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
hypohidrosis sparse scalp/body hair hypodontia depressed nasal bridge midface hypoplasia decreased sebaceous secretions dry eyes recurrent pneumonia raspy voice
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
alopecia hypodontia, abnormal tooth shape dystrophic nails peripheral vascularization of the retina, retinal detachment, strabismus, vision loss seizures developmental delays intellectual disability characteristic skin lesions (four stages)- I. Blistering (birth to about 4 months) II. Wart-like rash (for several months) III. Swirling macular hyperpigmentation (about 6 months to adulthood) IV. Liner hypopigmentation
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
symmetric, slow progressing distal motor neuropathy of arms and legs
weakness/atrophy of muscles in the feet and/or hands
SNHL
depressed tendon reflexes
pes cavus
moderate distal sensory loss
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
molar tooth sign (on brain MRI) hypotonia progressing to ataxia later in life developmental delays variable cognitive impairment episodic apnea/tachypnea atypical eye movements, retinal dystrophy, ocular coloboma renal disease occipital encephalocele hepatic fibrosis polydactyly oral hamartomas endocrine abnormalities
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
long palpebral fissures with eversion of lateral third of lower eyelid, arched/broad eyebrows, short columella with depressed nasal tip, large/prominent/cupped ears minor skeletal anomalies (sagittal cleft, hemivertebrae, butterfly vertebrae, narrow intervertebral disc space, scoliosis, brachydactyly V, clinodactyly of the 5th digit, brachymesophalangy) mild to moderate ID/DD infantile hypotonia postnatal growth deficiency persistence of fetal fingertip pad congenital heart defects hearing loss anal atresia ptosis, strabismus cleft lip/palate hypodontia seizures GU anomalies feeding problems endocrine abnormalities
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
severe ID, non-verbal agenesis of the corpus callosum HL brachydactyly seizures structural abnormalities of the brain hypotonia dysphagia microcephaly vision abnormalities cardiac malformations GI/GU/renal malformations deep set eyes, wide nasal bridge, long philtrum, midface retrusion, pointed chin, low set and posteriorly rotated ears failure to thrive
Monosomy 1p36 1p36 deletion 8-% de novo Diagnosed on CMA/FiSH/del-dup analysis Managed symptomatically
early childhood onset delayed motor milestones with rapid progression proximal weakness waddling gait wheelchair bound by 12 y/o cardiomyopathy respiratory complications most die by 3rd decade of life
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
Later in life onset skeletal muscle weakness
activity induced cramping
cardiomyopathy
heart failure
wheelchair bound after 16 (some can go until 3rd/4th or even 6th decade)
average age of death in 4th decade
may be asymptomatic/only have elevated muscle CK, muscle cramps, and/or myglobinuria
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
slow progressive ataxia (average age of onset 10-15 y/o) dysarthria muscle weakness spasticity (esp. lower limb) absent lower limb reflexes bladder dysfunction scoliosis cardiomyopathy loss of positional/vibrational sense diabetes mellitus hearing loss
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
recurrent acute sensory/motor neuropathy (single or multiple nerves) that recovers over the course of a few weeks and is often painful
painless nerve palsy after minor trauma/compression
focal weakness
atrophy
sensory loss
pes cavus
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
Progressive weakness/atrophy of voluntary muscles in hips/shoulders
Difficulty standing from a sitting position and going up stairs
Difficulty lifting arms above head and carrying heavy objects
Waddling gait
Scoliosis/lordosis
Contractures
Various muscle hypertrophy
Cardiomyopathy
Dysphagia
Dysarthria
Breathing difficulties
*note highly variable presentation among subtypes
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
Cataract, mild myotonia, normal lifespan Club foot Endocrine abnormalities Basal cell carcinoma Pilomatrixomas
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
Muscle weakness and wasting, myotonia, cataract, cardiac conduction abnormalities, adults with physical disabilities, balding, sometimes shortened lifespan Club foot Endocrine abnormalities Basal cell carcinoma Pilomatrixomas
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
Hypotonia and severe generalized weakness at birth, respiratory deficiency, ID, early death Club foot Endocrine abnormalities Basal cell carcinoma Pilomatrixomas
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
Muscular weakness (face, neck, proximal muscles) Hypotonia Reduced/absent reflexes Elongated face Retrognathia High arched palate Dysarthria Dysphagia Respiratory difficulties Delayed motor milestones Contractures Pectus excavatum Scoliosis Cardiac abnormalities
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
muscle weakness/atrophy (due to progressive degeneration and irreversible loss of anterior horn cells in spinal cord and brain stem nuclei) progressing symmetrically from proximal to distal (onset variable) poor weight gain/growth failure restrictive lung disease scoliosis joint contractures areflexia fatigue postrural tremor of fingers atrial septal defects (only one type)
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
progressive weakness loss of motor skills (3-6 months) cherry-red spot decreased visual attentiveness exaggerated startle response developmental plateau/loss of skills (8-10 months) seizures death by 2-3 y/o (some survive to 5-7 y/o)
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
spasticity seizures dysphagia dysarthria abnormal gait Death in 2nd decade
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
lower extremity weakness muscle atrophy dysarthria incoordination tremor mild spasticity/dystonia acute psychosis
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
neonatal hypoglycemia macrosomia macroglossia hemihyperplasia omphalocele, umbilical hernia embryonal tumors (Wilms tumor, hepatoblastoma, neuroblastoma, rhabdomyosarcoma) visceromegaly (liver, spleen, kidneys, pancreas, or adrenal glands) adrenocortical cytomegaly cytomegaly of fetal adrenal cortex ear pits/creases renal abnormalities (medullary dysplasia, nephrocalcinosis, medullary sponge kidney) cardiomyopathy cleft palate midface retrusion placental mesenchymal dysplasia
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)
broad, prominent forehead dolichocephalic head shape sparse frontotemporal hair downslanting palpebral fissures malar flushing long, narrow face long chin overgrowth Developmental delays/intellectual disabilities/behavior prolems seizures advanced bone age cardiac anomalies, renal anomalies joint hyperlaxity scoliosis maternal preeclampsia, neonatal complications cranial MRI/CT abnormalities
Sotos Syndrome NSD1 AD (most are del/dup) 95% de novo; fully penetrant Diagnosed on genetic testing (CMA/sequence analysis/del/dup) Managed symptomatically
progressive cerebellar ataxia (1-4 y/o) oculomotor apraxia choreoathetosis conjunctival telangiectasias immunodeficiency frequent infections leukemia/lymphoma, other malignancies progressive slurred speech premature aging (greying of hair) endocrine abnormalities
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
severe pre and post natal growth deficiency
immune abnormalities
sunlight sensitivity
insulin resistance
increased risk of early onset cancers (as well as other conditions typically associated with aging including COPD and diabetes mellitus)
male infertility
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
short stature abnormal skin pigmentation skeletal malformations microcephaly ophthalmic anomalies GU anomalies acute myeloid leukemia progressive bone marrow failure pancytopenia, thrombocytopenia, leukopenia solid tumors of the head, neck, skin, and GU tract hearing loss developmental delays
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
ADD dementia (early onset) progressive behavioral disturbances vision loss worsening handwriting incoordination progressive gait disorders leg stiffness/weakness abnormal sphincter control sexual dysfunction adrenocortical insufficiency (Addison's disease)
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
Severe, progressive dementia (beginning with subtle and poorly recognized failure of memory and slowly becoming more severe until it is eventually incapacitating) beginning before 65 y/o confusion poor judgement language disturbances visual complaints myoclonus incontinence mutism death usually from inanition, malnutrition, and pneumonia gross cerebral cortical atrophy
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)
Developmental delays, intellectual disabilities severe speech impairment gait ataxia/tremulousness of limbs unique behavior seizures microcephaly prognathia strabismus hypotonia flat occipit widely spaced teeth hypopigmented skin
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
mid-adult onset recurrent ischemic strokes
apathy
cognitive decline progressing to dementia
mood disturbances
migraines with aura
diffuse white matter lesions/subcortical infarcts
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
normal early life (until 3-5 m/o) hypotonia head lag macrocephaly developmental delays irritability sleep disturbances seizures feeding difficulties leukodystrophy (on neuro imaging) severe dysphagia joint stiffness elevated urine N-acetylaspartic acid
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)
Feeding difficulties, poor growth
emesis crises
recurrent aspiration pneumonia
altered sensitivity to pain/temperature
extreme blood pressure variability with postural hypotension
Breath holding behaviors (leading to cyanosis or fainting) starting in infancy and stopping by age 6
decreased/absent deep tendon reflexes
hypotonia, delayed motor milestones
decreased taste, absence of fungiform papillae of tongue
Learning disabilities
alacrima
optic neuropathy, progressive vision loss
broad based/ataxic gait and increasing difficulties with balance
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
developmental delays intellectual disability seizures behavioral issues Autism spectrum disorder hypotonia GERD strabismus sleep disorders joint laxity pes planus scoliosis recurrent otitis media mitral valve prolapse, aortic root dilation
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)
HIGHLY VARIABLE PRESENTATION (presents before or after 12 months) irritability feeding difficulties GERD lower extremity spasticity and fisting axial hypotonia loss of milestones staring episodes dyspahgia peripheral neuropathy vision loss hydrocephalus
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
multiple cafe au lait macules axillary/inguinal freckling multiple cutaneous neurofibromas Lisch nodules choroidal freckling learning disability optic nerve glioma tibial dysplasia scoliosis vasculopathy peripheral nerve sheath tumors
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
Progressive motor disability featuring chorea (may affect voluntary movement)
Mental disturbances including cognitive decline, personality changes, and/or depression
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)
Resting tremor Muscle rigidity Bradykinesia Insomnia Postural instability Limb dystonia Depression/anxiety Fatigue Constipation Dysautonomia Hyposmia Dementia Can present any time between younger than 20 to older than 50
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)
Normal psychomotor development 6-18 months, short period of developmental stagnation, rapid regression in language/motor skills, long term stability Repetitive, stereotypical hand movements Screaming fits Spectrum of intellectual disability Autistic features Panic-like attacks Bruxism Tremors Episodic apnea/hypernia Gait ataxia/apraxia Seizures Acquired microcephaly
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
Severe neonatal encephalopathy Metabolic degenerative type pattern Abnormal tone Involuntary movements Severe seizures Breathing abnormalities Death before age 2 y/o
Rett Syndrome MECP2 XL 99% de novo Diagnosed on molecular genetic testing Managed symptomatically, with periodic MDC visits, and avoidance of QT prolonging drugs
Recurrent jaundice Hepatitis Liver failure Chronic liver disease Tremor Poor coordination Choreoathetosis Chorea Loss of fine motor control Mask-like facies Rigidity Gait disturbances Pseudobulbar involvement Depression Neurotic behaviors Disorganized personality Intellectual deterioration Kayser-Fleischer rings
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)
recurrent bacterial infections (otitis, conjunctivitis, sinusitis, sinopulmonary infections, diarrhea, and skin infections)
pneumonia (S. pneumoniae)
empyema
meningitis
sepsis
cellulitis
septic arthritis
H. influenza
paucity of lymphoid tissue
severe, difficult to treat enteroviral infections
marked reduction in serum Ig and absent B cells
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)
Short episodes of inflammation and serositis Leukocytes Fever Peritoritis Synovitis Pleuritis Pericardits Meningitis Amyloidosis Abdominal pain Joint pain Skin eruptions Increased ESR Chest pain Elevated serum fibrinogen
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
Hepatic dysfunction
COPD
Panniculitus
C-ANCA-positive vasculitis
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
Multiple osteochobdromas Benign cartilage-capped bone tumors Reduced skeletal growth Bony deformity Short statute Restricted joint motion Premature osteoarthritis Compression of peripheral nerves
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
blepharophimosis ptosis epicanthus inversus telecanthus lacrimal duct anomalies amblyopia strabismus refractive errors broad nasal bridge short philtrum low-set ears \+/- premature ovarian insufficiency
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
pre- or postlingual mild to profound high frequency sensorineural hearing loss
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
oculocutaneous albinism bleeding diathesis pulmonary fibrosis granulomatous colitis immunodeficiency nystagmus reduced visual acuity solar keratoses
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
congenital profound bilateral sensorineural hearing loss
long QTc
tachyarrhythmias
syncope
iron-deficient anemia
elevated gastrin
sudden death (usually before age 15 y/o if intreated)
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
bilateral, painless, subacute visual failure postural tremor peripheral neuropathy nonspecific myopathy MS-like illness movement disorders retinal telangiectasias optic disc atrophy cardiac arrhythmias optic nerve dysfunction onset most often in the 2nd to 3rd decade
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
congenital, profound sensorineural hearing loss
vestibular dysfunction
bilateral enlarged vestibular aqueducts (EVA)
cochlear hypoplasia
euthyroid goiter
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
Degeneration of upper and lower motor neurons Weakness Muscle atrophy Hypereflexia Muscle cramps Fasciculations Stumbling Poor hand grip Dysplasia Dysarthria Lability of affect Frontotemporal degeneration Executive function defects Personality changes (severe apathy) Age of onset in men (~55 y/o) and women (60’s)
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
Congenital, profound sensorineural hearing loss
Vestibular areflexia
Retinitis pigmentosa (adolescent onset)
Absent speech without hearing intervention
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
Congenital bilateral sensorineural hearing loss (mild to moderate at low frequencies and severe to profound at high frequencies)
Intact/variable vestibular response
Retinitis pigmentosa
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
Congenital sensorineural hearing loss White forelock Premature greying (>30 y/o) Heterochromia iridium/partial or segmental heterochromia/hypo plastic or brilliant blue irides) Congenital leukoderma Telecanthus Synophrys Broad/high nasal root Low hanging columella Underdeveloped alae nasi
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
Disproportionate short stature Macrocephaly Rhizomelic shortening of limbs Frontal bossing Midface retrusion Hypotonia in infancy Delayed/aberrant motor milestones Sleep apnea Middle ear dysfunction Kyphosis Spinal stenosis Horizontal acetabula Brachydactyly Trident hands Square ilia Proximal femoral radiolucency
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
Delayed closure of cranial sutures Hypoplastic/aplastic clavicles Dental abnormalities Moderate short stature Recurrent sinusitis/otitis Hearing loss Upper airway obstruction Frontal bossing Mid face retrusion Brachydactyly Short, broad thumbs Tapering fingers
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
Limb shortening Hitchhiker thumbs Scoliosis/kyphosis/lordosis Contractures of large joints Early onset osteoarthritis Ulnar deviations of fingers Sandal toe Club foot Normal head size Protuberant abdomen
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
Coronal synostosis Facial asymmetry Strabismus Ptosis Small pinna with prominent superior and/or inferior crus 2,3 syndactyly Parietal foramina Vertebral segmentation defects Radioulnar synoatosis Maxillary hypoplasia Hypertrlorism Hallux valgus Duplicated/curved distal hallx Palatal abnormalities Obstructive sleep apnea Increased intracranial pressure Short atatute Congenital heart malformations Dysphagia Hearing loss
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
short stature stocky build disproportionately short arms and legs (long bones) broad, short hands and feet with brachydactyly mild joint laxity mild metaphyseal flare macrocephaly short, broad femoral neck squared, shortened ilia intellectual disability/learning disabilities epilepsy limitation of elbow extension
Hypochondroplasia FGFR3 AD; mostly de novo Diagnosed on molecular genetic testing Managed symptomatically Track height/weight/head circumference with achondroplasia specific growth charts
arachnodactyly
flexion contractures of digits, elbows, and knees
kyphoscoliosis
marfanoid habitus
“crumpled” ears
hypotonia
cardiac anomalies (VSD, ASD, interrupted aortic arch, mitral valve prolapse, and/or severe aortic root dilation/aneurysm)
severe GI anomalies (duodenal or esophageal atresia and/or intestinal malrotation)
club feet
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
broad clinical continuum- fractures with minimal/absent trauma adult onset hearing loss variable dentinogenesis imperfecta severe skeletal deformities mobility impairment short stature blue/grey scleral hue ligamentous laxity perinatal lethality (in severe cases)
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
Atrophic scarring Hypotonia Generalized joint hypermobility Skin that is… soft/doughy, fragile, hyperextensible Poor wound healing Frequent dislocations Delayed motor develolment Fatigue Muscle cramps Easy bruising
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
Normal prenatal growth with onset of growth and developmental abnormalities in the first two years of life (height/weight/head circumference <5th percentile by age 2)
Progressive hearing and vision loss
Progressive central and peripheral nervius system impairement
Death in 1st or 2nd decade of life
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
Growth failure at birth Little/no postnatal neurological development Congenital cataracts Postnatal contractures of spine/joints Death by age 5
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
Mild growth failure after 2 y/o (children/teens with short stature) Mild neurological impairment Progressive ataxia Cutaneous photosensitivity Mild opthalmologic findings
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
Severe prenatal growth failure, microcephaly, micropthalmia, and arthrogryposis
Congential cataracts and other structural defects of the eye
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
Arterial aneurysm/dissection/rupture Intestinal/uterine fragility/rupture Micrognathia Thin, translucent skin Spontaneous pneumothorax Easy bruising Narrow nose Prominent eyes Aged appearance of extrematies GI perforations Amniotic bands Clubfoot Neonatal hip dislocations Limb deficiency Distal joint hypermobility Thin vermilion of lips Tendon/muscle rupture Early onset vericose veins
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
profound failure to thrive during the 1st year of life narrow nasal ridge head disproportionately large for face narrow nasal tip/ridge small mouth, thin vermilion retro and micrognathia loss of subcutaneous fat delayed eruption and loss of primary teeth abnormal skin alopecia nail dystrophy coxa valga progressive joint contractures conductive hearing loss cardiac disease stroke death between 6 to 20 y/o
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
childhood onset, slowly progressive cerebellar ataxia oculomotor apraxia severe primary motor peripheral/axonal motor neuropathy gait imbalances (~4.5 y/o) dysarthria upper limb dysmetria mild intention tremor progressive external opthalmoplegia short, atrophic hands and feet quadriplegia (7-10 years after onset) generalized areflexia chorea upper limb dystonia variable cognitive impairment cerebellar atrophy on MRI
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
ataxia (onset between 3-30 years old) oculomotor apraxia axonal sensorimotor neuropathy cerebellar ataxia elevated serum AFP absent/diminished tendon reflexes
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
Primary adrenal insufficiency Hypogonadotrophic hypogonadism Delayed puberty Seizures Strabsimus Metabolic acidosis Hypoglycemia
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
Prenatal virulozation of females Hypoglycemia Salt wasting crises Hypertension Recurrent fever
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
feminization of external genitalia
abnormal secondary sexual development in puberty (including gynecomastia)
osteopenia/osteoporosis
absent/rudimentary Mullerian structures (fallopian tubes, uterus, cervix)
testicular malignancy
infertility (in karyotypic 46,XY individuals)
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
low serum luteinizing hormone and follicular stimulating hormone low circulating sex steroids anosmia micropenis, cryptorchidism, hypogonadism absence of secondary sexual features ED infertility decreased muscle mass primary amenorrhea
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
cafe au lait macules (apparent at or shortly after birth) fibrous dysplasia (craniofacial, axial, and/or appendicular skeleton); can lead to progressive scoliosis/facial deformity and loss of mobility/hearing/vision endocrinopathies (gonadotropin-independent precocious puberty from recurrent ovarian cysts/autonomous testosterone production; testicular lesions with/without associated gonadotropin-independent precocious puberty; thyroid lesions with/without non-autoimmune hyperthyroidism; growth hormone excess; FGFR23-mediated phosphate wasting with/without hypophosphatemia; neonatal hypercortisolism) prognosis based on disease location and severity
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
severe IUGR neonatal onset hyperglycemia (resolves by 18 months old) ABSENCE of ketoacidosis dehydration macroglossia umbilical hernia hypotonia congenital heart disease deafness epilepsy renal malformations
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
hematuria, proteinuria
progressive renal insufficiency, end stage renal disease
progressive sensorineural hearing loss
anterior lenticonus, maculopathy, corneal endothelial vesicles, recurrent corneal erosion
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)
late onset Cysts of the... bilateral kidneys liver seminal vesicle arachnoid membrane pancreas Intracranial aneurysm Aortic root dilation, thoracic aorta dissection, mitral valve prolapse Abdominal wall hernias Hypertension Renal insufficiency, end stage renal disease
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)
neonatal presentation enlarged, echogenic kidneys hypertension renal dysfunction/end stage renal disease oligohydramnios pulmonary hypoplasia hepatosplenomegaly hepatic fibrosis esophageal/gastric varices enlarged hemorrhoids hypersplenism protein-losing enteropathy GI bleeding common bile duct dilation
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)
