An 18-month-old girl is brought to the pediatrician’s office for failure to thrive and developmental delay. The patient’s mother says she has not started speaking and is just now starting to pull herself up to standing position. Furthermore, her movement appears to be restricted. Physical examination reveals coarse facial features and restricted joint mobility. Laboratory studies show increased plasma levels of several enzymes. Which of the following is the underlying biochemical defect in this patient?

Failure of mannose phosphorylation

Congenital lack of lysosomal formation

Inappropriate protein targeting to endoplasmic reticulum

Inappropriate degradation of lysosomal enzymes

A 21-year-old female presents to her obstetrician because she has stopped getting her period, after being irregular for the last 3 months. Upon further questioning, the patient reveals that she has had a 17 lb. unintended weight loss, endorses chronic diarrhea, abdominal pain, and constipation that waxes and wanes. Family history is notable only for an older brother with Type 1 Diabetes. She is healthy, and is eager to gain back some weight. Her OBGYN refers her to a gastroenterologist, but first sends serology laboratory studies for IgA anti-tissue transglutaminase antibodies (IgA-tTG). These results come back positive at > 10x the upper limit of normal. Which of the following is the gastroenterologist likely to find on endoscopy and duodenal biopsy?

Villous atrophy with crypt lengthening and intraepithelial lymphocytes

Friable mucosal pseudopolyps with biopsy notable for crypt abscesses

Cobblestoning with biopsy showing transmural inflammation and noncaseating granulomas

Foamy macrophages, which stain PAS positive

Normal appearing villi and biopsy

An 8-month-old boy is brought to the physician by his parents for gradually increasing loss of neck control and inability to roll over for the past 2 months. During this time, he has had multiple episodes of unresponsiveness with a blank stare and fluttering of the eyelids. His parents state that he sometimes does not turn when called but gets startled by loud noises. He does not maintain eye contact. He was able to roll over from front to back at 5 months of age and has not yet begun to sit or crawl. His parents are of Ashkenazi Jewish descent. Neurological examination shows generalized hypotonia. Deep tendon reflexes are 3+ bilaterally. Plantar reflex shows extensor response bilaterally. Fundoscopy shows bright red macular spots bilaterally. The remainder of the examination shows no abnormalities. Which of the following is the most likely cause of this patient's symptoms?

β-glucocerebrosidase deficiency

ATP-binding cassette transporter mutation

A 6-month-old boy is referred to a geneticist after he is found to have persistent hypotonia and failure to thrive. He has also had episodes of what appears to be respiratory distress and has an enlarged heart on physical exam. There is a family history of childhood onset hypertrophic cardiomyopathy, so a biopsy is performed showing electron dense granules within the lysosomes. Genetic testing is performed showing a defect in glycogen processing. A deficiency in which of the following enzymes is most likely to be responsible for this patient's symptoms?

Lysosomal alpha 1,4-glucosidase

A 6-year-old boy presents to the pediatrician with his parents. He is fully vaccinated and met most developmental milestones. His fine motor milestones are delayed; at present, he cannot eat by himself and has difficulty in self-dressing. His intelligence quotient (IQ) is 65. He listens quietly while spoken to and engages in play with his classmates. He neither talks excessively nor remains mute, but engages in normal social conversation. There is no history of seizures and he is not on any long-term medical treatment. On his physical examination, his vital signs are stable. His height and weight are normal for his age and sex, but his occipitofrontal circumference is less than the 3rd percentile for his age and sex. His neurologic examination is also normal. Which of the following is the most likely diagnosis?

Attention deficit hyperactivity disorder

A 3-year-old girl is brought to the physician for a well-child examination. She was born at term and has been healthy since. She can climb up and down the stairs and can pedal a tricycle. She has difficulty using a spoon to feed herself but can copy a line. She speaks in 2- to 3-word sentences that can be understood by most people. She is selfish while playing with children her age and throws tantrums quite often. She cannot put on her own shoes and socks. She does not tolerate separation from her parents. She is at 60th percentile for height and weight. Physical examination including neurologic examination reveals no abnormalities. Which of the following is the most appropriate assessment of her development?

Fine motor: Delayed | Gross motor: Normal | Language: Normal | Social skills: Delayed

Fine motor: Normal | Gross motor: Normal | Language: Delayed | Social skills: Delayed

Fine motor: Delayed | Gross motor: Delayed | Language: Normal | Social skills: Normal

Fine motor: Normal | Gross motor: Delayed | Language: Normal | Social skills: Delayed

Fine motor: Normal | Gross motor: Delayed | Language: Delayed | Social skills: Normal

A 28-year-old male presents to his primary care physician with complaints of intermittent abdominal pain and alternating bouts of constipation and diarrhea. His medical chart is not significant for any past medical problems or prior surgeries. He is not prescribed any current medications. Which of the following questions would be the most useful next question in eliciting further history from this patient?

"Can you tell me more about the symptoms you have been experiencing?"

"Does the diarrhea typically precede the constipation, or vice-versa?"

"Is the diarrhea foul-smelling?"

"Please rate your abdominal pain on a scale of 1-10, with 10 being the worst pain of your life"

"Are the symptoms worse in the morning or at night?"

A 15-month-old girl is brought to the pediatrician by her mother with a history of 3 episodes of breath-holding spells. The patient’s mother says that this is a new behavior and she is concerned. The patient was born at full term by spontaneous vaginal delivery with an uneventful perinatal period. She is also up to date on her vaccines. However, after the age of 6 months, the patient’s mother noticed that she was not as playful as other children of similar age. She is also not interested in interacting with others and her eye contact is poor. Her growth charts suggest that her weight, length, and head circumference were normal at birth, but there have been noticeable decelerations in weight and head circumference. On physical examination, her vital signs are normal. A neurologic examination reveals the presence of generalized mild hypotonia. She also makes repetitive hand wringing motions. Which of the following clinical features is most likely to develop in this patient during the next few years?

Loss of purposeful use of her hands

Developmental regression causes for USMLE Step 2 CK: High-Yield Pediatrics Lessons

Regression Essentials - The Backward Step

Loss of previously acquired milestones; a critical red flag requiring urgent evaluation. Key causes include:

Metabolic Disorders:
- Lysosomal Storage (e.g., Tay-Sachs)
- Wilson's Disease
Neurodegenerative Conditions:
- Rett Syndrome (MECP2 gene)
- Subacute Sclerosing Panencephalitis (SSPE)
- Leukodystrophies
Other Significant Causes:
- Autism Spectrum Disorder
- Hypothyroidism
- Landau-Kleffner Syndrome

⭐ Rett Syndrome classically presents with loss of purposeful hand skills between 6-18 months, replaced by stereotyped hand-wringing movements.

Metabolic & Genetic Causes - Inborn Sabotage

Regression often follows a period of normal development, as toxic metabolites accumulate or essential proteins are absent. Presentation varies by the specific pathway affected.

Disorder Category	Example(s)	Defective Gene/Enzyme	Onset & Key Regression Features
Lysosomal Storage	Tay-Sachs Disease	Hexosaminidase A	3-6 mos; exaggerated startle, cherry-red spot (no HSM)
	Niemann-Pick A/B	Sphingomyelinase	First few mos; Hepatosplenomegaly (HSM), cherry-red spot
	Metachromatic Leukodystrophy	Arylsulfatase A	1-2 yrs; Gait disturbance (ataxia), hypotonia, peripheral neuropathy
	Krabbe Disease	Galactocerebrosidase	2-6 mos; Extreme irritability, spasticity, optic atrophy
Peroxisomal	Adrenoleukodystrophy	VLCFA transporter (ABCD1)	4-10 yrs; Cognitive decline, adrenal insufficiency, visual loss
Other Genetic	Rett Syndrome	MECP2 (X-linked dom)	6-18 mos; Deceleration of head growth, loss of purposeful hand skills (wringing), ataxia

Neuro-Structural Syndromes - Brain Under Siege

Hydrocephalus: Excess CSF accumulation dilates ventricles, stretching and damaging periventricular white matter tracts, leading to loss of motor milestones.
- Causes:
  - Congenital: Aqueductal stenosis, Arnold-Chiari malformation, Dandy-Walker.
  - Acquired: Post-meningitic scarring, intraventricular hemorrhage, tumors.
- Signs: Rapidly increasing head circumference (>1 cm/week), tense fontanelle, "setting sun" sign, developmental delay.
Subdural Hematoma/Effusion: Often from trauma, especially non-accidental injury (shaken baby syndrome).
- Causes ↑ intracranial pressure, seizures, and direct cortical injury.
Intracranial Tumors: Space-occupying lesions disrupt neural circuits.
- Most are infratentorial in children (cerebellum, brainstem).
- Presents with morning headaches, vomiting, ataxia, and loss of coordinated skills.

⭐ Exam Favourite: In infants, the most common cause of communicating hydrocephalus is post-hemorrhagic changes (intraventricular hemorrhage in preterms) or post-meningitic inflammation.

Infant with hydrocephalus showing setting sun sign

Diagnostic Workup - The Detective's Flowchart

⭐ A fundus exam is key in suspected lysosomal storage disorders. A "cherry-red spot" is classic for Tay-Sachs or Sandhoff disease, indicating ganglion cell lipidosis.

High-Yield Points - ⚡ Biggest Takeaways

Rett Syndrome: Classic regression in girls, featuring loss of purposeful hand skills and speech.

Lesch-Nyhan Syndrome: Key features are self-mutilation and choreoathetosis in boys.

Metachromatic Leukodystrophy: Presents with gait ataxia first, followed by intellectual decline.

Adrenoleukodystrophy: Look for behavioral changes, visual loss, and adrenal insufficiency.

SSPE: A late complication of measles, causing myoclonus, seizures, and dementia.

Tay-Sachs: Regression at 3-6 months with a cherry-red spot; no hepatosplenomegaly.

Continue reading on Oncourse

CONTINUE READING — FREE

or get the app

App Store|Google Play