Illustrative Cases- Test Yourself! Flashcards by Shay Guetz

Tetralogy of Fallot (discharged at DOL3)
Twitching and jerking at home –> hospitalized for seizure and ? stroke
Calcium 4.7
Recurrent sinusitis/otitis with significant T-cell dysfunction (live viral vaccines held until 7 yo)
Speech/language delay
Enamal hypoplasia
Cervical, thoracic vertebral anomalies, Scoliosis
Short stature, ITP, constipation
ID, dyslexia, significant anxiety, ADHD

22q11.2 Deletion Syndrome

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Complex cardiac anomaly
Hypocalcemic seizures and ITP
Sepsis and necrotizing enterocolitis
Passed at 4 mo

22q11.2 Deletion Syndrome

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Failure to Thrive (in newborn period)
Mild dysmorphic features
Severe GERD (resulting in G-tube placement)
Intestinal malrotation
Mild learning differences
ADHD and anxiety

22q11.2 Deletion Syndrome

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Significant respiratory and swallowing issues at birth
Hypocalcemia
Severe GERD
Chronic otitis media
Mild delays (motor and speech milestones)

22q11.2 deletion syndrome

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Cleft palate
SN Hearing loss
Laryngotracheomalacia
Sleep apnea
GERD
Bilateral inguinal hernia repair
Cryptorchidism
Chronic infections (requiring IVIG therapy)
Polymicrogyria
Congenital nystagmus
Developmental Delay (non-verbal; non-ambulatory)

22q11.2 deletion syndrome

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Patient with autism and mild dysmorphisms on exam
Maternal aunt has anxiety
Maternal cousin (male) has ID
Maternal grandmother with bipolar disorder
Maternal great aunt with learning disability
Maternal Great-grandfather (father of maternal grandmother) with atypical Parkinson’s disease

Fragile X Syndrome

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7.5 y/o male
ASD and mild pulmonic stenosis
cryptorchidism bilaterally
ptosis, strabismus, and disconjugate gaze
short stature (with normal growth factors and thyroid function)
developmental delays/mild ID
down slanting palpebral fissures
hypertelorism
low set ears
wide spaced nipples

Noonan syndrome

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13 y/o male
normal intelligence
severe cryptophthalmia with micropthalmia bordering on anopthalmia
low set ears with thick, over-folded superior helices
bilateral, cutaneous syndactyly of all digits (both fingers and toes)
prognathia
flared, upturned nares with prominent colomela
positive for consanguinity (parents are first cousins)
mother had 3 miscarriages (including a late pregnancy loss) and one stillbirth children, one with similar birth defects to the patient

Fraser Syndrome (AR mutations in the FRAS-1 or FREM2 genes)

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6 y/o 4 m/o female
benign heart murmur
learning difficulties (regular kindergarten but problems with concentrating, distractible)
hooded eyelids
bulbous nose
low set ears with thickened/protuberant helices

22q11.2 del

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newborn infant
white forelock 
hypertelorism
hearing loss
broad, high nasal root
mom has white forelock, light irises, and telecanthus

Waardenburg syndrome

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newborn infant
metaphyseal flare
dumbbell long bones
'halberd' appearance
micromelic long bones
no fractures

Metatropic dysplasia

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3 y/o female
hypotonia
long, smooth philtrum invading the Vermilion border with tented upper lip
ptosis
macrocephally
low set ears
frontal bossing
frontal-pariatal balding
umbilical hernia
three supernumerary nipples
hyperpigmented areas following the dermatome

Palliser-Killian Syndrome

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7 day old male presented to ER for breathing problems
initially feeding well, but began spitting up and refusing feeds at DOL 5, then over the next few days he became increasingly listless and had difficulty breathing - parents took to pediatrician who sent them to ER
Very lethargic and hypotonic
Pale
PE normal (no hepatosplenomegaly, no murmur, normal breath sounds)
CBC and spinal tap negative
No fever or sign of infection

Inborn error of metabolism

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Normal early development
Decreased R eye visual acuity following an eye injury at 15 y/o male with progressive worsening over a year (not correctable with glasses)
Decreased left eye vision
Decreased color vision
Bilateral peripheral vision loss
Nyctlopia
Bilateral optic nerve pallor on  eye exam
Normal brain imaging

Leber Hereditary Optic Neuropathy (LHON) homoplasmy (m.11778G>A ND4)

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10 y/o male with…
scapla winging
exercise intolerance (can only walk about 10 minutes)
proximal leg weakness
emesis with exertion
sleep apnea
dysphagia
normal development and pregnancy
fhx significant for…
mom with exercise intolerance, fatigue, confusion, headaches, and fainting
sister with easy fatigue, severe sleep apnea, dysphagia, g-tube dependent, and needs assistance with daily living
mat uncle with h/o severe respiratory issues requiring trach at 18 y/o, spinal fusion due to severe scoliosis, severe weakness, emesis
MGM with hearing loss and DM

MELAS syndrome

heteroplasmy (m.3288A>G 58% in blood)

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7 y/o Saudi Arabian boy with…
normal pregnancy to a G5P4 mom (positive consanguinity- parents are cousins)
developmental regression (lost ability to walk at 12 months, regained at 15 months, now wheelchair bound and cannot hold pen or utensil; first words occurred around 2 y/o but has lost all words)
Dystonia around 6 y/o
Dysarthria
Failure to thrive
Ptosis
Strabismus
All siblings are healthy and so are parents

Leigh Syndrome

heteroplasmy (m.10197G>A 65% in blood ND3)

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2 y/o healthy African American boy with…
pancytopenia on routine CBC (decreased hemoglobin, retiulocyte count, leukocyte count, neurtophil, and platelets)
Recent viral infection
Decreased activity and appetite
Fatigue
Symptoms improved with blood transfusion
F/u labs show persistent pancytopenia
Bone marrow aspiration reveals sideroblastic anemia

Pearson Syndrome

heteroplasmy (72% blood)

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13 y/o Puerto Rican boy with…
Hearing aides at age 6 for SNHL
Autism dx at 7 y/o
limited early childhood history (mother passed away from ovarian cancer when he was young)
In regular classes in school with 1:1 and modified assignments
Presented to ED with acute encephalopathy
Bilateral ptosis
Cerebellar ataxia
Short stature

Kearn Sayer Syndrome (KSS)

heteroplasmy (23% in blood)

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Female
9 months old had...
L side tremor, seizure lasting 1-2 minutes
Developmental regression
Poor feeding
Brain MRI with R thalamus changes
EEG showing EPC
11 months...
Feeding intolerance, fever, and significant transaminitis
Emesis, FTT leading to G-tube placement
18 months...
Seizures in good control
Rolls in both directions
Pushes up on her hands
Says "mama" and "dada" with meaning
Elevated lactate on UOA, CSF, and blood (x3)

POLG

35 y/o Caucasian male presents with…
normal development
ptosis (noted during high school)
numbness and tingling in feet (began in his 20’s)
severe calf pain
Hashimotos thyroiditis
Dysphagia
Dyspnea
Restriction of abduction and adduction slow horizontal saccades with gaze evoked horizontal nystagmus on eye exam
Normal optic nerve and no retinal pigmentary changes
Exonal polyneuropathy, foreleg fasiculations, and involuntary movements on EMG?NCS
Negative Fhx

POLG (c.1399G>A; p.A467T)

21 y/o male
friendly, outgoing, black belt in karate
multiple congenital anomalies noted at birth (sagittal synostosis, partial agenesis of the corpus callosum)
Fhx of father who had a twin who died in the neonatal period due to reported twin-to-twin transfusion syndrome, three miscarriages by his paternal grandmother, and a paternal cousin with multiple congenital anomalies (none of which overlap with the patient)
Normal karyotype at birth and in childhood

Duplication- small piece at the end of chromosome 21
Deletion- small piece at the end of chromosome 6
Unbalanced translocation

28 y/o prima gravida presenting for high risk obstetrical care due to “suspected connective tissue disorder” and secondarily for fetus with “gastroschisis” - declined amnio but accepted cfDNA screening
Pt has a h/o lax joints, double jointedness, tall stature, and long limbs. Had been seen by a geneticist who raised suspicion for connective tissue disorder and referred to an expert, but pt did not follow-up

47,XXX for mother

46,XX for baby

1 y/o female, previously healthy (normal birth and delivery, generally good health, normal growth and diet)
No dysmorphic features
Hepatomegaly found on routine pediatric visit
Late to sit up (8 months)
Not yet standing alone or walking (unusual in a 1 y/o)
Mild hypotonia
Referred to GI/liver service for evaluation

Storage diseases-
Lysosomal storage disorders (Gaucher, Niemann-Pick)
Glycogen storage diseases (liver type)

7 month old female presents with extreme lethargy/barely responsive and hypoglycemia
Born at term, no problems in the new born nursery
Fed well, normal growth
Slept through the night, but often awoke for a feeding
Mild cold, didn’t eat well during the day and couldn’t be awakened the next morning so she was brought immediately to the ER
No dysmorphic features, low muscle tone, mild hepatomegaly on exam
No ketones in urine (which should be present with hypoglycemia)

MCAD

8 month old boy presents because of developmental delays Normal birth, initially did well Some early weakness noted at 4 m/o At 6 months, slumped over when sitting Never tried to pull to stand, never rolled over Less attentive in the coming months, but did startle to loud noises Difficult to feed with dysphagia No dysmorphic features Poor muscle tone Unusual eye movements No hepatosplenomegaly

Tay-Sachs Disease

10 y/o male presents to the ED with syncopal episodes His mother reports that he has been experiencing these episodes more and more recently During this episode he was playing tag with some of the other kids in the neighborhood, however he has had some episodes at home when he is not being active She notes that her and her husband are getting a divorce EKG during his hospital say shows a long QTc His pregnancy and birth history are normal, however he failed his new born hearing screen and has bilateral profound sensorineural hearing loss His mother notes that he is taking iron supplementation for anemia, but is otherwise a healthy child

Jervell and Lange-Nielsen Syndrome

``` 17 y/o female with clear muscle weakness of unknown etiology at 6 y/o had difficulties washing hair at 8 y/o difficulties getting up from a chair can walk slowly only for 15-20 minutes has developed contractures and scoliosis elevated CK (3000's) 26 y/o cousin who is wheelchair bound parents are first cousins ```

Sarcoglyconopathy (Limb Girdle Muscular Dystrophy Recessive 5)

24 m/o female born to 29 y/o G2P1101->2 mom decreased fetal movement and polyhydramnios preeclampsia, HELLP syndrome born via SVD after ROM at 34 weeks 5 days Low 1 minute Apgar (6) but improved to good at 5 minutes (8) intubated shortly after birth; extubated DOL48 severe hypotonia and weakness involving face; minimal antigravity movements feeding intolerance contractures of hips, knees, and ankles MOC with hand grip and percussion myotonia (inability to relax muscle contracture)

Myotonic Dystrophy Type 1 | 110 CTG repeats (mosaic expansion)

4 y/o female with history of motor milestone delays sat and crawled 11 months; first steps 22 months, walked with Tredelenburg gait; ran at 3 y/o seen by local neurologist for motor delays and was noted to have elevated CK (11000's) and white matter changes on brain MRI despite normal cognitive development

Merosin Deficient Congenital Muscular Dystrophy (LAMA2 mutations) compound heterozygous

9 y/o female initially diagnosed with likely congenital CMV bilateral esotropia (s/p surgery at 2 y/o) normal hearing born with VSD that closed spontaneously asthma diagnosed at 18 mo; outgrew during 3rd year of life persistently elevated transaminase without liver disease hypotonia, normal strength, no seizures speech and cognitive delays elevated CK (2230)

Muscular-Eye-Brain disease spectrum | LARGE gene

``` 6 m/o female microcephaly global DD cortical visual impairment hand fisting elevated transaminase ```

Muscle-Eye-Brain disease spectrum | POMT1 (alphadystroglycanopathy)

8 y/o old female initially presented with bilateral sensorineural hearing loss, tortuous retinal vessels with microaneurysms (Coat's disease), normal development for age, normal neurologic/neuromuscular examinations; head US normal; TORCH titers negative at 8 months old facial diplegia with slurred speech Trendelenburg gait; Growers sign; increase in falls doing excellent academically

Facio-Scapular-Humoral Disease | 13 kb deletion; >48 kb deletion (this is what caused it- less residual repeats)

6 y/o male evaluated by PCP for weight gain and noted elevated transaminases (ALT/AST) Referred to GI locally who noted there was no significant liver disease, but CK was mildly elevated (586 and 625) Referred to neurology who noted earlier fatigue/decreased endurance compared to peers; less agile than peers; occasional leg pain post-exercise Physical Exam- normal strength in all muscle groups; normal DTRs; runs, hops, and jumps; negative Gowers sign Mild increase in echogenicity on muscle US

Pompe Disease GAA mutations 0 GAA enzymatic activity

12 y/o male with 1 year history of mild motor decline (with decreased endurance, increased fatigue, decline in handwriting, chronic hip pain, mildly affected speech) and prior clinical diagnosis of "Mobious syndrome" respiratory distress with tracheostomy at 1 mo-18 mo dysphagia with G-tube feeds from 1 mo to 12 mo hypotonia and weakness including facial weakness and bilateral ptosis (s/p 5 repairs due to recurrences) walked at 12-14 mo; PT/OT d/c at 3 y/o skateboarding and participating in sports always some difficulties with stairs, hills, inclines, and other more difficult tasks No bulbar symptoms or clear fluctuation Positive 1 handed Growers normal CK muscle biopsy was non-diagnostic *electrodecrement with repetitive stimulation*

MUSK related Congenital Myesthenic Syndrome

4 y/o male presents with gait differences, difficulties with balance, and parasthesias Mother to-walking since childhood; maternal grandfather and maternal aunt had similar symptoms, but very mild MOC had abnormal EMG testing

Charcot-Marie-Tooth Type 1A

5 y/o female with 9-12 month history of gait differences, increased falling, and fatigue seen by general neurology who suspected peripheral neuropathy; EMG showed bilateral motor axonal neuropathy with normal sensory response motor and cognitive milestones were on target (though MOC retrospectively noted slow progression of overpronation since pt started walking at 12 mo) mild distal weakness of foot dorsiflexion and toe extension with preserved plantar flexion, inversion and eversion mild intrinsic hand weakness of the FDI, ADM, and APB mildly decreased DTRs able to walk on toes but showed fatigue pattern with heel dip after 10 steps difficulties with heel walking with quickly evolving foot drop able to hop, can accelerate into run, one handed Growers MOC with mild foot drop, resting tremor, toe-walked as a child s/p bracing maternal grandfather with unusual gait (maybe foot drop, balance issues, thin quads/hamstrings, played tennis into late 70's (currently 80) maternal uncle with congenital arthrogryposis, non-ambulatory since 40's, hearing loss in 50's, above average IQ; daughter with congenital arthrogryposis, never walked, above average IQ

Charcot-Marie-Tooth Type 2C | TRPV4

``` Failure to thrive since birth hypotonia and developmental delays regression in motor skills at 6 months (loss of head control, loss of reach and grasp); developed arthrogryposis/contractures rapidly loss of PO feeding ability respiratory decompensation ```

Severe Demyelinating Charcot-Marie-Tooth Disease (Dejerine-Sottas Syndrome) EGR2

48 y/o male was identified to have a low-grade fever and enlarged spleen at routine PCP visit blood work revealed elevated white blood cell count referred to hem/onc

Chronic Myeloid Leukemia | due to t(9;22) with BCR-ABL1 fusion

80 y/o female with history of CLL dx in 2009 Bone marrow biopsy showed hypercellular marrow with persistent chronic lymphocytic leukemia (NO morphologic or immunophenotypic evidence of large cell transformation OR significant dyspoiesis or an increased number of blasts) H/o lung cancer dx in 1989 treated with chemo Invasive breast ductal carcinoma dx 2015 treated with radiation therapy

Stimulated cells normal | Unstimulated cells with a complex karyotype with structural rearrangements

38 y/o female presents to OB for first prenatal visit concerned about increased risk of Down Syndrome due to age 9 week post-last menstrual period NIPS was performed which showed genomic imbalances with gains and losses of nearly every chromosome

Occult malignancy- diffuse large B cell lymphoma

4 y/o male presents with short stature, bilateral short thumbs (radial ray defects), anemia/pancytopenia, and cafe-au-lait spots tetraradials noted on chromosome staining

Fanconi Anemia

38 y/o female who does not have cancer and no fhx of cancer Sister who died suddenly of a MI at age 41 after running a marathon- she was found to have had a pheochromocytoma on autopsy Mother died at 45 y/o from complications of a surgical procedure

Conditions that were on the DDx include- von Hippel Lindau Syndrome (note that sister's age at dx fits and has variable expressivity) MEN2 (though without MTC in the family this is less likely) Hereditary PGL-Pheo Syndrome (sister's age fits) Sporadic pheochromocytoma

35 y/o male with metastatic kidney cancer (tumor pathology was read as mixed, possibly papillary tumor; re-review was unsuccessful) Mother and maternal aunt had hysterectomies at 40 y/o for unknown reasons NO fhx of cancer, skin leiomyomas, retinal angiomas, or lung blebs/pneumothorax

Conditions that were on the DDx include- Hereditary Leiomyomatosis Renal Cell Cancer (given aggressive tumor and fhx of hysterectomy make this more likely) Hereditary Papillary Renal Carcinoma Syndrome (due to lack of clear pathology or hx skin leiomyomas make this likely) Birt Hoge Dube (should be considered whenever pathology is complex, however this is less likely) von Hippel Lindau (most common RCC gene, but typically linked to clear cell) Sporadic kidney cancer

12 month old male with strabismus due to a unilateral retinal mass- pathology report this was either unilateral retinalblastoma or retinal hamartoma Normal developmental milestones Fhx unremarkable

``` Conditions on the DDx include- Hereditary Retinoblastoma (RB1)- specific to unilateral retinalblastoma Tuberous Sclerosis (TSC1/TSC2*)- specific to retinal hamartoma ```

45 y/o female with multiple nevi, including a few small dysplastic nevi (notes Irish ancestry with personal history of excessive sun exposures and sunburns) Father and paternal uncle died from pancreatic cancer in their 60's (note they were both alcoholics) Paternal grandmother with breast cancer at age 60 Paternal grandfather with colon cancer in 50's

Conditions on the DDx include- Lynch syndrome (two generations of GI cancers) *FAMMM (personal hx of dysplastic nevi plus fhx of pancreatic cancer) HBOC syndromes (less likely due to age at onset of breast and pancreatic cancers) Sporadic cancer (environmental risk factors could explain all cancers)

6 month old male with unilateral kidney mass (which could be early stage Wilms tumor or cystic nephroma) No congenital birth defects or developmental delay Father has a history of thyroidectomy at age 18 due to thyroid nodules, fhx otherwise negative

Conditions on the DDx include: Familial Wilms' Tumor (though less common to see it unilaterally, early diagnosis makes this more suspicious) Beckwith-Weidmann Syndrome (less likely in the context of the absence of congenital anomalies) *DICER1 Syndrome (very likely if mass is a cystic nephroma- father's thyroid nodules would be consistent with this) Li-Fraumeni syndrome (any abdominal tumor before 1 y/o is concerning for this) Sporadic kidney mass (since it is unilateral and no fhx of renal masses)

4 y/o female with bone marrow failure and acute myelogenous leukemia History of frequent infections and some history of bone marrow failure (may have been intermittent) Thumbs appear normal, but less reactive muscle tone on palms of hands bilaterally Maternal great aunt with ovarian cancer age 65 y/o Paternal grandmother with breast cancer age 40 y/o No AJ ancestry

Conditions on the DDx include: *Fanconi Anemia (bone marrow failure and childhood cancer plus decreased palmar muscle tone are all associated and HBOC on both sides makes more suspicious) Familial AML (could be de novo since no fhx of blood cancers) Li-Fraumeni Syndrome (early onset cancers - especially leukemia- is a feature) Sporadic leukemia (most common cancer of childhood and most cases are sporadic)