Student challenge questions Flashcards
Hyptonia in 4 month old-
Hypotonia is a common pediatric finding and the differential is broad. Important clues to narrow the differential diagnosis include characteristic onset/progression, distinctive features, the child’s sex, family history and reflexes. The biggest clue in this case is that the baby does not have reflexes; this should immediately make you think of the diagnosis Spinal Muscular Atrophy (SMA). Those with SMA are usually healthy at birth but develop symptoms anywhere from infancy to adulthood. Trisomy 21 can present with hypotonia but is usually associated with distinctive features and will have reflexes. Congenital muscular dystrophy is usually present at birth with respiratory failure, hyporeflexia, hypotonia and subtle distinctive features. Duchenne Muscular Dystrophy (DMD) is an X-linked condition so less likely given this is a female. DMD usually presents in childhood, as opposed to infancy, with delayed motor skills. Finally Prader Willi can also present with hypotonia at birth but should not lack reflexes. They also typically have distinctive facial features such as a narrow forehead, almond-shaped eyes, and a triangular mouth.
Williams syndrome
Williams syndrome is associated with multiple endocrine abnormalities including idiopathic hypercalcemia, hypercalciuria, hypothyroidism, and early puberty. Williams syndrome can be inherited in an autosomal dominant matter but is usually de novo in the index case. A small percentage of cases of Williams syndrome occur due to a parent with a microdeletion or germline mosaicism. Thus the risk of recurrence is low but not 0%. It typically does not follow an autosomal dominant inheritance pattern from parents who appear to be unaffected.
Duchenne Muscular Dystrophy other features
In addition to muscle weakness, another common symptom of DMD is cardiomyopathy. Among children with DMD, the incidence of cardiomyopathy increases steadily in the teenage years, with approximately one third of individuals being affected by age 14 years, one half by age 18 years, and all individuals after age 18 years. It is a common cause of death. Interestingly most patients typically also have varying degrees of cognitive impairment and calf muscle “pseudo-hypertrophy.” Despite intellectual disability, they do not typically have any anatomical brain abnormalities. There are usually no abnormalities of their eyes, ears, or kidneys.
Tay-Sachs
Hexosaminidase A deficiency is seen in a group of neurodegenerative conditions, most notably the infantile onset condition Tay-Sachs (TSD). The hexosaminidase A deficiency results in accumulation of GM2 ganglioside, a glycosphingolipid, in the lysosomes. Tay-Sachs disorder is characterized by progressive muscle weakness, loss of motor skills, decreased attentiveness and increased startle response between 3-6 months of age. Classic physical exam findings are a cherry-red spot of the fovea centralis of the macula of the retina, a normal-sized liver and spleen and generalized muscular hypotonia with sustained ankle clonus and hyperreflexia. Additional symptoms that occur over time include seizures, blindness, spasticity, and eventually early childhood death. Tay-Sachs disorder is more common in those of Ashkenazi Jewish ancestry.
Tay-Sachs disorder is typically confirmed genetically by gene sequencing of the HEXA gene.
Unfortunately, there is no specific treatment for these patients at this time. Supportive therapy is the current mainstay of treatment. Gene therapy and enzymatic replacement are being considered but remain in the experimental phase of treatment developments.
Maple Syrup Urine Disease
The above patient has maple syrup urine disease (MSUD) which is an inherited metabolic condition where the body is unable to process certain amino acids, specifically branched chain amino acids (leucine, isoleucine and valine). The condition gets its name from the distinctive sweet odor that occurs in the urine of affected patients. Patients with MSUD also characteristically exhibit poor feeding, vomiting, lethargy, abnormal movements, and delayed development. If untreated, maple syrup urine disease can lead to seizures, coma, and death.
Branched chain amino acids are detected in plasma amino acids, which is the test of choice to diagnose and monitor patients with MSUD.
Most neurotoxic branched chain AA
Of the branched chain amino acids, leucine is the most neurotoxic. Thus, the biggest concern with uncontrolled MSUD is elevated leucine levels.
Upon arrival to the pediatric emergency room, his glucose was 15 mg/dL. Critical labs were drawn at this time and were notable for an elevated cortisol, low insulin, and low-normal betahydroxybutyrate.
This clinical presentation is classic for a fatty acid oxidation condition. Fatty acids are a major source of energy once glycogen stores from the liver are depleted during a prolonged fast or high energy state. Since this patient recently started sleeping through the night, that means that he also was exposed to a prolonged fasting state for the first time. If glycogen stores are used up but you cannot break down fats for glucose/energy, you end up with a non-ketotic hypoglycemia as seen in this patient; low glucose and inappropriately low/normal beta-hydroxybutyrate (a ketone).
An acylcarnitine profile
An acylcarnitine profile is a screening test that looks for condition of fatty acid oxidation and organic acid metabolism. Acylcarnitine is the product of fatty acids bound to carnitine, which allows for transport of fatty acids across membranes. In general, fatty acids start off as long chains and breakdown through a process of fatty acid oxidation. Fatty acid oxidation conditions are characterized by a problem in this breakdown process. Thus, fatty acids get stuck at varying lengths, re-bind to acylcarnitine, and can then be measured in the blood at such lengths reported as C2 to C26. Specific profiles of acylcarnitines raise suspicion for fatty acid oxidation disorders.
The elevation in this question (C6, C8, C10) demonstrates increased amounts of short to medium chain fatty acids. This acylcarnitine profile is specific for medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency. MCAD deficiency is the most common condition of fatty acid β-oxidation.
MCAD treatment
The most important treatment in MCAD is avoiding fasting. This is done by frequent feeding for infants and cornstarch overnight for children. Given the defect is in fat breakdown, patients with MCAD should be on a relatively low fat diet. Carnitine supplementation is controversial but is recommended when free carnitine levels are low.
NF1 clinical diagnosis
Neurofibromatosis 1 (NF1) is a clinical diagnosis that should be suspected in any patient with two or more of the following:
• Six or more café au lait macules (hyperpigmented lesions) > 5 mm in diameter in pre-pubertal individual and > 15mm in post-pubertal individual.
• Two or more neurofibromas or one plexiform neurofibroma
• Freckling in axilla or inguinal area
• Optic glioma
• Two or more Lisch nodules
• Specific osseous lesions; sphenoid dysplasia or tibial pseudoarthrosis
• A first degree relative with NF1
The patient describes in this vignette is pre-pubertal and has more than 6 café au lait spots, inguinal freckling and Lisch nodules, meeting the clinical criteria for NF1.
NF1 inheritance pattern
NF1 is inherited in an autosomal dominant manner. About 50% of cases diagnosed clinically have an affected parent while the other 50% are de novo (sporadic) mutations.
Genomic DNA sequencing picks up 60-90% of mutations, thus negative testing does not rule out NF1. It is now recommended to do stepwise testing of both genomic DNA (gDNA) and reverse-transcribed mRNA (cDNA), bringing diagnostic rate up to >95%. This is because 20-30% of the mutations are splice mutations, which can be missed by sequencing gDNA alone.
A patient being referred to genetics for easy bruising should always include Ehlers-Danlos syndrome (EDS) in the differential diagnosis. There are four (more) common EDS types and then additional less common subtypes. In this vignette, given significant family history of vascular dysfunction and the findings of easy bruising, flexible fingers and an aged appearance of her hands/skin, concern for vascular EDS (previously type IV) would be high.
Vascular EDS is defined clinically by vessel fragility (easy bruising, arterial rupture), thin translucent skin, hypermobility of small joints, characteristic facies (thin vermilion of the lips, micrognathia, narrow nose, prominent eyes), acrogeria (aged appearance of extremities, most commonly hands), intestinal rupture, and/or uterine rupture.
In contrast, Hypermobile EDS (previously type III) is characterized by joint hypermobility and occasional skin findings but is not associated with vascular abnormalities, making this less likely. She does not have the classic features of Marfan syndrome or Stickler syndrome. Polycystic kidney disease can be associated with brain aneurysms but is not associated with skin changes, bruising or uterine rupture.
Females with vascular EDS have a 5% mortality risk with each pregnancy, although risk is higher if the condition is not diagnosed and monitored appropriately during pregnancy. Pregnancy-associated complications include prematurity, uterine tear/rupture, cervical tear or vaginal tear. Due to known risks, C-section deliveries between 36-38 weeks are becoming a more common recommendation in this subset of patients. However, risk of hemorrhage and damage to abdominal organs during C-section must be considered.
PKU cofactor
Tetrahydrobiopterin (BH4) is a cofactor for phenylalanine hydroxylase, promoting the change from phenylalanine to tyrosine. Some individuals with PKU may be responsive to BH4 supplementation, known as Sapropterin (Kuvan). All patients with PKU are given a Sapropterin trial, with 30% or more decrease in plasma phenylalanine levels being responsive. Patients who are found to be responsive are started on a daily dose of BH4.
Beckwith-Wiedemann syndrome (BWS)
Beckwith-Wiedemann syndrome (BWS) is a syndrome represented by a spectrum of symptoms that may include neonatal hypoglycemia, macrosomia, large tongue, hemihyperplasia, omphalocele, embryonal tumors, enlarged organs, kidney abnormalities, and ear creases or pits. Given that it is a spectrum, some individuals have many symptoms and some have only one or two. Thus, your clinical suspicion must remain high if any or multiple of these abnormalities are noted together.
About 30% of infants born with an omphalocele have either Trisomy 13, 18, or 21. However, given the varying features that are consistent with BWS, this is the most likely diagnosis in the vignette above.
BWS
BWS can be caused by multiple different genetic abnormalities including methylation abnormalities, paternal uniparental disomy of chromosome 11, CDKN1C point mutation, microdeletions, microduplications, translocations, and inversions. Thus, theoretically all of the above can be considered to evaluate for BWS.
According to the consensus statement (link below), DNA methylation testing is considered first line when patient has more than 2 clinical features of BWS. This is because methylation abnormalities are the most common cause of BWS, occurring in over 50% of cases. The microarray, which was negative in this patient, can evaluate for microdeletions, microduplications and uniparental disomy. Gene sequencing can evaluate for point mutations and a karyotype can evaluate for translocations and inversions, however these are less common and should not be ordered before methylation studies.
