Diseases to Review Flashcards

Question

``` bilateral vestibular schwannomas (or other schwannomas) balance dysfunction tinnitus hearing loss meningiomas ependymomas astrocytomas retinal hamartomas thickened optic nerves cortical wedge cataracts third cranial nerve palsy mononeuropathy ```

Answer 1

Neurofibromatosis Type II (NF2) NF2 AD Clinical criteria (1+ of the following) -bilateral vestibular schwannomas -first degree relative with NF2 AND any two (meningioma, schwannoma, glioma, neurofibroma, cataract in the form of posterior subcapsular lenticular opacities or cortical wedge cataract) -unilateral vestibular schwannoma AND any two (meningioma, schwanoma, glioma, neurofibroma, cataract in the form of posterior subcapsular lenticular opacities or cortical wedge cataract) -multiple meningiomas AND unilateral vestibular schwanoma OR any two (schwannoma, glioma, neurofibroma, cataract in the form of posterior subcapsular lenticular opacities or cortical wedge cataract) OR molecular genetic testing Managed with stereotactic radiosurgery (with gamma knife), annual MRI exams starting at 10-12 y/o until 4th decade, avoidance of radiation therapy for NF2 associated tumors

Answer 2

Cowden Syndrome PTEN AD Diagnosed with mol gen testing treatment of tumors (topical agents, curettage, cryosurgery, or laser ablation) thyroid US and cancer screening (mammograms and colonoscopy)

Answer 3

Bannayan-Riley-Ruvalcaba syndrome PTEN AD Mol gen testing treatment of tumors (topical agents, curettage, cryosurgery, or laser ablation) thyroid US and cancer screening (colonoscopy)

Answer 4

``` Proteus Syndrome PTEN AD Mol gen testing treatment of tumors (topical agents, curettage, cryosurgery, or laser ablation) thyroid US and cancer screenings ```

Answer 5

Tuberous Sclerosis TSC1, TSC2 AD Diagnosed clinically- 2 major criteria OR 1 major and 2+ minor: Major (>3 angiofibromas or fiberous cephalic plaque, cardiac rhabdomyoma, multiple cortical tubers and/or radial migration lines, >3 hypomelanotic macules at least 5 mm in diameter, lymphangioleiomyomatosis (LAM), multiple retinal nodular hamartomas, >2 renal angiomyolipomas, shagreen patch, subependymal giant cell astrocytoma, >2 subependymal nodules, >2 ungual fibromas) Minor (sclerotic bone lesions, numerous confetti skin lesions, >3 dental enamel pits, >2 intraoral fibromas, multiple renal cysts, nonrenal hamartomas, retinal achromic patch) Managed with mTOR inhibitors for SEGA, renal angiomyolipomas, and LAM (topical for facial angiofibromas), brain MRI Q1-2 years and MRI abdomen, ECHO Q1-3 years in infants/children with cardiac findings, annual renal function assessment, HRCT to assess/look for LAM, avoid smoking, estrogen, and nephrectomy

Answer 6

Von-Hippel-Lindau Syndrome VHL AD Clinical diagnosis - NO known fhx with 2+ characteristic lesions (2+ hemangioblastomas of retina, spinal cord, or brain OR 1 in association with visceral manifestations; renal call carcinoma; adrenal or extra-adrenal pheochromocytomas; endolymphatic sac tumors, papillary cystadenomas of the epididymis or broad ligament, or neuroendocrine tumors of the pancreas) -Known fhx AND 1+ of symptoms (retinal angioma, spinal/cerebellar hemangioblastoma, adrenal/extra-adrenal pheochromocytoma, renal cell carcinoma, multiple renal/pancreatic cysts) Mol gen testing Surgical removal of tumors/lesions Renal transplant Annual neuro, opthal, audio evals and bp monitoring beginning at 1 y/o Annual plasma/24-hour urine fractioned metanephrines starting at age 5 Annual abdominal US and MRI of abdomen and brain with total spine every 2 years beginning at 16 y/o

Answer 7

Xeroderma Pigmentosum XPC, XPA, ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, POLH, DDB2 AR Managed with treatment per malignant/non-malignant lesion per general recommendations, avoidance of sun/UV exposures, supplementation of vitamin D PRN, and skin exams every 3-12 months and routine eye/neuro evaluations Molecular genetic testing to diagnose

Answer 8

``` Aaskog-Scott Syndrome FDG1 AR/AD/XL (most are XL) Rare Diagnosed with mol gen testing Learning/behavioral assessment and neuopsych interventions Growth hormone not helpful ```

Answer 9

CHARGE Syndrome CHD7 AD (most de novo) Diagnosis requires clinically significant findings AND a mutation/deletion in CHD7 Managed with a complex care/multidisciplinary team Avoid/minimize procedures requiring anesthesia

Answer 10

Coffin-Lowry Syndrome RPS6KA3 XL Diagnosed with mol gen testing (note that biallelic pathogenic variants, whole X dels with mutations on the other copy, skewed X inactivation, etc can modify female presentation) Managed symptomatically PRN Specifically for SIDAs use clonazapam/valproate/selective serotonin reuptake inhibitors/benzodiazapine and protective gear (consider wheelchair) and avoid being startled

Answer 11

Cornelia de Lange Syndrome AD- NIPBL, SMC3, BRD4, RAD21 XL- SMC1A, HDAC8 most de novo wide phenotypic spectrum Diagnosed by mol gen testing (sever/classic form vs milder form are diagnosed by severity of clinical symptoms) Managed with traditional treatments per symptoms and initiation of PT/ST/OT with early intervention

Answer 12

Cri du Chat 5p- terminal deletion (severity of symptoms is somewhat correlated to size of deletion) AD most de novo (~90%) Diagnosed in individuals with clinical features AND positive genetic testing Managed symptomatically including with early intervention therapies such as PT/OT/ST

Answer 13

``` FRYNS Syndrome PIGN AR Diagnosed clinically (must have all)- -diaphragmatic defect -characteristic facial features -distal digital hypoplasia -pulmonary hypoplasia -more than 1 characteristic associated anomaly -fhx consistent with AR inheritance Mol gen testing can be used to confirm dx Managed symptomatically and recommended initiation of early intervention therapies such as PT/OT/ST/feeding therapy and other supportive services ```

Answer 14

Grieg Cephalopolysyndactyly Syndrome GLI3 (7p14.1) AD Diagnosed by clinical findings paired with het variant in GLI3 OR het deletion of 7p14.1 involving GLI3 Managed with cosmetic surgery for hand malformations (if desired)

Answer 15

Antley-Bixler Syndrome POR (with genital anomalies and disordered steroidogenesis) FGFR2 (without genital anomalies or disordered steroidogenesis) AR Diagnosed with urinary steroid profiling with gas chromatography/mass spec and/or molecular genetic testing Managed with glucocorticoid replacement therapy with stress dosing during acute illness, testosterone/estrogen therapies, surgical interventions for malformation PRN, and PT/OT for joint contractures

Answer 16

Bardet-Biedl Syndrome BBS1, BBS2, BBS4, BBS5, BBS7, BBS9, ARL6, TTC8, BBS10, BBS12, MKKS, CFAP418, SCLT1, MSK1, SCAPER, CEP290, CEP164, IFT27, SDCCAG8, IFT74, IFT172, LZTFL1, TRIM32, WDPCP, BBIP1 AR Diagnosed clinically (4+ major features OR 3+ major and 2+ minor) or with molecular genetic testing Major- obesity, hypogonadism, rod-cone dystrophy, postaxial polydactyly, cognitive impairment, renal malformations/disease Minor- anosmia, dental crowding, high-arched palate, GI disease, ataxia, seizures, speech abnormalities, cardiac malformations, endocrine/metabolic abnormalities Managed with early intervention education regarding blindness, symptomatic management as usual PRN, surgical correction of anatomic abnormalities

Answer 17

Branchiootorenal Syndrome EYA1, SIX1, SIX5 AD Diagnosed clinically (3+ major OR 2+ major and 2+ minor) Major- hearing loss, branchial cleft/fistulae/cysts, renal malformations, auricular malformations, preauricular pits Minor- outer/inner/middle ear malformations, preauricular tags, facial asymmetry, palate abnormalities Managed with excision of branchial cleft cysts/fistulae, avoidance of nephrotoxic medications, and close monitoring of renal function by nephrology and/or urology

Answer 18

Prader Willi Syndrome 15q11.2-q13 Caused by paternally derived deletion maternal UPD 15, or imprinting defect Gold standard for diagnosis is methylation study of the PWS critical region (CMA will only detect about 70% of cases) Clinical criteria by age exists and is accurate, but molecular diagnosis is needed for confirmation Managed with hormone treatment and regulation of food intake for weight control

Answer 19

``` Rubenstein-Taybi Syndrome CREBBP, EP300 AD Diagnosed with molecular genetic testing Managed with early intervention therapies, standard symptomatic management, and surgical repair for thumbs/halluces PRN ```

Answer 20

Smith-Magenis Syndrome 17p11.2 deletion (including the RAI1 gene) OR intragenic, heterozygous, pathogenic variant in the RAI1 gene AD deletion is mostly de novo, mutation can be de novo (also have seen complex inheritance patterns) Detected on CMA (first line testing) - if negative and still clinically suspicious, single gene testing for RAI1 or panel testing with RAI1 included Managed with early childhood intervention programs, regular MDC evaluations, psychotropic medications, standard symptomatic management, and annual ophthalmology, audiology, and otolaryngology evaluations

Answer 21

Triploidy Presence of a full extra set of chromosomes (e.g. 3x(23,XX) or 3x(23,XY)) Caused by: two sperm fertilizing one egg, one sperm with an extra set of chromosomes fertilizes a normal egg, one sperm fertilizes an egg with an extra set of chromosomes Diagnosed on karyotype (during or after pregnancy on invasive testing only) or via abnormal hormone screen (increased risk can be identified) Symptomatic management (comfort)

Answer 22

Trisomy 13 (Patau Syndrome) Mostly due to non-dysfunction/unbalanced translocation Some individuals are mosaic Increased risk with advancing maternal age Diagnosed prenatally with NIPS (cfDNA), CVS, amino, or US (after 17 weeks most sensitive) Postnataly use karyotype or CMA (or clinical dx)

Answer 23

Trisomy 18 (Edward Syndrome) complete, partial, or mosaic trisomy 18 caused by non-disjunction (increasing risk with increasing maternal age) Diagnosed by maternal serum screening (hormone screening/US findings, NIPS/cfDNA, amnio/CVS) or postnatally (clinical diagnosis, microarray, karyotype) Management is controversial, but mostly palliative care

Answer 24

Trisomy 21 (Down Syndrome) Full (caused by nondisjunction), mosaic, or translocation Trisomy 21 Increased risk with increasing maternal age Diagnosed on maternal screening (serum/US markers, NIPS, CVS/amnio) or post-natally with karyotype or clinical diagnosis Managed with early intervention therapies, symptomatic management, and routine cardiac/renal/ophthalmologic/audiology (and other specialists) evaluations

Answer 25

VACTERL/VACTRL Association no known genetic cause at this time (though can be present in some syndromes) No clear clinical criteria, but "secure designation" of diagnosis with 1+ malformation in EACH of the 3 involved body parts (limbs, thorax, pelvis/lower abdomen) Managed with surgical repair of present malformations and other supportive/symptomatic treatments PRN

Answer 26

Wolf-Hirschorn Syndrome (4p minus, monosomy 4p) 4p deletion (terminal end of 4p16.3); 40-45% due to unbalanced translocations with deletions of 4p and duplications of part of another chromosome 50-60% de novo; can be inherited from a parent with a balanced rearrangement Diagnosed by presence of clinical symptoms AND genetic confirmation (CMS or FiSH are best) Managed symptomatically

Answer 27

Hidrotic Ectodermal Dysplasia (Clouston Syndrome has hyperkeratosis/Christianson-Fourie Type has cardiac arrhythmias) GJB6 AD Symptomatic management (monitor with EKG for Christianson-Fourier Type) Diagnosed with molecular genetic testing

Answer 28

Hypohidrotic Ectodermal Dysplasia EDAR (mild AD/classic AR), EDA (XL), EDARADD (mild AD/classic AR), WNT10A (AR) Diagnosed clinically based on physical features (can use iodine test to identify hypohidrosis, especially in het females with EDA muts) Confirm with mol gen testing Managed with wigs and hair care, dental implants with regular dental evals, and avoidance of extreme heat exposure

Answer 29

``` Incontinentia Pigmenti IKBKG XL (male lethal- some living cases in XXY males and mosaic) 65% de novo Diagnosed via clinical criteria (1+ major criteria- characteristic skin lesion for age OR alopecia) Confirm with mol gen testing Managed symptomatically Recommend frequent eye exams ```

Answer 30

Charcot Marie Tooth Hereditary Neuropathy (general overview) AD/AR- GDAP1, MFN2 XL- GJB1 AD- MPZ, PMP22 AR- HINT1, SORD, SH3TC2 Diagnosed with mol gen testing (phenotypic diagnosis is becoming less used) Managed symptomatically Recommend MDC evals (psych, neuro, ortho, PT/OT) For musculoskeletal pain use NSAIDS, for nerve pain use tricyclic antidepressants

Answer 31

Joubert Syndrome 34 genes currently known (most common listed here)- AHI1, CPLANE1, TMEM67, CEP290, KIAA0586, CSPP1, INPPSE, MSK1, NPHP1, RPGRIP1, TMEM216, TCTN2, OFD1 Mostly AR (OFD1 is XL) Diagnosed clinically with presence of molar tooth sign, hypotonia progressing to ataxia later in life, and developmental delays/intellectual disability Mol gen testing (typically with a panel) to confirm Managed symptomatically- recommend OT/PT/ST and early intervention/educational support Avoid nephrotoxic medications

Answer 32

``` Kabuki Syndrome KMT2D (AD), KDM6A (XL) Diagnosed clinically with presence of ID, infantile hypotonia AND one of each of the cardinal manifestations (skeletal anomalies, dysmorphic features, DD, persistence of fetal fingertip pad, postnatal growth deficiency) OR molecular genetic diagnosis Managed symptomatically Recommend psychoeducational testing ```

Answer 33

``` Monosomy 1p36 1p36 deletion 8-% de novo Diagnosed on CMA/FiSH/del-dup analysis Managed symptomatically ```

Answer 34

Duchenne Muscular Dystrophy DMD XL Diagnosed by elevated serum CK (10x normal in males; 2-10x normal in females) AND molecular genetic testing Managed with ACE inhibitors/beta blockers for cardiomyopathy, corticosteroid therapy, PT, annual/biannual cardio eval, baseline PFT, and avoidance of Botox and inhaled anesthetics

Answer 35

Becker Muscular Dystrophy DMD XL Diagnosed by elevated serum CK (5x normal in males; 2-10x normal in females) AND molecular genetic testing Managed with ACE inhibitors/beta blockers for cardiomyopathy, consideration of heart transplant (if no skeletal muscle involvement), PT, annual/biannual cardiac eval, baseline PFTs, and avoidance of Botox and inhaled anesthetics

Answer 36

Friedreich's Ataxia FXN AR- trinucleotide repeat expansion (GAA) Normal: 5-33 Premutation: 34-36 (no symptoms) Borderline: 46-66 (phenotypic effect unclear) Full mutation: 66-1300 Diagnosed by mol gen testing with targeted repeat analysis Managed with walking aids PRN, ST/OT/PT, annual ECG/ECHO/fasting A1c, hearing assessment every 2-3 years, and symptomatically PRN Some therapies are in development

Answer 37

Hereditary Neuropathy with Liability to Pressure Palsies PMP22 (80% are 1.5 mb deletions; 20% are sequence variation) AD 20% de novo Diagnosed by suggestive radiographical/clinical findings AND a molecular genetic test (must include del/dup obviously) Managed with PT/OT, bracing, protective padding, and analgesic medications for neuropathic pain

Answer 38

Limb Girdle Muscular Dystrophy 8 AD subtypes and 17 AR subtypes each with distinct genes Diagnosed with molecular genetic testing (gold standard); previously used muscle biopsy and elevated CK as markers Managed with PT/OT and ambulatory assistance devices Recommend baseline cardiac evaluation with ECHO/EKG

Answer 39

``` Myotonic Dystrophy Type 1 (Mild) DMPK AD trinucleotide repeat disorder (CTG) Normal- 5-34 Premutation- 35-49 Full- >50 (mild is 50-150) Diagnosed on molecular genetic testing Managed symptomatically Recommend slot lamp eye exam every 2 years ```

Answer 40

``` Myotonic Dystrophy Type 1 (classic) DMPK AD trinucleotide repeat disorder (CTG) Normal- 5-34 Premutation- 35-49 Full- >50 (classic is 100-1000) Diagnosed on molecular genetic testing Managed symptomatically Avoid statins, vecuronium, succinylcholine, propofol, doxorubicin, smoking, illicit drug use, and excessive alcohol Recommend cardiac evaluation with EKG/Holter annually Slit lamp eye exam every 2 years ```

Answer 41

``` Myotonic Dystrophy Type 1 (congenital) DMPK AD trinucleotide repeat disorder (CTG) Normal- 5-34 Pre- 35-49 Full- >50 (congenital is >1000) Diagnosed on molecular genetic testing Managed symptomatically Avoid statins, doxorubicin, vecuronium, succinylcholine, propofol, smoking, illicit drug use, and excessive alcohol consumption ```

Answer 42

``` Nemaline Myopathy ACTA1 (AD/AR- 15-25% of cases) NEB (AR- 50% of cases) TPM2, TPM3, TNNT1, CFL2, KBTBD13, KLHL40, KLHL41, LMOD3 (mixture of AD/AR- rare) Diagnosed on molecular genetic testing or muscle biopsy showing “nemaline bodies” Managed symptomatically PT/OT Recommend baseline cardiac exam ```

Answer 43

Spinal Muscular Atrophy (Type 0-IV) SMN1 (SMN2 copy number modulates phenotype- the more SMN2 copies you have the more mild the phenotype) AR Wild type has one copy of each (SMN1 and 2) per chromosomal copy Carrier has one copy of SMN1 and two copies SMN2 Silent carrier has two copies of SMN1 on SAME chromosomal copy and one copy SMN2 (c.*3+80T>G SNP increases risk of silent carrier status) 2% de novo rate Diagnosed on molecular genetic testing (MLPA/qPCR) Managed with spinraza (nusinersen) for all types, zolgensma (onasemnogene abeparvovec-xioi for SMAI only (gene therapy), otherwise symptomatic MDC eval every 6 months (or more frequent for weaker children) avoid prolonged fasting

Answer 44

Tay-Sachs Disease (Classic) HEXA AR Diagnosed with enzyme (beta-hexoaminidase A) testing on NBS Children with classic typically have no residual enzyme function (note that there is a pseudoallele that does not allow for enzyme to interact with artificial substrates leading to false positive on NBS) Molecular genetic testing to confirm Managed with supportive/palliative care

Answer 45

Tay-Sachs Disease (Subacute Juvenile) HEXA AR Diagnosed on enzyme (beta-hexoaminidase A) on NBS Children with this type typically have minimal residual enzyme function Molecular genetic testing to confirm Managed with supportive/palliative care

Answer 46

Tay-Sachs Disease (Late-onset) HEXA AR Diagnosed on enzyme (beta-hexoaminidase A) on NBS Individuals with this type typically have moderate residual enzyme function Molecular genetic testing to confirm Managed symptomatically

Answer 47

Beckwith-Wiedemann Syndrome 11p15.5 (BWS critical region) Imprinting center 1- IGF2, H19 Imprinting center 2- CDKN1C, KCNQ10T1, KCNQ1 Inheritance- -loss of methylation at IC2 (maternal) -loss of methylation at IC2 AND gain of methylation at IC1 (paternal UPD) -gain of methylation at IC1 (maternal) -CDKN1C pathogenic variants (AD)- maternal -micro del/dups, paternal UPD -cytogenetic dup/inversion/translocation of 11p15.5 Diagnosed clinically (cannot rule out BWS clinically though) Confirm with genetic testing (methylation analysis, sequence analysis/del/dup, microarray, karyotype) Managed symptomatically Abdominal US every 3 months (until 8 y/o)

Answer 48

``` Sotos Syndrome NSD1 AD (most are del/dup) 95% de novo; fully penetrant Diagnosed on genetic testing (CMA/sequence analysis/del/dup) Managed symptomatically ```

Answer 49

Ataxia Telangiectasia ATM AR (note that hets have increased risk for cancers) Diagnosed on molecular genetic testing (sequence analysis) Managed with IVIG, early and continued PT, supportive therapy, and medications when appropriate Careful monitoring of ionizing radiation and some chemotherapeutic agents due to increased sensitivity of A-T cells

Answer 50

Bloom Syndrome BLM AR Diagnosed with molecular genetic testing- if negative, use dx by rule out of other sister-chromatid exchange conditions (RMI1, RMI2, TOP3A) Managed with skin protection Screenings- abdominal US every 3 months until 8 y/o, whole body MRI every 1-2 years starting at 12, annual colonoscopy starting at 10, annual breast MRI starting at 18, annual fasting A1c, serum TSH, and lipids starting at 10

Answer 51

Fanconi Anemia 23+ genes identified at this time, most common listed here (most others are FANC_ and less than 2%) FANCA (60-70%), FANCC (14%), FANCG (10%), BRCA2/FANCD1 (2%), BRIP1 (2%) most are AR (carriers still have an increased risk of cancers, though) RAD51 is AD (and 100% de novo) RANCB is XL Diagnosed on molecular genetic testing Managed with oral androgens to promote blood cell counts, HSCT (curative for most symptoms other than solid tumor risk), HPV vaccine and safe sex practices, frequent cancer screening, avoidance of excessive sun exposure, further symptomatic management

Answer 52

X-Linked Adrenoleukodystrophy ABCD1 XL Diagnosed by clinical features AND elevated VLCFA Confirm with molecular genetic testing Managed with corticosteroid replacement therapy PRN, supportive care, and PT

Answer 53

Early-Onset Familial Alzheimer's Disease PSEN1, PSEN2 AD Diagnosed with neuropathic findings of beta-amyloid plaques, interneuronal neurofibrillary tangles (containing tau protein), and amyloid angiopathy (GOLD STANDARD) Molecular genetic testing to diagnose when living Managed with supportive/palliative care Donepezil (variable efficacy)

Answer 54

Angelman Syndrome 15q11.2-q13 (including UBE3A) caused by abnormal methylation at the critical region due to... -deletion of maternally inherited region -UPD of paternal region -imprinting defect of maternal region pathogenic variant of maternally derived UBE3A Managed with symptomatic therapies and avoidance of over-treating with sedating medication and anti-epileptics

Answer 55

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) NOTCH3 AD Diagnosed on molecular genetic testing If mol gen testing is non-diagnostic then use electron microscopy and immunohistochemistry of skin biopsy Managed with supportive/palliative care and avoidance of thrombolytic therapy and smoking Recommend regular neurological evaluations

Answer 56

Canavan Disease ASPA AR Detected using molecular genetic testing Managed with supportive/palliative care, PT, and special education for communication NOTE- there is a mild/juvenile form that presents without developmental delays (at most minimal speech/motor delays without regression) and otherwise healthy children (few may have macrocephaly, seizures, and retinitis pigmentosa)

Answer 57

Familial Dysautonomia ELP1 (previously known as IKBKAP) AR Diagnosed by presence of clinical features AND molecular genetic testing Managed by multidisciplinary team per symptoms with routine monitoring Avoid hot/humid weather and full bladder

Answer 58

Fragile X syndrome FMR1 XL Trinucleotide repeat disorder diagnosed with molecular genetic testing- normal- <55 CGG repeats premutation- 55-200 CGG repeats (risk for FXTAS/FXPOI) full mutation- >200 Managed symptomatically and with supportive therapies (PT/OT/speech language therapy/educational assistance)

Answer 59

Krabbe Disease GALC AR Diagnosed via NBS (GALC enzyme testing) or on molecular genetic testing Managed with HSCT (in individuals who present earlier than 12 m/o) or supportive/palliative care in those who present earlier or who don't qualify for transplant

Answer 60

Neurofibromatosis Type 1 NF1 AD; 50% de novo Diagnosed by molecular genetic testing OR clinical criteria (>2 of the following) ->/=6 cafe au lait macules (>5 mm in prepubescent individuals; >15mm in postpubescent individuals) ->/=2 neurofibromas of any type (>/=1 plexiform neurofibromas) -optic glioma -inguinal/axillary freckling ->/=2 Lisch nodules -a distal osseous lesion such as sphenoid dysplasia OR tibial pseudoarthrosis -1st degree relative with NF1 diagnosed by this criteria Managed symptomatically Recommend annual physical exam and ophthalmology evaluation; regular BP monitoring

Answer 61

Huntington Disease HTT AD Diagnosed with molecular genetic testing (CAG trinucleotide repeats) Normal- <26 Intermediate- 27-35 (not at risk for symptoms) Pathogenic- >36 (reduced penetrante- 36-39; full penetrante- >40)

Answer 62

Parkinson Disease AD Early/Late onset- GBA, LRRK2, SNCA, VPS35 AR Early/Late onset- PARK7 (DJ71), PINK1, PRKN, VPS13C AR Juvenile- ATPI3A2, DNAJC6, FBX07, PODXL, SLC6A3, SYNJ1 Diagnosed on molecular genetic testing (above are only monogenista causes) Managed symptomatically (some clinical trials going on now for select genes)

Answer 63

``` Rett Syndrome (Females) MECP2 XL: 99% de novo Diagnosed on molecular genetic testing Managed symptomatically, recommend periodic MDC visits, and avoidance of drugs known to prolong QT intervals ```

Answer 64

``` Rett Syndrome MECP2 XL 99% de novo Diagnosed on molecular genetic testing Managed symptomatically, with periodic MDC visits, and avoidance of QT prolonging drugs ```

Answer 65

Wilson Disease ATP7B AR Diagnosed biochemically with copper measurements (serum copper concentration, urine copper, hepatic copper, etc) or on molecular genetic testing Low ceruloplasmin levels AND Kayser-Fleisher rings are almost pathognomonic Managed with copper chelation agents and/or zinc, liver transplant, annual biochemical checks (serum copper/ceruloplasmin, liver biochemistry, CBC, UA), annual neuro and physical exam, and avoidance of foods high in copper (liver, brain, chocolate, mushrooms, shellfish, nuts)

Answer 66

``` X-Linked Agammagloblinemia BTK XL Diagnosed on molecular genetic testing Managed with IVIG/SQIG every 2-4 weeks, prophylactic antibiotics (some centers), and avoidance of live viral vaccines (especially the oral polio vaccine) ```

Answer 67

Familial Mediterranean Fever Type 1- presents with above symptoms Type 2- presents with amyloidosis (other wise asymptomatic) MEFV AR Diagnosed by clinical criteria (fever AND 1 major OR 2 minor) Major- joint pain, abdominal pain, chest pain, and skin eruptions Minor- leukocytosis, increased ESR, elevated serum fibrinogen Confirm with molecular genetic testing Managed with colchicine, supportive care for acute episodes, and renal transplant

Answer 68

``` Alpha-1-Antitrypsin Deficiency SERPINA1 AR (codominant?) Diagnosed with low serum concentration of alpha-1-antitrypsin or molecular genetic testing Managed with augmentation therapy, periodic IV pooled human serum alpha-1 antitrypsin, lung transplant, dapsone and doxycycline, PFTs every 6-12 months, liver function testing, platelet counts, liver US, elastography, MRI, and avoidance of smoking/occupational exposures/excessive alcohol ```

Answer 69

Hereditary Multiple Osteochobdromas (Multiple Exostoses Syndrome) EXT1, EXT2 AD (96% penetrance in females; 100% penetrance in males) 10% de novo Diagnosed by characteristic radiographic findings and/or molecular genetic testing Managed with surgical excision of bony deformities and one time MRI screening of the spine

Answer 70

Blepharophimosis, Ptosis, and Epicanthus Inversus FOXL2 (occasionally cytogenetic rearrangements involving 3q23) AD Diagnosed with clinical diagnosis (three findings in the name plus telecanthus) OR with molecular/cytogenetic testing (first line is sequencing, then CMA/karyotype) Managed with eyelid surgery (most often two different surgeries) with regular ophthalmology visits

Answer 71

DFNA3/ Congenital Hearing Loss (Connexin 26/30) GJB2 OR GJB6 AD (Note- DFNB1 is AR; individuals are homozygous for GJB2 or are compound hets for GJB2/GJB6) Managed with hearing aids/cochlear implants, educational program to decrease speech/education delays, semiannual exam by a physician who is familiar with hearing loss, repeat audiometry, and avoidance of environmental exposures known to cause hearing loss

Answer 72

Hermansky-Pudlak Syndrome HPS6, HPS4, HPS1, HPS3, HPS5, AP3B1 (less common- AP3D1, BLOC1S3, BLOC1S5, BLOC1S6, DTNBP1) AR Diagnosed with clinical diagnosis (oculocutaneous albinism AND absence of platelet delta granules [dense bodies]); confirm with molecular genetic testing Managed symptomatically Recommend skin protection from the sun and avoidance of direct sun exposure Recommend medical alert bracelet (for bleeding risk) Recommend annual ophthalmology exam, skin exam, and PFTs Avoid aspirin containing meds, activities that increase risk for bleeding, and cigarette smoke

Answer 73

Jervell and Lange-Nielsen Syndrome KCNE1, KCNQ1 AR Diagnosed on molecular genetic testing Managed with cochlear implants, beta blocker therapy (not enough alone) AND ICD placement, with periodic evaluations of dosage and ICD performance Avoid drugs that further prolong the QT and activities that are known to precipitate syncopal episodes

Answer 74

Leber Hereditary Optic Neuropathy MT-ND4, MT-ND6, MT-ND1 mitochondrial (maternally inherited only) Diagnosed with molecular genetic testing Managed with supportive care (visual aids, OT, enrolment in relevant social services) and MDC care for neurological symptoms Avoid smoking, excessive alcohol intake/binge drinking, head trauma, industrial toxins, drugs toxic to the mitochondria, and other environmental triggers for vision loss

Answer 75

Pendred Syndrome SLC26A4 (FOXI1 and KCNJ10 are rare and only found as compound hets with SLC26A4) AR Diagnosed clinically- Pendred= SNHL + characteristic temporal bone abnormalities (EVA AND cochlear hypoplasia) + euthyroid goiter Nonsyndromic Enlarged Vestibular Aquaducts (NDEVA) = SNHL + EVA Molecular genetic testing Managed with hearing habituation, hearing aids, and educational programs (consider cochlear implants) Repeat audiometry every 3-6 months Baseline thyroid US; thyroid function testing every 2-3 years Consider avoiding contact sports and weightlifting

Answer 76

Amyotrophic Lateral Sclerosis AD: ERBB4, FUS, VCP, TARDBP, C9orf72*, TBK1, SQSTM1, FIG4, ANG, VAPB, SETX, ANXA11, TUBA4A, HNRNPA1, CFAP410, CHCHD10, CHMP2B, PFN1, DAO, MATR3, DCTN1, NEK1 AR: ALS2, SPG11 XL: UBQLN2 *expansion of GGGGCC repeats (>60 certain; >23 may be sufficient) Diagnosed with the revised Escorial criteria (presence of degeneration of upper AND lower motor neurons with progressive spread of symptoms AND absence of electrophysiologic or pathological evidence of other disease process that could explain the signs of LMN/UMN degeneration and neuroimaging evidence of other disease processes that could explain the observed clinical/electrophysiological signs Managed with MDC palliative care Some meds have been FDA approved (Ruzole/Tegulik and Edaravone/Radicava) AD/AR: SOD1, OPTN

Answer 77

``` Usher Syndrome Type I MYO7A, USH1C, CDH23, PCDH15, USH1G, CIB2 AR Diagnosed on molecular genetic testing Managed with hearing aids in infancy and transition to cochlear implants as soon as medically feasible, specialized training for hearing impaired/sign language education for families, vestibular compensation therapy, standard RP treatment, annual full ear/hearing exams, annual eye exams, and avoidance of sports especially swimming ```

Answer 78

``` Usher Syndrome Type II ADGRV1, USH2A, WHRN AR Diagnosed with molecular genetic testing Managed with hearing aids (can consider cochlear implants), standard care for RP, annual comprehensive hearing/ear exams, vestibular rehab, annual eye exams, avoidance of sports and driving ```

Answer 79

Waardenburg Syndrome PAX3; SOX10 AD (very few de novo) Diagnosed with clinical criteria (2 major OR 1 major and 2 minor) Major- congenital SNHL, white forelock, any of the aforementioned iris pigment changes, telecanthus (W score >1.95) Minor- premature greying (<30 y/o), congenital leukoderma, synophrys, broad/high nasal root with low hanging columella, underdeveloped alae nasi Molecular genetic testing used to confirm or if clinical findings are inconclusive Managed with hearing loss support per severity

Answer 80

Achondroplasia FGFR3 AD ~80% de novo Diagnosed with clinical/radiographic features and/or molecular genetic testing Managed with monitoring of height and milestones on achondroplasia specific charts, Vosoritide (CNP analog) between 5 y/o and growth plate closure, symptomatic management, baseline neuroimaging and exam, and avoidance of collision sports; trampolines; diving boards; vaulting; and hanging upside down from feet/knees on playground equipment

Answer 81

Cleidocranial Dysplasia FUNX2 AD High de novo rate Diagnosed by classic clinical/radiographical findings (delayed closure of cranial sutures, hypoplastic/aplastic clavicles, dental abnormalities) and/or molecular genetic testing Managed with protection of head from blunt trauma with helmet, otherwise symptomatic ST may be indicated during times of dental transition

Answer 82

Diastrophic Dysplasia SLC26A2 AR Diagnosed with characteristic clinical/radio graphical features OR molecular genetic testing- if mol Gen testing is negative, can use fibroblasts and/or chondrocytes (rare) Managed with PT for contractures, surgical intervention for musculoskeletal malformations, and avoidance of obesity Otherwise symptomatic care

Answer 83

``` Saethre-Chotzen Syndrome TWIST1 AD Diagnosed with molecular genetic testing Managed symptomatically Recommend annual ophthalmologic and speech exams with audiological exams every 6-12 months ```

Answer 84

``` Hypochondroplasia FGFR3 AD; mostly de novo Diagnosed on molecular genetic testing Managed symptomatically Track height/weight/head circumference with achondroplasia specific growth charts ```

Answer 85

Congenital Contractural Arachnodactyly (Beal Syndrome) FBN2 AD; as much as 505 de novo Diagnosed with clinical scoring system (>/= 7) -crumpled ears, arachnodactyly, campodactyly, large joint contractures (3 each) -pectus deformity, dolichostenomelia (2 each) -kyphoscoliosis, muscle hypoplasia, high arched palate, micrognathia (1 each) Molecular genetic testing only identifies 25-75% Managed symptomatically and with PT initiated early, avoidance of contact sports and LASIK, and routine aortic arch monitoring and visual acuity assessment

Answer 86

``` Osteogenesis Imperfecta COL1A1, COL1A2 AD; high de novo rate Diagnosed on molecular genetic testing Managed with MDC care, safe handling techniques including bracing, PT/OT, twice yearly dental visits, audiology evaluations every 3-5 years, and further symptomatic care ```

Answer 87

Ehler’s Danlos Sybdrome Classic Type I/II COL5A1, COL5A2, COL1A1 AD; 50% de novo Diagnosed with clinical criteria (>5 Beighton and/or 3+ minor criteria OR major criteria skin hyperextensibility and atrophic scars) AND positive molecular genetic testing Minor- easy bruising, soft/doughy skin, skin fragility/truamatic splitting, molluscoid pseudotumors, subcutaneous spheroids, hernia, epicanthal folds, complications of joint hypermobility (sprains, dislocations/subluxations, pain, etc) family history of first degree relative who meets clinical criteria Managed with physiotherapy with non-weight-bearing exercise, wear pads for skin protection in children, and further symptomatic management Avoid sports with heavy joint strain and aspirin

Answer 88

Cockayne Syndrome Type I (“classic”/“moderate”) ERCC6, ERCC8 AR Diagnosed on molecular genetic testing- clinical findings deliniate what type (I-III or COFS); certainty improves with age Managed symptomatically with supportive/palliative care Avoid excessive sun exposure

Answer 89

Cockayne Syndrome Type II ERCC6, ERCC8 AR Diagnosed with molecular genetic testing- clinical findings can deliniate type (I-III and COFS); certainty of tupe improves over time Managed symptomatically, and with supportive/paliative care Avoid extended sun exposure

Answer 90

``` Cockaney Syndrome Type III “mild”) ERCC6, ERCC8 AR DIAGNOSED ON MOLECULAR GENETIC TESTING- clinical features deliniate type (I-III and COSF); improved certainty with age Managed symptomatically Avoid extended sun exposure ```

Answer 91

Cerebrooculofacioskeletal Syndrome ERCC6, ERCC8 AR Diagnosed eith molecular genetic testing- clinical fearures deliniate type (Cockayne syndrome type I-III or COFS); certainty improves with age

Answer 92

Ehler’s Danlos Syndrome Vascular Type IV COL3A1 Diagnosed with molecular genetic testing Managed with periodic aeterial screening by US /MRIa and BP monitoring Avoid trauma, arteriography, routine colonoscopy, elective surgeries Women have a 5% mortality rate in pregnancy MedAlert/emergency letter

Answer 93

Hutchinson-Gilford Progeria Syndrome LMNA AD (almost all de novo) Diagnosed on molecular genetic testing - classic has c.1824C>T variant - non-classic has pathogenic variants in exon 11 or intron 11 Managed symptomatically and with low dose aspirin; annual/semiannual ECG; annual ECHO, carotid duplex US, neuro exam, MRI/MRA of head and neck, lipid profile, dental exam, hip XR, DEXA, audiology exam, and ophthalmology exam; PT; avoidance of dehydration, large crowds, and trampolines; and limitation of physical activity and general anesthesia/intubation

Answer 94

Ataxia with Oculomotor Apraxia Type I APTX AR Diagnosed by ruling out ataxia-telangiectasia and then with molecular genetic testing Managed with PT and a wheelchair when necessary (typically by 15-20 y/o), routine neurology follow-ups, and a high protein, low cholesterol diet

Answer 95

Ataxia with Oculomotor Apraxia Type 2 SETX AR Diagnosed by excluding ataxia-telangiectasia, AOA1, and AOA4 and on molecular genetic testing Managed with PT and wheelchair as needed as well as with a low cholesterol diet

Answer 96

X-Linked Adrenal Hypoplasia Congenita NORB1 XL (females normally unaffected carriers) Diagnosed on molecular tenetic testing (needs tech for deletion detection and pathogenic variants) Management of acute adrenal insufficiency in the ICU After acute episodes trear with glucocorticoids, mineralocorticoids, and sodium chloride supplements Steess doses of steroids as needed Hormone replacement therapy as needed

Answer 97

21-Hydroxylase-Deficient Congenital Adrenal Hypoplasia CYP21A2 AR Diagnosed on NBS mostly; can also be seen as elevated serum 17-OHP and adrenal androgens Can also be diagnosed with molecular genetic testing Managed with glucocorticoid replacement (increased in times of stress) and genitoplasty and/or vaginal dilation for virulization of females

Answer 98

Androgen Insensitivity Syndrome (Testicular Feminization) AR gene XL inheritance Diagnosed in individuals with XY,46 karyotype AND characteristic findings AND/OR hemizygous AR pathogenic mutations Managed with gonadectomy with estrogen replacement therapy in pre-pubertal individuals OR surgical removal of the testes in post-pubertal individuals (both are controversial); +/- vaginal dilation; management of external genitalia and secondary sexual characteristics per patient/family; regular DEXA screening with weight bearing exercise and vitamin D supplementation

Answer 99

Kallmann Syndrome Genes associated only with KS- ANOS1 (KAL1)*, SOX10** Genes associated with KS and/or nIGD- CHD7**, FGFR1**, IL17RD, PROKR2*** XL*, AD**, or AR*** Diagnosed by low serum testosterone/estadoil resulting from partial/full GnRH mediated release of LH and FSH in the setting of otherwise normal anterior pituitary anatomy/function AND anosmia Molecular genetic testing can identify some but not all

Answer 100

McCune-Albright Syndrome (Fibrous Dysplasia) GNAS NOT inherited- mutations are somatic activating pathogenic variants and ALWASY mosaic Diagnosed clinically with 2+ typical clinical features IF only monostotic fibrous dysplasia is present- assess for somatic variants Managed with letrozole (aromatase inhibitor) in females for precocious puberty (no treatment known for males); methimazole/thyroidectomy; octreotide/growth hormone receptor antagonists (pegvisomant); screening for symptoms regularly Avoid contact sports/high risk activities, prophylactic optic nerve decompression, surgical removal of ovarian cysts, radiation therapy, and risk factors for malignancy

Answer 101

Transient Neonatal Diabetes Mellitus 6q24 (PLAGL1, HYMAI) hypomethylation (maternally inherited- paternal UPD/duplication) of the differentially methylated region (including the above genes); some single gene causes (in other genes) have been noted Diagnosed on methylation studies Managed with rehydration and IV insulin at onset with introduction of subcutaneous insulin ASAP until blood glucose stabilizes (normally insulin need decreases over time) Later onset DM may require traditional treatment with diet/oral agents/insulin Avoid factors that predispose to late-onset DM and cardiovascular disease

Answer 102

Alport Syndrome COL4A3 (AR/AD), COL4A4 (AR/AD), COL4A5 (XL) Diagnosed with molecular genetic testing (urinalysis can be a helpful screening to identify individuals who may be at risk) Managed with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, routine care for HTN and SNHL, and renal transplant (for end stage renal disease)

Answer 103

Autosomal Dominant Polycystic Kidney Disease PKD1, PKD2, GANAB, DNAJB11 AD Diagnosed using age specific imaging criteria AND molecular genetic testing Managed with vasopresin V2 receptor antagonists (tolvaptan), ACE inhibitors/angiotensin II receptor blockers/diet management for HTN, conservative pain management/aggressive management (decompression/fenestration/renal denervation/nephrectomy) of cysts, early BP monitoring, MRI screening for intracranial aneurysm (if believed high risk), and ECHO (if murmur appreciated or fhx of thoracic aortic dissection)

Answer 104

Autosomal Recessive Polycystic Kidney Disease PKHD1, DZIP1L AR Diagnosed in individuals with clinical suspicion and unaffected parents AND molecular genetic testing Managed with neonatal mechanical ventilation and peritoneal dialysis, symptomatic management for HTN and kidney disease, consideration of nephrectomy/renal transplant/dial renal-liver transplant, ursodiol (may help minimize the risk for gal stones and increase bile acid), prophylactic antibiotics, periodic abdominal US of liver and spleen, esophagogastroduodenoscopy to monitor for varices, and avoidance of nephrotoxic agents/hepatotoxic agents/sympathomimetic agents (in individuals with HTN)