Diseases to Review Flashcards
acute neurovisceral attacks of severe abdominal pain (without peritoneal signs) with nausea, emesis, tachycardia, and hypertension as well as potentially mental changes, convulsions, and peripheral neuropathy +/- hyponatremia- attacks are provoked by drugs, alcoholic beverages, endocrine factors, calorie restrictions, stress, and infections
Urine may be reddish-brown or red which will deepen when exposed to air and light
attacks resolve in ~ 2 weeks
Acute intermittent porphyria
AD
HMBS gene
test for with urine porphobilinogen FIRST before mol gen
Treat attacks with human hemin and symptomatic management
liver transplant is last resort
generalized edema (neonatal onset) pleural and pericardial effusions (due to congenital heart failure) hepatosplenomegaly severe anemia extramedulary erythropoesis large placenta death in neonatal period
Alpha-thalassemia Hemoglobin Barts (HbB)/ hydrops fetalis
HBA1 & HBA2
deletion of all 4 alpha-globin genes (–/–)
Test with hemoglobin analysis first (profoundly decreased/absent HbA; significantly increased HbB; no HbF; presence of Hb Portland) before confirmation with mol gen (must include del/dup tech)
intrauterine blood transfusions can be helpful
some (very rarely) successful HSCT
mild jaundice splenomegaly thalassemia-like bone changes acute episodes of hemolysis gallstones
Alpha-thalassemia Hemoglobin H (HbH)
HBA1 & HBA2
deletion of 3/4 alpha-globin genes (–/-alpha)
Test with hemoglobin analysis first (mildly decreased HbA; mildly present HbB; some HbH)
may need blood transfusions depending on severity
severe anemia
severe hepatosplenomegaly
failure to thrive
mild jaundice
Beta Thalassemia Major
HBB
homozygous Beta null mutations
Test with NBS looking for beta globin production first and then with peripheral blood smear (looking for microcytic hypochromic anemia with anisopoikilocytosis and nucleated red blood cells) and mol gen testing last
Require regular blood transfusions, blood chelation, BMT, and surveillance of organs for iron overload
Avoid alcohol and iron-containing preparations
mild anemia
secondary iron overload
Beta Thalassemia Intermedia
HBB
heterozygous beta null mutations OR homozygous beta + mutations
Test with NBS looking for beta globin production first then with peripheral blood smear and final testing with mol gen
+/- blood transfusion PRN and potentially splenectomy?
avoid alcohol and iron-containing preparations
Monitor for organ failure with iron overload
increased risk for venous thrombosis (esp. DVT)
poor anticoagulation response to activated protein C (APC)
Factor V Leiden Thrombophilia
F5
AD/AR (hets have 3-8x higher risk for VTE; homo have 9-40x higher risk for VTE)
Test with mol gen testing AND APC resistance assay (+ confirms dx; borderline confirms dx; very low indicates hets/”pseudohomozygotes”)
Managed with standard treatment of thrombosis and avoidance of estrogen containing contraception/HRT, smoking, and other things that increase risk of VTE
Hemarthrosis
Deep-muscle hematomas
Intracranial bleeding in the absence of major trauma
Neonatal cephalohematoma or intracranial bleeding
Prolonged oozing or renewed bleeding after initial bleeding stops following tooth extractions, mouth injury, or circumcision
Prolonged or delayed bleeding or wound healing following surgery or trauma
Unexplained GI bleeding or hematuria
Menorrhagia (esp. with onset at menarche)
Prolonged nose bleeds (esp. recurrent and bilateral)
Excessive bruising (esp. with firm, subcutaneous hematomas)
Factor VIII deficiency
Hemophilia A
F8
XL
Test with Factor VIII clotting assay for males (severe <1%; moderate 1-5%; mild 6-40%) and normal von Willebrand factor +/- molecular testing
Test with Factor VIII clotting assay for females (“low” activity is affected)- NOTE carriers (hets) will not be detected on this assay so mol gen testing is needed
Treat with IV Factor VIII concentrate
Hemarthrosis
Deep muscle hematomas
Intracranial bleeding in the absence of major trauma
Neonatal cephalohematoma or intracranial bleeding
Prolonged oozing or renewed bleeding after initial bleeding stops following tooth extractions, mouth injury, or circumcision
Prolonged or delayed bleeding or wound healing following surgery or trauma
Unexplained GI bleeding or hematuria
Menorrhagia (esp. with onset at menarche)
Prolonged nose bleeds (esp. recurrent and bilateral)
Excessive bruising (esp. with firm, subcutaneous hematomas)
Factor IX deficiency
Hemophilia B
F9
XL
Test using Factor IX clotting assay in males (severe <1%; moderate 1-5%; mild >5-40%) +/- mol gen testing
Testing using Factor IX clotting assay in females (“low” indicates affected) BUT hets/carriers ineffectively detected with assay so need mol gen testing
Managed with IV plasma-derived/recombinant Factor IX
Avoid elective surgical procedures, activities likely to result in trauma, intramuscular injections, medication/supplements that decrease platelet function, and aspirin
abdominal pain weakness/lethargy arthritis arthralgias arthropathy cardiomyopathy hepatomegaly hepatic cirrhosis primary liver cancer progressive increase in skin pigmentation weight loss diabetes mellitus hypogonadism
HFE-Associated Hereditary Hemochromatosis
HFE
AR
Test with mol gen testing; confirm with serum ferritin (some people can be asymptomatic)
Treat with phlebotomy (to achieve serum ferritin concentration = 50 ng/mL)
Vaccination against Hep A and Hep B
bile duct paucity (on liver biopsy) butterfly vertebrae cholestasis opthalmologic abnormalities (esp. posterior embryotoxon) congenital cardiac defects renal anomalies DD growth failure splenomegaly vascular abnormalities triangular face broad forehead hypertelorism deep set eyes long nose with bulbous tip large ears
Alagille Syndrome
JAG1, NOTCH2 (other undiscovered genes- 3.2%)
AD (50-70% de novo)
Test with mol gen (single gene or panel testing with consideration of comphrehensive genome testing in the context of unknown genes)
Treat symptomatically per organ system with regular monitoring as well as with choloretic agents
Consider liver transplant (not curative, just symptom management)
Avoid contact sports and minimize alcohol
ventricular arrhythmias syncope ST-segment abnormalities in leads V1-V3 on EKG first degree AV blocks intraventricular condition delays RBBB sick sinus syndrome sudden death (on average by the age of 40; SIDs included)
Brugada Syndrome
23 different genes- ABCC9, CACNA1C, CACNA2D1, CACNB2, SEMA3A, FEF12, GDP1L, HCN4, KCND2, SLMAP, KCND3, KCNE3, KCNH2, KCNE5, TRPM4, KCNJ8, PKP2, RANGRF, SCN1B, SCN2B, SCN3B, SCN5A**, SCN10A
AD (except KCNE5 which is XL)
**most common (15-30% of cases)
Diagnosed clinically- Type 1 EKG AND at least one clinical criteria (documented ventricular fibrillation, self-terminating polymorphic ventricular tachycardia, fhx of sudden cardiac death, coved-type EKG in family members, electrophysiologic inducibility, syncope/nocturnal agonal respiration)
Confirm with mol gen testing
Manage with ICD placement, isoproterenol (for electrical storms), and EKG monitoring
Avoid high fevers, anesthetics, antidepressants, antipsychotics with sodium-blocking effects, and class 1A agents
frequent, spontaneous epistaxis
mucocutaneous telangiectasias (characteristic sites- lips, oral cavity, fingers, and nose)
multiple arteriovenous malformations that lack intervening capillaries (typically pulmonary, cerebral, hepatic, spinal, GI, or pancreatic)
+/- hamartomatous GI polyps
Hereditary Hemorrhagic Telangiectasia
ACVRL1, ENG, SMAD4, other (~3% unknown)
AD
Diagnosed with Curacao criteria (3+ of suggestive findings- frequent, spontaneous epistaxis; multiple mucocutaneous telangiectasias; visceral arteriovenous malformations; fhx of first degree relative diagnosed with HHT according to Curacao criteria) and/or confirmed with mol gen testing
Managed symptomatically per organ affected by AVM (consider liver transplant)
transthoracic contrast ECHO Q5 years to monitor
colonoscopy starting @ 15 y/o (for pts with SMAD4 mutations)
avoid aspirin, scuba diving, liver biopsies, and heavy lifting/straining/baring down
upper limb defects (any/all)
cardiac conduction disease
congenital heart malformations
pulmonary HTN
Holt-Oram Syndrome
TBX5
AD (~85% de novo)
Diagnosed clinically (preaxial radial ray anomaly AND personal/family history of cardiac septation and/or conduction defects)
Confirm with mol gen testing
Managed with medication/implant for arrhythmias and surgery for heart defects (in some) with annual EKG and Holter; ECHO Q5 years
increased risk of... male/female breast cancer ovarian cancer (including fallopian tubes and primary peritoneal) prostate cancer pancreatic cancer melanoma
BRCA-Related Hereditary Breast and Ovarian Cancer (HBOC)
BRCA1/BRCA2
AD
Test in individuals with AJ ancestry and fhx of breast cancer, 2+ relatives with breast cancer before 50 y/o, 3+ relatives with breast cancer at any age, personal/fhx of triple negative breast cancer (esp. before 60 y/o), male breast cancer, ovarian cancer, multiple primary breast cancers in the same person, and/or combo of pancreatic and/or prostate cancer (Gleason >/= 7) with breast and/or ovarian cancer
Consider bilateral mastectomy and recommend risk reducing salpingo-oophorectomy between 35-40 y/o
Consider risk reducing medications (e.g. tamoxifen)
Recommend annual breast MRIs (25-29 y/o) and annual mammogram (30-75 y/o)
Recommend annual full body skin exams
hundreds-thousands of adenomatous colonic polyps (7-36 y/o) colon cancer by age of 35 polyps of gastric fundus and duodenum desmoid tumors gastric fundus cancer duodenal cancer
Familial Adenomatous Polyposis (FAP)
APC
AD
Consider molecular genetic testing in individuals with multiple colorectal adenomatous polyps (10-20), fhx multiple colorectal adenomatous polyps (10+ in a single individual or fewer if >1 relative has multiple) or other findings, hepatoblastoma, multifocal/bilateral congenital hypertrophy of the retinal pigment epithelium, desmoid tumor, or cribriform-morular variant of papillary thyroid cancer
Manage with colonoscopy every 12 months starting at 10-15 y/o, consideration of total abdominal colectomy with ileorectal anastomosis and/or proctocolectomy
consider annual thyroid US
increased risk for... colorectal cancer endometrial cancer ovarian cancer stomach cancer small bowel cancer urinary tract cancer pancreatic cancer prostate cancer glioblastoma skin cancer (sebaceous carcinoma, sebaceous adenoma, and keratoacanthomas)
Lynch Syndrome
MLH1, MSH2, MSH6, PMS2, EPCAM
AD
Test individual with colorectal or endometrial cancer and dx <50 y/o, 1st or 2nd degree relative with LS related cancer diagnosed under 50 y/o, >/= 2 first or second degree relatives with Lynch syndrome related cancer at any age, a synchronus or metachronus LS-related cancer at any age
Manage with colonoscopy every 2-5 years starting 20-25 y/o, consideration of daily aspirin therapy, and consideration of total abdominal hysterectomy/bilateral salpingo-oophorectomy
lentigines short stature pectus deformity ID hypertrophic cardiomyopathy widely spaced eyes ptosis SNHL cryptorchidism skeletal anomalies
Noonan Syndrome with Multiple Lentigines (LEOPARD)
PTPN11 (90%), RAF1 (<5%), BRAF (rare), MAP2K1 (rare)
AD
Clinical diagnosis is 1+ cardinal feature (lentigines, short stature, pectus deformity, hypertrophic cardiomyopathy/other cardiac abnormality, widely spaced eyes/ptosis) AND/OR molecular genetic testing
Symptomatic management, close cardiac surveillance, and avoidance of growth hormone (in pts with cardiomyopathy)
low set, posteriorly rotated ears with fleshy helices hearing loss vivid blue/green irises wide spaced eyes down slanting palpebral fissures ptosis epicanthal folds short stature pectus congenital heart defects broad, webbed neck mild ID cryptorchidism coagulation defects lymphatic dysplasia ocular abnormalities malignancies (JMML)
Noonan Syndrome
BRAF, KRAS, MAP2K1, MRAS, NRAS, PTPN11, RAF1, RASA2, RIT1, RRAS2, SOS1, SOS2, LZTR1*
AD (*can be AD or AR)
Diagnosed with molecular genetic testing
Symptomatic management, annual ophthalmology/audiology evaluation in childhood, regular cardiac evaluations, and avoidance of aspirin therapy
cardiovascular disease (elastin arteriopathy, peripheral pulmonary stenosis, supravalvular stenosis, hypertension) connective tissue abnormalities broad forehead periorbital fullness strabismus short nose with broad nasal tip long philtrum small jaw malocclusion mild ID growth abnormalities hypercalcemia hypercalcinuria hypothyroidism hypotonia precocious puberty feeding difficulties overfriendliness specific phobias and generalized anxiety ADD
Williams Syndrome
recurrent 7q11.23 contiguous deletion of Williams-Beuren syndrome critical region (WBSCR)- includes the ELN gene- 1.5-1.8 Mb
AD (most de novo)
Test with molecular genetic testing (FiSH or CMA recommended)
Symptomatic management, early intervention and behavioral therapy, and annual full medical evaluation with serum calcium screening every 4-6 months in childhood
increased risk (esp. in childhood/young adulthood) for... breast cancer osteosarcomas adrenocortical carcinomas central nervous system tumors soft tissue sarcomas leukemia lymphoma GI cancers cancer of the head and neck, kidney, ovary, pancreas, prostate, testicle, thyroid
Li-Fraumeni Syndrome
TP53
AD
Diagnosed via clinical criteria (must have ALL 3)-
1. proband with sarcoma dx before 45 y/o
2. 1st degree relative with any cancer before 45 y/o
3. 1st or 2nd degree relative with any cancer diagnosed before 45 y/o or sarcoma dx at any age
Managed with regular comprehensive physical exam and routine management per malignancy (except recommendation of bilateral double mastectomy for breast cancer treatment
Avoidance of sun exposure, tobacco use, and exposure to known/suspected carcinogens
hypercalcemia lethargy depression constipation nausea/emesis kidney stones short QT parathyroid tumors pituitary tumors oligomenorrhea/amenorrhea gastro-entero-pancreatic tumors gastrinoma insulinoma hyperglycemia anemia diarrhea hypokalemia carcinoid tumors lipomas adenocortical tumors facial angiofibromas meningiomas collagenomas ependymomas leiomyomas
Multiple Endocrine Neoplasia 1
MEN1
AD
Diagnosed clinically (2+ endocrine tumors- parathyroid tumor, pituitary tumor, or GEP tract tumor) and/or mol gen testing
Managed with normal surgical/medication response pre malignancy and regular monitoring of serum calcium
medullary carcinoma of the thyroid (MTC) pheochromocytoma parathyroid adenoma parathyroid hyperplasia onset in early adulthood
Multiple Endocrine Neoplasia Type 2A
RET
AD
Diagnosed with clinical criteria (2+ specific endocrine tumors in a single individual/close relative)
Managed with surgical removal of tumors per usual practice and annual measurements of serum calcitonin
Avoid dopamine D2 receptor antagonists and beta-adrenergic receptor antagonists for individuals with pheochromocytoma
medullary carcinoma of the thyroid (MTC) pheochromocytoma mucosal neuromas of the lips and tongue enlarged lips ganglioneuromatosis of the GI tract marfanoid habitus onset in early childhood
Multiple Endocrine Neoplasia 2B
RET
AD
Diagnosed with clinical criteria (early onset MTC mucosal neuromas, as well as medulated corneal nerve fibers and distinct facies)
Managed with surgical removal of tumors per usual practice and annual measurements of serum calcitonin
Avoid dopamine D2 receptor antagonists and beta-adrenergic receptor antagonists for individuals with pheochromocytomas
medullary carcinoma of the thyroid (MTC)
onset in middle age
Multiple Endocrine Neoplasia 2 - Familial medullary thyroid carcinoma (FMTC) type
RET
AD
Diagnosed with clinical criteria (families with 4+ cases of MTC without pheochromocytoma or parathyroid adenomas/hyperplasia)
Managed with surgical removal of tumors per usual practice and annual measurements of serum calcitonin
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
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
high risk for benign and malignant tumors of the thyroid, breast, kidney, and endometrium
macrocephaly
trichilemmomas
papillomatous papules
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)
macrocephaly
intestinal hammartomatous polyposis
lipomas
pigmented macules of the glans penis
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)
congenital malformations hamartomatous overgrowth of multiple tissues connective tissue nevi epidermal nevi hyperostoses
Proteus Syndrome PTEN AD Mol gen testing treatment of tumors (topical agents, curettage, cryosurgery, or laser ablation) thyroid US and cancer screenings
hypomelanotic macules confetti skin lesions angiofibromas retinal nodular hamartomas shagreen patches fibrous cephalic plaques subependymal giant astrocytomas (SEGA) ungual fibromas subependymal nodules cortical tubers seizures psychiatric illness ID/DD renal cysts renal angiomyolipomas renal cell carcinoma cardiac rhabdomyomas arrhythmias LAM multifocal micronodular pneumocyte hyperplasia dental enamel pits intraoral fibromas sclerotic bone lesions nonrenal hamartomas renal achromic patches
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
brain hemangioblastomas spinal cord hemangioblastomas retinal hemangioblastoma renal cysts pheochromocytoma clear cell renal cell carcibnoma pancreatic cysts emesis neuroendocrine tumors epididymal/ broad ligament cysts endolymphatic sac tumors cerebellar hemangioblastomas headache gait disturbances/ataxia hearing loss vision loss
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
sun sensitivity (severe sunburn with blistering, persistent erythema after minimal sun exposure) freckle-like pigmentation of face photophobia SNHL keratitis atrophy of the skin of the lids melanoma basal cell carcinoma squamous cell carcinoma microcephaly diminished/absent deep tendon stretch reflexes progressive cognitive impairment
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
widow's peak downslanting palpebral fissures hypertelorism broad nasal bridge anteverted nares low set, protuberant ears maxillary hypoplasia clinodactyly syndactyly swan neck deformity of fingers short stature short, broad hands and feet delayed puberty cryptorchidism/macroorchidism learning and behavioral disabilities
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
coloboma choanal atresia growth retardation intellectual disabilities/developmental delays heart defects cranial nerve anomalies vestibular defects genital hypoplasia hearing loss ear abnormalities cleft lip and/or palate hypothyroidism tracheoesophageal anomalies brain anomalies seizures renal anomalies respiratory issues (central/obstructive apnea)
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
severe to profound ID loss of strength stroke behavioral problems progressive spasticity or paraplegia sleep apnea stimulus-induced drop attacks (SIDAs) hypertelorism broad forehead and supraorbital ridges coarsness thick eyebrows prominent ears nasal malformations pectus kyphoscoliosis short, soft, fleshy hands with tapered fingers females may have mild to moderate ID and typical facial/hand/skeletal findings
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
microcephaly synophrys (monobrow)/highly-arched and/or thick eyebrows long-thick eyelashes short nasal bridge, upturned nasal tip, anteverted nares high arched palate with or without cleft small, widely spaced teeth micrognathia growth restriction hypertrichosis upper-limb reduction defects ID cardiac septal defects GI dysfunction hearing loss myopia cryptorchidism hypoplastic genitalia
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
high-pitched cry ID/DD microcephaly hypotonia low birth weight hypertelorism low set ears IUGR micrognathia round face cardiac defects hearing loss
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
diaphragmatic defects (diaphragmatic hernia, hypoplasia, eventration, agenesis) coarse facies hypertelorism seizures wide, depressed nasal bridge broad nasal tip low set anomalous ears short distal phalanges of fingers and toes pulmonary hypoplasia polyhydramnios orofacial clefting micropthalmia severe ID/DD renal dysplasia renal cortical cysts Malformations of the GI tract, brain, cardiovascular system, genitalia typically lethal in neonatal period
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
macrocephaly
hypertelorism with increased intrapupillary distance
preaxial polydactyly
cutaneous syndactyly
hypoplasia/agenesis of the corpus callosum (rare)
ID/DD (rare)
seizures (rare)
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)
microcephaly frontal bossing conductive hearing loss midface hypoplasia hypertelorism choanal stenosis/atresia laryngomalacia/bronchomalasia anteriorly placed anus hypospadias, micropenis, cryptorchidism fused labia, vaginal hypoplasia, clitoromegaly polycystic ovaries horseshoe kidney craniosynostosis, cloverleaf skull scoliosis hemivertebrae elbow synostosis femoral fractures arachnodactyly rocker bottom feet Chiari malformation oligohydramnios cortisol deficiency congenital bowing of the long bones club feet joint contractures
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
obesity macrocephaly rod-cone dystrophy, night blindness, strabismus hypogonadism postaxial polydactyly, brachydactyly/syndactyly motor delays cognitive impairment renal malformations/disease hearing loss anosmia dental crowding high-arched palate GI disease liver disease ataxia seizures speech abnormalities cardiac malformations endocrine/metabolic abnormalities
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
outer/inner/middle ear malformations hearing loss (all kinds) branchial cleft/fistulae and cysts renal malformations preauricular pits/tags facial asymmetry palate abnormalities auricular malformations
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
severe hypotonia feeding difficulties (in infancy) excessive eating (in late infancy/early childhood) leading to morbid obesity delayed motor milestones and language development cognitive impairment genital hypoplasia incomplete pubertal development infertility short stature strabismus narrow nasal bridge temper tantrums, stubbornness, manipulative behaviors
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
broad, often angulated thumbs and halluces moderate to severe ID low hanging columella high palate talon cusps short stature ocular abnormalities hearing loss respiratory difficulties congenital heart defects cryptorchidism renal abnormalities feeding problems recurrent infections severe constipation
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
developmental delays cognitive impairment behavioral abnormalities (self-injury, temper tantrums) sleep disturbances abdominal obesity (childhood onset) feeding difficulties (in infants) failure to thrive hypotonia hyporeflexia generalized lethargy broad, square face epilepsy brachycephaly midface retrusion relative prognathism with age
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
Heart defects Abnormal brain development Neural tube defects Adrenal/ kidney defects Hypertelorism Low nasal bridge Low-set, malformed ears Micrognathia Absent/small eye Cleft lip Cleft palate 3/4 finger syndactyly 2/3 toe syndactyly Liver/gallbladder defects “Twisted” intestines Maternal preeclampsia Placental abnormalities (immature, large, filled with cysts) Typically die in first days of life (or miscarriage)
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)
IUGR microcephaly Cyclopia Cleft lip Cleft palate Sloping forehead Malformed ears Anopthalmia/micropthalmia Micrognathia Preauricular tags Eqinovarus Alobar holoprosencephaly Postaxial polydactyly Congenital talipes Rocker-bottom feet Cardiac defects Cryptorchidism, hypospadia, bicornuate uterus Hearing loss Omphalocele Incomplete colonic rotation Polycystic kidney Failure to thrive Meckel diverticulum Hydronephrosis Horseshoe kidneys Failure to thrive Seizures Severe psychomotor disorder ID Median survival 733 days
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)
IUGR polyhydramnios agenesis of the corpus callosum choroid plexus cysts nuchal thickening brachycephaly overlapping fingers/clenched hands cardiac defects omphalocele single umbilical artery seizures ID poor suck neonatal hypotonia progressing to hypertonia microcephaly delayed psychomotor development triangular face micropthalmia hypertelorism cataract iris coloboma narrow, arched palate cleft lip and/or palate microtia hip dislocation rocker-bottom feet cardiac defects tracheobronchomalasia umbilical hernia horseshoe kidney genitourinary malformations median survival 3-14.5 days
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
congenital hypothyroidism hearing loss seizures congenital heart defects vision disorders brachycephaly brachydactyly depressed nasal bridge intellectual disability hypotonia chronic/recurrent infections developmental delays increased risk of malignancy increased risk of Alzheimer's short stature thickened nuchal skin fold flat face
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
vertebral anomalies (hemivertebrae, butterfly vertebrae, vertebral clefts fusion of vertebrae, missing ribs, supernumerary ribs, rub fusion/splitting, scoliosis, sacral agenesis, absence of the tailbone)
anal atresia
cardiac defects (VSDs - most common-, ASDs, hypoplastic left heart syndrome, transposition of the great arteries, tetralogy of Fallot, patent ductus arteriosus)
tracheoesophageal fistulae/esophageal atresia
renal abnormalities (renal aplasia, renal dysplasia, renal ectopia, vesicoureteral reflux resulting in hydronephrosis, hypospadia)
limb anomalies (radial aplasia/hypoplasia, underdeveloped/absence of thumb, triphalangeal thumb, polydactyly, syndactyly, radioulnar synostosis, clubfoot, hypoplasia of the great toe and tibia)
hemifacial microsomia
abnormal ears
laryngeal stenosis
choanal atresia
lung malformations
omphalocele
intestinal malrotation
tethered spinal cord
impaired growth
failure to thrive
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
ataxia hypotonia dolichocephaly frontal bossing failure to thrive developmental delay severe ID IUGR hypertelorism hypospadia low set, posteriorly rotated ears microcephaly micrognathia seizures wide nasal bridge vertebral abnormalities "Greek-helmet" profile hearing loss ptosis ear pits/tags iris coloboma heart defects nystagmus cleft lip/palate
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
Sparse hair and eyelashes (partial to complete alopecia) Absent/sparse eyebrows Dystrophic nails Palmoplantar hyperkeratosis Supraventricular tachycardia Sinus bradicardia Onychodysplasia
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
