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Often, the diagnostic odyssey for a person with L1 syndrome begins prenatally (before they are born) after [[Obstetric ultrasonography|prenatal ultrasounds]] reveal brain abnormalities.<ref name="Hofstra_2010" /><ref name="GHR" /> [[Fetus|Fetuses]] with X-linked hydrocephalus with [[Aqueductal stenosis|stenosis of the aqueduct of Sylvius]] (HSAS) will typically have hydrocephalus severe enough to be discovered upon routine fetal ultrasound as early as 18-20 weeks gestation.<ref name="Kahle_2016" /> In the presence of suggestive features (such as [[macrocephaly]]), [[hydrocephalus]] can be confirmed with noninvasive imaging including head [[Magnetic resonance imaging|magnetic resonance imaging,]] [[CT scan|computed tomography,]] or [[ultrasound]] showing [[Ventriculomegaly|ventriculomegaly,]] or direct measurement of [[intracranial pressure]] through invasive techniques such as [[Lumbar puncture|lumbar puncture.]]<ref>{{Cite book|url=http://worldcat.org/oclc/1021807976|title=Volpe's Neurology of the Newborn E-Book.|last=J.|first=Volpe, Joseph|date=2017|publisher=Elsevier Health Sciences|isbn=9780323508650|oclc=1021807976}}</ref> Further, the [[spasticity]] found in patients with HSAS can be easily demonstrated by examining the [[Stretch reflex|deep tendon reflexes]] and the extensor plantar reflex (which will both be abnormally brisk and strong due to damage to the cortex and internal capsule of the brain).<ref>{{Cite journal|last=Dick|first=J. P. R.|date=2003-02-01|title=The deep tendon and the abdominal reflexes|url=https://jnnp.bmj.com/content/74/2/150|journal=J Neurol Neurosurg Psychiatry|language=en|volume=74|issue=2|pages=150–153|doi=10.1136/jnnp.74.2.150|issn=0022-3050|pmid=12531937}}</ref><ref name="GeneReviews" />
Often, the diagnostic odyssey for a person with L1 syndrome begins prenatally (before they are born) after [[Obstetric ultrasonography|prenatal ultrasounds]] reveal brain abnormalities.<ref name="Hofstra_2010" /><ref name="GHR" /> [[Fetus|Fetuses]] with X-linked hydrocephalus with [[Aqueductal stenosis|stenosis of the aqueduct of Sylvius]] (HSAS) will typically have hydrocephalus severe enough to be discovered upon routine fetal ultrasound as early as 18-20 weeks gestation.<ref name="Kahle_2016" /> In the presence of suggestive features (such as [[macrocephaly]]), [[hydrocephalus]] can be confirmed with noninvasive imaging including head [[Magnetic resonance imaging|magnetic resonance imaging,]] [[CT scan|computed tomography,]] or [[ultrasound]] showing [[Ventriculomegaly|ventriculomegaly,]] or direct measurement of [[intracranial pressure]] through invasive techniques such as [[Lumbar puncture|lumbar puncture.]]<ref>{{Cite book|url=http://worldcat.org/oclc/1021807976|title=Volpe's Neurology of the Newborn E-Book.|last=J.|first=Volpe, Joseph|date=2017|publisher=Elsevier Health Sciences|isbn=9780323508650|oclc=1021807976}}</ref> Further, the [[spasticity]] found in patients with HSAS can be easily demonstrated by examining the [[Stretch reflex|deep tendon reflexes]] and the extensor plantar reflex (which will both be abnormally brisk and strong due to damage to the cortex and internal capsule of the brain).<ref>{{Cite journal|last=Dick|first=J. P. R.|date=2003-02-01|title=The deep tendon and the abdominal reflexes|url=https://jnnp.bmj.com/content/74/2/150|journal=J Neurol Neurosurg Psychiatry|language=en|volume=74|issue=2|pages=150–153|doi=10.1136/jnnp.74.2.150|issn=0022-3050|pmid=12531937}}</ref><ref name="GeneReviews" />


There are various types of genetic testing that can be used to confirm an L1 syndrome diagnosis in a patient.<ref name="GHR" /> After birth, genetic tests carry a low-risk of physical complications and are minimally-painful: for the patient, the process requires a small amount of [[Venipuncture|blood being drawn from your arm]] using a needle.<ref>{{Cite web|url=http://www.eurogentest.org/index.php?id=622|title=EuroGentest: what is a genetic test?|last=|first=|date=|website=www.eurogentest.org|archive-url=|archive-date=|dead-url=|access-date=2019-03-19}}</ref> However, prenatal genetic testing carries significant risks for both the fetus and mother due to the need to remove genetic material from the fetus while it is still in utero.<ref>{{Cite web|url=https://www.canada.ca/en/public-health/services/fertility/genetic-testing-screening.html|title=Public Health Agency of Canada: Genetic testing and screening|last=|first=|date=2013-02-05|website=aem|archive-url=|archive-date=|dead-url=|access-date=2019-03-19}}</ref> In order to conduct prenatal genetic testing, the mother and fetus must undergo either amniocentesis (the surgical puncturing of the amniotic sac, which holds the fetus in the womb) or, less frequently, chorionic villous sampling.<ref>{{cite journal | vauthors = Alfirevic Z, Navaratnam K, Mujezinovic F | title = Amniocentesis and chorionic villus sampling for prenatal diagnosis | journal = The Cochrane Database of Systematic Reviews | volume = 9 | issue = 9 | pages = CD003252 | date = September 2017 | pmid = 28869276 | doi = 10.1002/14651858.CD003252.pub2 }}</ref>
There are various types of genetic testing that can be used to confirm an L1 syndrome diagnosis in a patient.<ref name="GHR" /> After birth, genetic tests carry a low-risk of physical complications and are minimally-painful: for the patient, the process requires a small amount of [[Venipuncture|blood being drawn from your arm]] using a needle.<ref>{{Cite web|url=http://www.eurogentest.org/index.php?id=622|title=EuroGentest: what is a genetic test?|last=|first=|date=|website=www.eurogentest.org|archive-url=|archive-date=|dead-url=|access-date=2019-03-19}}</ref> However, prenatal genetic testing carries significant risks for both the fetus and mother due to the need to remove genetic material from the fetus while it is still in utero.<ref>{{Cite web|url=https://www.canada.ca/en/public-health/services/fertility/genetic-testing-screening.html|title=Public Health Agency of Canada: Genetic testing and screening|last=|first=|date=2013-02-05|website=aem|archive-url=|archive-date=|dead-url=|access-date=2019-03-19}}</ref> In order to conduct prenatal genetic testing, the mother and fetus must undergo either amniocentesis (the surgical puncturing of the amniotic sac, which holds the fetus in the womb) or, less frequently, chorionic villous sampling.<ref>{{cite journal | vauthors = Alfirevic Z, Navaratnam K, Mujezinovic F | title = Amniocentesis and chorionic villus sampling for prenatal diagnosis | journal = The Cochrane Database of Systematic Reviews | volume = 9 | issue = 9 | pages = CD003252 | date = September 2017 | pmid = 28869276 | doi = 10.1002/14651858.CD003252.pub2 }}</ref> Amniocentesis provides a sample that can be used to screen for sequence variants, whereas samples obtained through chorionic villous sampling can only be used to detect major chromosomal abnormalities (such as trisomy 21), making chorionic villous sampling less relevant in the context of diagnosing L1 syndrome (which is caused by genetic sequence variants).<ref>{{Cite journal|last=Alfirevic|first=Zarko|date=1999-01-25|title=Early amniocentesis versus transabdominal chorion villus sampling for prenatal diagnosis|url=https://doi.org/10.1002/14651858.CD000077|journal=Cochrane Database of Systematic Reviews|doi=10.1002/14651858.cd000077|issn=1465-1858}}</ref>


For any child born with multiple physical abnormalities, the first-line diagnostic test is [[Comparative genomic hybridization|chromosomal microarray.]]<ref>{{cite journal | vauthors = Miller DT, Adam MP, Aradhya S, Biesecker LG, Brothman AR, Carter NP, Church DM, Crolla JA, Eichler EE, Epstein CJ, Faucett WA, Feuk L, Friedman JM, Hamosh A, Jackson L, Kaminsky EB, Kok K, Krantz ID, Kuhn RM, Lee C, Ostell JM, Rosenberg C, Scherer SW, Spinner NB, Stavropoulos DJ, Tepperberg JH, Thorland EC, Vermeesch JR, Waggoner DJ, Watson MS, Martin CL, Ledbetter DH | title = Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies | journal = American Journal of Human Genetics | volume = 86 | issue = 5 | pages = 749–64 | date = May 2010 | pmid = 20466091 | pmc = 2869000 | doi = 10.1016/j.ajhg.2010.04.006 }}</ref>
For any child born with multiple physical abnormalities, the first-line diagnostic test is [[Comparative genomic hybridization|chromosomal microarray.]]<ref>{{cite journal | vauthors = Miller DT, Adam MP, Aradhya S, Biesecker LG, Brothman AR, Carter NP, Church DM, Crolla JA, Eichler EE, Epstein CJ, Faucett WA, Feuk L, Friedman JM, Hamosh A, Jackson L, Kaminsky EB, Kok K, Krantz ID, Kuhn RM, Lee C, Ostell JM, Rosenberg C, Scherer SW, Spinner NB, Stavropoulos DJ, Tepperberg JH, Thorland EC, Vermeesch JR, Waggoner DJ, Watson MS, Martin CL, Ledbetter DH | title = Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies | journal = American Journal of Human Genetics | volume = 86 | issue = 5 | pages = 749–64 | date = May 2010 | pmid = 20466091 | pmc = 2869000 | doi = 10.1016/j.ajhg.2010.04.006 }}</ref>
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=== MASA syndrome ===
=== MASA syndrome ===
[[MASA syndrome]] is named after its four principle features: mental retardation, adducted thumbs (clasped, or brought inwards towards the palm), shuffling gait, and aphasia (a language disability affecting the comprehension and production of speech as well as reading and writing abilities.<ref>{{cite web|url=https://www.aphasia.org/aphasia-definitions/|title=Aphasia Definitions|website=National Aphasia Association|language=en-US|access-date=2019-03-19}}</ref><ref name="GeneReviews" />{{clear}}
[[MASA syndrome]] is named after its four principle features: mental retardation, adducted thumbs (clasped, or brought inwards towards the palm), shuffling gait, and aphasia (a language disability affecting the comprehension and production of speech as well as reading and writing abilities.<ref>{{cite web|url=https://www.aphasia.org/aphasia-definitions/|title=Aphasia Definitions|website=National Aphasia Association|language=en-US|access-date=2019-03-19}}</ref><ref name="GeneReviews" />

== References ==
== References ==
{{Reflist}}
{{Reflist}}

Revision as of 20:45, 19 March 2019

L1 syndrome
Other namesL1CAM syndrome

CRASH syndrome

Corpus callosum hypoplasia-retardation-adducted thumbs-spasticity-hydrocephalus syndrome
SpecialtyPediatrics

Neurology

Medical genetics
Usual onsetNeonatal
FrequencyUnknown; frequency of HSAS is approximately 1 per 30,000 live births.

L1 syndrome is a clinical spectrum of mild to severe X-linked recessive disorders that includes X-linked complicated corpus callosum agenesis, spastic paraplegia type 1, MASA syndrome, and X-linked hydrocephalus with stenosis of the aqueduct of Sylvius (HSAS).[1][2] It is also called L1CAM syndrome (for the disorder's causative gene) and CRASH syndrome, an acronym for its primary clinical features: corpus callosum hypoplasia, retardation (intellectual disability), adducted thumbs, spasticity, and hydrocephalus.[2]

Diagnosis

Computed tomography scan showing enlargement of the lateral ventricles due to hydrocephalus, a feature suggestive of possible stenosis (narrowing) of the aqueduct of Sylvius (cerebral aqueduct).[3]

A healthcare provider, usually a medical geneticist (a physician with special training in diagnosing and managing genetic disorders) can provide a clinical diagnosis of L1 syndrome by examining a patient and ordering certain imaging studies,[3] however the presence of L1 syndrome can only be confirmed when a molecular diagnosis has been made through genetic testing.[4]

Often, the diagnostic odyssey for a person with L1 syndrome begins prenatally (before they are born) after prenatal ultrasounds reveal brain abnormalities.[4][2] Fetuses with X-linked hydrocephalus with stenosis of the aqueduct of Sylvius (HSAS) will typically have hydrocephalus severe enough to be discovered upon routine fetal ultrasound as early as 18-20 weeks gestation.[5] In the presence of suggestive features (such as macrocephaly), hydrocephalus can be confirmed with noninvasive imaging including head magnetic resonance imaging, computed tomography, or ultrasound showing ventriculomegaly, or direct measurement of intracranial pressure through invasive techniques such as lumbar puncture.[6] Further, the spasticity found in patients with HSAS can be easily demonstrated by examining the deep tendon reflexes and the extensor plantar reflex (which will both be abnormally brisk and strong due to damage to the cortex and internal capsule of the brain).[7][3]

There are various types of genetic testing that can be used to confirm an L1 syndrome diagnosis in a patient.[2] After birth, genetic tests carry a low-risk of physical complications and are minimally-painful: for the patient, the process requires a small amount of blood being drawn from your arm using a needle.[8] However, prenatal genetic testing carries significant risks for both the fetus and mother due to the need to remove genetic material from the fetus while it is still in utero.[9] In order to conduct prenatal genetic testing, the mother and fetus must undergo either amniocentesis (the surgical puncturing of the amniotic sac, which holds the fetus in the womb) or, less frequently, chorionic villous sampling.[10] Amniocentesis provides a sample that can be used to screen for sequence variants, whereas samples obtained through chorionic villous sampling can only be used to detect major chromosomal abnormalities (such as trisomy 21), making chorionic villous sampling less relevant in the context of diagnosing L1 syndrome (which is caused by genetic sequence variants).[11]

For any child born with multiple physical abnormalities, the first-line diagnostic test is chromosomal microarray.[12]

Phenotypic spectrum

L1 syndrome presents as a spectrum ranging from mild to severe features.[3] There is a genotype-phenotype correlation across the L1 spectrum, meaning that the specific genetic variant causing an L1-spectrum disorder in a patient determines the severity of the L1 syndrome in that patient.[4] Patients with truncating (loss-of-function) variants in L1CAM, which prevent the full synthesis of L1 (protein) experience more severe features than patients with missense variants in L1CAM, which may result in an abnormal protein but do not prevent its synthesis.[4] Illustrating this difference in L1 syndrome severity, up to 50% of infants born with L1 syndrome caused by a truncating mutation will die before the age of 3 years despite provision of best available medical treatment.[4] In comparison, roughly 10% of infants born with L1 syndrome caused by a missense mutation will die before the age of 3 years.[4]

Despite its presentation on a continuous spectrum, L1 syndrome is loosely divided into into four discrete phenotypes.[13][2]

X-linked hydrocephalus with stenosis of the aqueduct of Sylvius (HSAS)

An 11-month-old child with macrocephaly (note the increased occipitofrontal circumference) due to untreated severe hydrocephalus.

HSAS is the most severe phenotype on the L1 spectrum and is predominantly known for its major feature: profound hydrocephalus, typically beginning before birth.[3] Due to its prenatal onset (i.e. before the bones of the skull have fused together), hydrocephalus associated with HSAS results in progressive macrocephaly (abnormal enlargement of the skull) due to markedly increased intracranial pressure.[5] The signs and symptoms of hydrocephalus can vary depending on severity and age of onset, however irritability (due to pain) and vomiting are common amongst infants with the condition.[5] Without treatment, congenital hydrocephalus can be fatal in infancy.[14] In less severe cases of untreated hydrocephalus, a child may progress beyond infancy but often experiences nausea and vomiting, missed developmental milestones (both physical and cognitive/social), diplopia (double vision), and papilledema (swelling of the optic disc) which can progress to permanent visual impairment due to increased intracranial pressure if definitive treatment is withheld.[14][15][16]

Neurological damage caused by L1 syndrome results in nearly all people with the syndrome experiencing severe intellectual disability.[4]

People living with HSAS will also frequently experience spasticity,[2] a condition causing some muscles to be continuously contracted, thereby causing stiffness of the body and challenges with walking and speaking.[17] Spasticity is also known to cause difficulty in performing activities of daily living such as bathing and showering, dressing, and self-feeding.[17][18][19]

The aqueduct of Sylvius (cerebral aqueduct) highlighted in red within the skull. In X-linked hydrocephalus with stenosis of the aqueduct of Sylvius (HSAS), this aqueduct is abnormally narrow, leading to accumulation of excess cerebrospinal fluid (CSF) within the brain's ventricular system.[20]

Despite HSAS frequently being considered an isolated disorder of the central nervous system, its genetic basis also causes musculoskeletal defects that result in more than half of males with HSAS displaying thumbs that are adducted (clasped, or brought inwards towards the palm).[3] Specifically, this abnormal presentation of the hand is due to congenital malformations in the extensor pollicis brevis and/or extensor pollicis longus muscle of forearm.[21]

MASA syndrome

MASA syndrome is named after its four principle features: mental retardation, adducted thumbs (clasped, or brought inwards towards the palm), shuffling gait, and aphasia (a language disability affecting the comprehension and production of speech as well as reading and writing abilities.[22][3]

References

  1. ^ "Orphanet: MASA syndrome". www.orpha.net. Retrieved 2019-03-13. {{cite web}}: Cite has empty unknown parameter: |dead-url= (help)
  2. ^ a b c d e f "L1 syndrome". Genetics Home Reference. Retrieved 2019-03-13. {{cite web}}: Cite has empty unknown parameter: |dead-url= (help)
  3. ^ a b c d e f g Stumpel C, Vos YJ (2015). "L1 Syndrome". In Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Stephens K, Amemiya A (eds.). GeneReviews. University of Washington, Seattle. PMID 20301657.
  4. ^ a b c d e f g Vos YJ, de Walle HE, Bos KK, Stegeman JA, Ten Berge AM, Bruining M, van Maarle MC, Elting MW, den Hollander NS, Hamel B, Fortuna AM, Sunde LE, Stolte-Dijkstra I, Schrander-Stumpel CT, Hofstra RM (March 2010). "Genotype-phenotype correlations in L1 syndrome: a guide for genetic counselling and mutation analysis". Journal of Medical Genetics. 47 (3): 169–75. doi:10.1136/jmg.2009.071688. PMID 19846429.
  5. ^ a b c Kahle KT, Kulkarni AV, Limbrick DD, Warf BC (February 2016). "Hydrocephalus in children". Lancet. 387 (10020): 788–99. doi:10.1016/S0140-6736(15)60694-8. PMID 26256071.
  6. ^ J., Volpe, Joseph (2017). Volpe's Neurology of the Newborn E-Book. Elsevier Health Sciences. ISBN 9780323508650. OCLC 1021807976.{{cite book}}: CS1 maint: multiple names: authors list (link)
  7. ^ Dick, J. P. R. (2003-02-01). "The deep tendon and the abdominal reflexes". J Neurol Neurosurg Psychiatry. 74 (2): 150–153. doi:10.1136/jnnp.74.2.150. ISSN 0022-3050. PMID 12531937.
  8. ^ "EuroGentest: what is a genetic test?". www.eurogentest.org. Retrieved 2019-03-19. {{cite web}}: Cite has empty unknown parameter: |dead-url= (help)
  9. ^ "Public Health Agency of Canada: Genetic testing and screening". aem. 2013-02-05. Retrieved 2019-03-19. {{cite web}}: Cite has empty unknown parameter: |dead-url= (help)
  10. ^ Alfirevic Z, Navaratnam K, Mujezinovic F (September 2017). "Amniocentesis and chorionic villus sampling for prenatal diagnosis". The Cochrane Database of Systematic Reviews. 9 (9): CD003252. doi:10.1002/14651858.CD003252.pub2. PMID 28869276.
  11. ^ Alfirevic, Zarko (1999-01-25). "Early amniocentesis versus transabdominal chorion villus sampling for prenatal diagnosis". Cochrane Database of Systematic Reviews. doi:10.1002/14651858.cd000077. ISSN 1465-1858.
  12. ^ Miller DT, Adam MP, Aradhya S, Biesecker LG, Brothman AR, Carter NP, Church DM, Crolla JA, Eichler EE, Epstein CJ, Faucett WA, Feuk L, Friedman JM, Hamosh A, Jackson L, Kaminsky EB, Kok K, Krantz ID, Kuhn RM, Lee C, Ostell JM, Rosenberg C, Scherer SW, Spinner NB, Stavropoulos DJ, Tepperberg JH, Thorland EC, Vermeesch JR, Waggoner DJ, Watson MS, Martin CL, Ledbetter DH (May 2010). "Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies". American Journal of Human Genetics. 86 (5): 749–64. doi:10.1016/j.ajhg.2010.04.006. PMC 2869000. PMID 20466091.
  13. ^ Finckh U, Schröder J, Ressler B, Veske A, Gal A (May 2000). "Spectrum and detection rate of L1CAM mutations in isolated and familial cases with clinically suspected L1-disease". American Journal of Medical Genetics. 92 (1): 40–6. doi:10.1002/(SICI)1096-8628(20000501)92:13.0.CO;2-R. PMID 10797421.
  14. ^ a b Gmeiner M, Wagner H, Zacherl C, Polanski P, Auer C, van Ouwerkerk WJ, Holl K (January 2017). "Long-term mortality rates in pediatric hydrocephalus-a retrospective single-center study". Child's Nervous System. 33 (1): 101–109. doi:10.1007/s00381-016-3268-y. PMID 27766469.
  15. ^ Vinchon M, Rekate H, Kulkarni AV (August 2012). "Pediatric hydrocephalus outcomes: a review". Fluids and Barriers of the CNS. 9 (1): 18. doi:10.1186/2045-8118-9-18. PMC 3584674. PMID 22925451.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  16. ^ Wang, An-Guor (2018). Wang, An-Guor (ed.). Papilledema. Springer Singapore. pp. 85–89. doi:10.1007/978-981-10-7668-8_15. ISBN 9789811076688. {{cite book}}: |work= ignored (help); Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
  17. ^ a b Pandyan AD, Gregoric M, Barnes MP, Wood D, Van Wijck F, Burridge J, Hermens H, Johnson GR (January 2005). "Spasticity: clinical perceptions, neurological realities and meaningful measurement". Disability and Rehabilitation. 27 (1–2): 2–6. doi:10.1080/09638280400014576. PMID 15799140.
  18. ^ "Spasticity – Causes, Symptoms and Treatments". www.aans.org. Retrieved 2019-03-19.
  19. ^ Hardy, Susan E. (2014). "Consideration of Function & Functional Decline". In Williams, Brie A.; Chang, Anna; Ahalt, Cyrus; Chen, Helen (eds.). Current Diagnosis & Treatment: Geriatrics (2 ed.). McGraw-Hill Education. Retrieved 2019-03-19. {{cite book}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
  20. ^ "L1 syndrome". Genetics Home Reference. Retrieved 2019-03-18. {{cite web}}: Cite has empty unknown parameter: |dead-url= (help)
  21. ^ Akinleye SD, Culbertson MD, Cappelleti G, Richardson N, Choueka J (August 2018). "Intracompartmental Versus Extracompartmental Transposition of the Extensor Pollicis Longus for Treating Thumb-in-Palm Deformity: A Biomechanical Comparison". The Journal of Hand Surgery. 43 (8): 774.e1-774.e5. doi:10.1016/j.jhsa.2018.01.015. PMID 29500047. {{cite journal}}: no-break space character in |title= at position 145 (help)
  22. ^ "Aphasia Definitions". National Aphasia Association. Retrieved 2019-03-19.
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