Developmental delay, ID, or seizures (<10%)-more common in those with large (>300 kb) deletions including GLI3.Allelic with Pallister-Hall syndrome (caused by GLI3frame shifting mutations).
Clinical Tests: 500-600 band karyotype 7p13 translocation or interstitial deletion (5-10%)
Molecular Tests:GLI3sequence analysis (70%)
Disease Mechanism: GLI proteins regulate genes distal to Sonic Hedgehog in the SHH pathway. Pathogenesis of GCPS is haploinsufficiency
Treatment/Prognosis: Surgical correction of polydactyly and syndactyly as indicated. CNS imaging if HC increasing faster than normal to r/o hydrocephalus
JOUBERT SYNDROME
Responsible genes:
Proteins:
Inheritance:
Clinical Features and Diagnostic Criteria:
Clinical Tests:
Molecular Tests:
Treatment/Prognosis:
Responsible genes: NPHP1, AHI1, CEP290, TMEM67 and others (19 genes)
Proteins: Nephrocystin-1, Jouberin, Centrosomalprotein Cep290, MeckelinCytogenetic loci: 2q13, 6q23.3, 12q21.32, 8q21.1-q22.1
Inheritance: AR (19 genes with rare-4% prevalence)
Clinical Features and Diagnostic Criteria: Hypotonia in infancy leading to ataxia later, DD/ID, alternating tachypnea and/or apnea), pigmentary retinopathy, oculomotor apraxia or difficulty in smooth visual pursuits and jerkiness in gaze tracking. M:F, 2:1. Renal disease seen in those with retinal involvement. Rarely hepatic fibrosis.
Clinical Tests: Molar tooth sign (cerebellar vermis hypoplasia) on MRI, ERG, renal US, LFT’s
Molecular Tests:NPHP1FISH or deletion analysis (1-2%), Sequencing AHI1 (11%), CEP290(10%), TMEM67 (10%)
Disease Mechanism: The CEP290protein product modulates ATF4, a transcription factor implicated in renal cyst formation. Meckelinlocalizes to the primary cilium and plasma membrane of renal and biliary epithelial cells and other ciliated cells
Treatment/Prognosis: apnea monitoring, ST, G tube if severe dyspahgia, surgery as needed for eye disease, dialysis for nephronophthisis
KABUKI SYNDROME
Responsible genes:
Proteins:
Cytogenetic loci:
Inheritance:
Clinical Features and Diagnostic Criteria:
Clinical Tests:
Molecular Tests:
Disease Mechanism:
Treatment/Prognosis:
Responsible genes: KMT2D (66%), KDM6A
Proteins: MLL2, Lysine-specific demethylase 6A
Cytogenetic loci: 12q12-q14, Xp11.3
Inheritance: AD, XLD
Clinical Features and Diagnostic Criteria: unique facial features, fetal finger pads, IQ<80, joint laxity, high palate, hypotonia, short stature, CHD, CL/P, scoliosis, renal anomalies, hearing loss, speech delay
Clinical Tests: echocardiogram, renal ultrasound, eye exam, neuropsychological testing
Molecular Tests:MLL2 gene sequencing, KDM6A gene sequencing and deletion testing
Disease Mechanism: MLL2 encodes a protein that is part of the SET family of proteins, important to the epigenetic control of active chromatin states. Mutations are predicted to truncate the polypeptide chain before translation of the SET domain. H3K4 methylation by MLL2 is linked to the demethylation of H3K27 by KDM6A.
Treatment/Prognosis: Individual medical problems are treated as in the general population. GH for short stature if deficient. At risk for immunodeficiency.
MONOSOMY 1p36
Responsible genes:
Proteins:
Cytogenetic locus:
Clinical Features and Diagnostic Criteria:
Clinical Tests:
Molecular Tests:
Disease Mechanism:
Treatment/Prognosis:
Responsible genes: unknown Proteins: unknown
Cytogenetic locus: 1p36
Clinical Features and Diagnostic Criteria: The most common terminal deletion syndrome. Hypotonia, developmental delay, growth retardation, obesity, microcephaly, orofacial clefting, typical facial features. Also minor cardiac malformations, cardiomyopathy, seizures, ventricular dilation, SNHL
Clinical Tests: Brain CT/MRI
Molecular Tests:The deletion can be detected by HR karyotype, confirmatory FISH required in most cases. The majority are maternally derived.
Disease Mechanism: contiguous gene deletion syndrome
Treatment/Prognosis: symptomatic treatment
PRADER-WILLI SYNDROME
Responsible genes:
Cytogenetic locus:
Inheritance:
Clinical Features and Diagnostic Criteria:
Molecular Tests:
Disease Mechanism:
Treatment/Prognosis:
Responsible genes: Paternally expressed genes within the imprinted locus on 15q11-13 (SNURF-SNRPN, MKRN3, MAGEL2,and NDN)
Cytogenetic locus: 15q11-13
Inheritance: autosomal, expressed from paternal Ch 15
Clinical Features and Diagnostic Criteria: Hypothalamic insufficiency, neonatal hypotonia, developmental delay, hyperphagia leading to obesity, short stature, small hands and feet, hypogonadism, ID
Molecular Tests:3-5 Mb deletion of 15q11.2-q13 (~70%), matUPD(15%), PWS imprinting center defect (1-2%)
Disease Mechanism: unknown
Treatment/Prognosis: Monitor for feeding problems in infancy, obesity, OCD, psychosis, scoliosis, obstructive sleep apnea, diabetes, osteopenia
RUBENSTEIN-TAYBI SYNDROME
Responsible gene:
Protein:
Cytogenetic locus:
Inheritance:
Clinical Features and Diagnostic Criteria:
Clinical Tests:
Molecular Tests:
Disease Mechanism:
Treatment/Prognosis:
Responsible gene: CREBBP, EP300
Protein: CREB-binding protein, histone acetyltransferase-p300
Cytogenetic locus: 16p13.3, 22q13
Inheritance: AD though only a few cases of affected parent and child
Clinical Features and Diagnostic Criteria: microcephaly, beaked nose, broad thumbs and toes, cryptorchidism, growth delay, severe ID (35-50), congenital heart defect, strabismus, ptosis, sleep apnea, tumors (meningioma, pilomatrixoma, leukemia), behavior problems
Clinical Tests: ERG, echocardiogram, deletion or translocation occasionally seen on karyotype
Molecular Tests:FISH CREBBP (~10%), direct sequencing CREBBP (40-60%), EP300(~3%)
Disease Mechanism: Some CREBBPmutations lead to abnormal acetylation of histones, an important step in transcription activation
Treatment/Prognosis: Standard care for vision, hearing loss, heart defects, feeding problems. Some require thumb/toe surgery, behavior modification programs
SMITH-MAGENIS SYNDROME
Responsible gene:
Protein:
Cytogenetic locus:
Inheritance:
Clinical Features and Diagnostic Criteria:
Clinical Tests:
Molecular Tests:
Disease Mechanism:
Treatment/Prognosis:
Responsible gene: RAI1
Protein: Retinoic acid-induced protein 1
Cytogenetic locus: 17p11.2
Inheritance: AD (sporadic unless secondary to a parental balanced translocation)
Clinical Features and Diagnostic Criteria: mild-moderate infantile hypotonia, feeding problems and FTT, short stature, brachydactyly, ophthalmologic and ORL abnormalities, early speech delay with or without hearing loss, peripheral neuropathy, sleep problems, and stereotypic maladaptive behaviors (self-injurious behaviors, inattention+hyperactivity, impulsivity, disobedience, the “self-hug” and “lick and flip” page turning motion), mild-mod ID, coarsening face over time
Clinical Tests: Renal US, echo, spine x-ray, FISH, CMA for 17p11.2 deletion (~90%)
Molecular Tests:RAI1sequencing (5-10%)
Disease Mechanism: The RAI1gene product is thought to function in transcriptional regulation
Treatment/Prognosis: ST, sensory integration, psychotropic meds for attention issues, behavioral therapies, melatonin may help with sleep, monitoring for hypercholesterolemia. Annual team eval, TFTs, fasting lipid profile, UA, scoliosis check, eye exam
TRIPLOIDY
Cytogenetic abnormality:
Inheritance:
Clinical Features and Diagnostic Criteria:
Parent of origin effect:
Clinical Tests:
Molecular Tests:
Disease Mechanism:
Treatment/Prognosis:
Cytogenetic abnormality: 69,XXY>69,XXX (69,XYY very rare)
Inheritance: Sporadic without incrisk of recurrence
Clinical Features and Diagnostic Criteria: >99% lost in first trimester, accounts for 6-10% of all SAb’sand 16-20% of all chromosomally abnormal SAb’s. Dysplastic calvariawith large posterior fontanelle, ¾ finger syndactyly, ASD, VSD, hydrocephalus, holoprosencephaly.
Parent of origin effect: If Maternal: small placenta, severe asymmetric IUGR with a large head If Paternal: hydropic large placenta, well grown to mod symmetric IUGR, nlor microcephalichead
Clinical Tests: Prenatal US, maternal serum hCGlow
Molecular Tests:Karyotype
Disease Mechanism: Gynogenic triploidy(digyny): NDJ producing diploid oocyte, fertilization of ovulated primary oocyte, or polar body retention. Androgenic triploidy(Diandry) NDJ producing a diplodsperm or dispermy(most common)
Treatment/Prognosis: Very poor prognosis, may be better if triploid mosaic
TRISOMY13, PATAU SYNDROME
Inheritance: 20% due to a translocation
Clinical Features and Diagnostic Criteria:
Clinical Tests:
Molecular Tests:
Disease Mechanism:
Treatment/Prognosis:
Inheritance: 20% due to a translocation
Clinical Features and Diagnostic Criteria: The least common of the live born trisomy disorders. Holoprosencephaly, polydactyly, seizures, HL, microcephaly, midline CL/P, omphalocele, cardiac and renal anomalies, ID. Mosaic Tri 13: very broad phenotype from typical features of full trisomy to more mild ID and physical features and longer survival.
Clinical Tests: Brain MRI, EEG, audiogram, echo, renal US
Molecular Tests:Karyotype is diagnostic
Disease Mechanism: 75% are due to maternal nondysjunction, 20% to a translocation, and 5% to mosaicism. Defect in fusion of the midline prechordialmesoderm in the first three weeks of gestation cause the major midline dysmorphic features.
Treatment/Prognosis: 44% die in the first month, >70% die within one year. Severe ID exists in all survivors.
TRISOMY 18, EDWARDS SYNDROME
Inheritance:
Clinical Features and Diagnostic Criteria:
Clinical Tests:
Molecular Tests:
Disease Mechanism:
Treatment/Prognosis:
Inheritance: Less than 1% due to a translocation
Clinical Features and Diagnostic Criteria: clenched hand, fingers 2/5 overlap 3/4, IUGR, rocker bottom feet, micrognathia, prominent occiput, microphthalmia, VSD, ASD, PDA, generalized muscle spasm, renal anomalies, ID. Mosaic Tri 18 has variable but usually somewhat milder expression.
Clinical Tests: Echo, abdominal US. Maternal serum screen: low AFP, hCG, and UE3.
Molecular Tests:karytypeis diagnostic
Disease Mechanism: Maternal nondysjunction(90%), mosaicism (10%)
Treatment/Prognosis: 50% die in first week, 90% die by one year
TRISOMY 21,DOWNSYNDROME
Cytogenetic locus (loci):
Inheritance:
Clinical Features and Diagnostic Criteria:
Clinical Tests:
Molecular Tests:
Disease Mechanism:
Treatment/Prognosis:
Cytogenetic locus (loci): 21.22.1-22.2 has been called the DS critical region though there have been cases of duplication outside of this region who manifest DS
Inheritance: 95% de novo, 5% due to Robertsoniantranslocation or isochromosome21
Clinical Features and Diagnostic Criteria: mild-mod ID, hypotonia, growth delay, strabismus, adult cataracts, myopia, conductive HL, macroglossia, hypodontia, joint hyperflexibility, hypogenitalism, congenital heart defect, duodenal atresia, hirschprung, thyroid disease, early onset Alzheimers, transient myeloproliferation, ALL
Clinical Tests: prenatal US abnormalities detected in 50%, maternal serum screen: high free beta HCG, low PAPP-A,
Molecular Tests:maternal fetal free DNA testing, karyotype is diagnostic
Disease Mechanism: 90% due to maternal meiosis nondisjunction (¾ MI error, ¼ MII error)
Treatment/Prognosis: Supportive care, overall life expectancy is reduced
WOLF-HIRSCHORN SYNDROME
(4p minus, Monosomy 4p)
Responsible genes:
Protein:
Cytogenetic locus:
Inheritance:
Clinical Features and Diagnostic Criteria:
Clinical Tests:
Molecular Tests:
Disease Mechanism:
Treatment/Prognosis:
Responsible genes: 4p deletion, critical region includes two genes, WHSC1and WHSC2 of unknown significance
Protein: unknown
Cytogenetic locus: 4p; critical region: 165-kb region between markers D4S166 and D4S3327
Inheritance: 87% de novo, 13% due to unbalanced translocation from a balanced parent
Clinical Features and Diagnostic Criteria: “greekwarrior helmet appearance”, microcephaly, pre and postnatal growth deficiency, ID of variable degree, seizures, facial asymmetry, ptosis, IgA deficiency, structural brain anomalies, CL/P, CHD (ASD>PVS>VSD>PDA>AI>TOF), renal US
Clinical Tests: Distinctive EEG, Brain MRI, echo, plasma IgA level
Molecular Tests:HR karyotype for 4p16.3 deletion (60-70%), FISH/array CGH for critical region deletion (>95%)
Disease Mechanism: The function of WHSC1, WHSC2, and LETM1in normal development and in WHS patients is not known
Treatment/Prognosis: 2/3 develop valproate responsive atypical absence seizures, standard treatment of other medical problems
