Peds Flashcards
Trigonocephaly results from premature closure of which of the following sutures?
Answers:
A. Coronal
B. Lambdoid
C. Sagittal
D. Squamosal
E. Metopic
Metopic
Discussion:
Closure of a major cranial suture typically results in a characteristic head shape. This is predicted
by Virchow’s Law which states that when a suture closes early, the skull cannot grow
perpendicular to the suture and instead grows parallel to it. Metopic closure results in
trigonocephaly, sagittal closure results in scaphocephaly, unilateral coronal closure results in
anterior synostotic plagiocephaly, bilateral coronal closure results in brachycephaly, and lambdoid
closure results in posterior synostotic plagiocephaly. The squamosal suture is a considered a
minor suture without significant effect on head shape.
References:
Craniosynostosis.
Governale LS.
Pediatr Neurol. 2015 Nov;53(5):394-401. doi: 10.1016/j.pediatrneurol.2015.07.006. Epub 2015 Jul
22. PMID: 26371995
Identifying the Misshapen Head: Craniosynostosis and Related Disorders.
Dias MS, Samson T, Rizk EB, Governale LS, Richtsmeier JT; SECTION ON NEUROLOGIC
SURGERY, SECTION ON PLASTIC AND RECONSTRUCTIVE SURGERY.
Pediatrics. 2020 Sep;146(3):e2020015511. doi: 10.1542/peds.2020-015511.
PMID: 32868470
A patient with which of the following craniofacial syndromes is most likely to have normal
intelligence?
Answers:
A. Antley-Bixler syndrome
B. Muenke syndrome
C. Crouzon syndrome
D. Pfeiffer syndrome
E. Apert syndrome
Crouzon syndrome
Discussion:
Apert and Crouzon syndrome commonly present with multiple cranial suture involvement and
midface hypoplasia. Syndactyly, however, is typical in Apert syndrome and presents only rarely in
Crouzon syndrome. Hydrocephalus and developmental delay are present in the majority of
children with Apert syndrome, compared to only approximately 1/3 of those with Crouzon
syndrome. Patients with Apert syndrome often have some degree of ventriculomegaly but without
progressive hydrocephalus. Chiari malformations are present in a very high percentage of patients
with syndromic craniosynostosis while arachnoid cysts are rare. Apert and Crouzon syndrome
have an autosomal dominant inheritance pattern, and most patients with either disease appear to
have mutations in fibroblast growth factor receptor genes.
References:
Collmann H, Sorensen N, Krauss J: Hydrocephalus in craniosynostosis: a review. Childs Nerv
Syst. Oct;21(10):902-12. 2005. Cinalli G, Spennato P, Sainte-Rose C, Arnaud E, Aliberti F,
Brunelle F, Cianciulli E, Renier D: Chiari malformation in craniosynostosis. Childs Nerv Syst. 2005
Oct;21(10):889-901. Carinci F, Pezzetti F, Locci P, Becchetti E, Carls F, Avantaggiato A, Becchetti
A, Carinci P, Baroni T, Bodo M: Apert and Crouzon syndromes: clinical findings, genes and
extracellular matrix. J Craniofac Surg. 2005 May;16(3):361-8.
The x-ray films of a patient who has a brain tumor show vertebral body scalloping and absence of
the roof of the left orbit. Which of the following is the most likely diagnosis?
Answers:
A. Neurofibromatosis type 2
B. Sturge-Weber syndrome
C. Von Hippel-Lindau
D. Neurofibromatosis type 1
E. Tuberous sclerosis
Neurofibromatosis type 1
Discussion:
Neurofibromatosis-1 (NF1) is one of the most common genetic disorders and involves
mutations/deletion of the neurofibromin gene on 17q. This gene acts as a tumor suppressor by
negatively regulating the Ras oncogene pathway. It is inherited in an autosomal dominant manner,
though almost 50% of cases arise sporadically from new mutations. In an attempt to reflect the
diverse nature of the disease, the NIH released consensus criteria for the diagnosis of NF1 and
NF2. These diagnostic criteria for NF1 are met if a person has two or more of the following:
1) Six or more cafe-au-lait macules that have a maximum diameter of greater than 5 mm in
prepubertal patients and greater than 15 mm in post pubertal patients
2) Two or more neurofibromas of any type, or one plexiform neurofibroma
3) Freckling in the axillary or inguinal region
4) Optic glioma
5) Two or more Lisch nodules
6) A characteristic osseous lesion, such as sphenoid wing dysplasia or thinning of long bone
cortex
7) A first-degree relative with NF1 by the above criteria
Tuberous sclerosis is commonly associated with pervasive developmental delays; imaging
demonstrates subependymal giant cell astrocytoma (SEGA) and multiple tubers. Von Hippel
Lindau is associated with development of hemangioblastomas and endolymphatic sac tumors.
Neurofibromatosis type 2 is associated with bilateral vestibular schwannomas and meningiomas.
Ocular abnormalities in NF2 include juvenile sublenticular opacity (cataract).
References:
Debella K, Szudek J, Friedman JM. Use of the national institutes of health criteria for diagnosis of
neurofibromatosis 1 in children. Pediatrics 2000;105 (3 pt 1):608-14. Gutmann DH, Aylsworth A,
Carey JC, Korf B, Marks J, Pyeritz RE, Rbenstein A, Viskochil D, The dignostic evaluation and
multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA 1997;
278(1):51-7. Yohay K, Neurofibromatosis types 1 and 2. Neurologist 2006;12(2):86-93.
An autopsy specimen is shown. Which of the following is the most likely diagnosis?
Answers:
A. Chiari I malformation
B. Chiari III malformation
C. Dandy-Walker malformation
D. Chiari II malformation
E. Rhombencephalosynapsis
Chiari II malformation
Discussion:
The pathology specimen shows elongated, pointed cerebellar tonsils with evidence of previous
compression at the level of the foramen magnum. There is also tectal beaking. In addition, there
appears to be thinning of the corpus callosum and lateral ventricle enlargement suggestive of
hydrocephalus. These findings are characteristic of Chiari II malformation.
Dandy-Walker malformation will appear as an enlarged posterior fossa, with cystic dilation of the
fourth ventricle and vermis agenesis.
Rhombencephalosynapsis presents as fusion of the cerebellar hemispheres, vermis
hypo-/agenesis, fusion of dentate nuclei and superior cerebellar peduncles.
Chiari III malformation will show herniation of cerebellum and brainstem through a posterior
encephalocele.
Chiari I malformation will show elongated, pointed cerebellar tonsils but not tectal beaking.
References:
Bejjani GK. Definition of the adult Chiari malformation: a brief historical overview. Neurosurg
Focus. 2001 Jul 15;11(1):E1.
Pubmed Web link
https://pubmed.ncbi.nlm.nih.gov/16724811/
Sasaki-Adams D, Elbabaa SK, Jewells V, Carter L, Campbell JW, Ritter AM. The Dandy-Walker
variant: a case series of 24 pediatric patients and evaluation of associated anomalies, incidence of
hydrocephalus, and developmental outcomes. J Neurosurg Pediatr. 2008 Sep;2(3):194-9. doi:
10.3171/PED/2008/2/9/194. PMID: 18759601.
Pubmed Web link
https://pubmed.ncbi.nlm.nih.gov/18759601/
Weaver J, Manjila S, Bahuleyan B, Bangert BA, Cohen AR. Rhombencephalosynapsis:
embryopathology and management strategies of associated neurosurgical conditions with a review
of the literature. J Neurosurg Pediatr. 2013 Mar;11(3):320-6. doi: 10.3171/2012.12.PEDS12188.
Epub 2013 Jan 18. PMID: 23331215.
Pubmed Web link
https://pubmed.ncbi.nlm.nih.gov/23331215/
Joshua J Chern, MD, PhD, Robert J Bollo, MD, Lance S Governale, MD, Kyle G Halvorson, MD,
Kristopher Hooten, MD, Abhaya V Kulkarni, MD, PhD, William Lo, MBBChir, FRCS(SN), François
Mathieu, MD, Oliver Mrowczynski, MD, Joseph Piatt, MD, Elias Rizk, MD, Eric Thompson, MD,
Pediatrics, Operative Neurosurgery, Volume 17, Issue Supplement_1, August 2019, Pages S182–
S208
Pubmed web link
https://pubmed.ncbi.nlm.nih.gov/31099844/
Holoprosencephaly and medulloblastoma are caused by abnormalities in which of the following
signaling molecules?
Answers:
A. MYCN
B. SHH
C. CTNNB1
D. WNT
E. CDK6
SHH
Discussion:
Medulloblastoma and holoprosencephaly represent diseases with heterogenous genetic
landscapes, but both share a propensity for perturbations in the sonic hedgehog (SHH) gene. SHH
is responsible for directing neuronal organization and survival in the developing central nervous
system. It has been implicated in numerous diseases related to failures in organogenesis. While
MYCN, CDK6, CTNNB1, and WNT are frequently altered in medulloblastomas, they are not
commonly associated with holoprosencephaly.
References:
Purves D, Augustine GJ, Fitzpatrick D, Hall WC, LaMantia A-S, McNamara JO, White LE.
Neuroscience. 4th ed. Sunderland, MA: Sinauer Associates, Inc.; 2008.
Roessler E, Belloni E, Gaudenz K, Jay P, Berta P, Scherer SW, Tsui LC, Muenke M. Mutations in
the human Sonic Hedgehog gene cause holoprosencephaly. Nat Genet. 1996 Nov;14(3):357-60.
doi: 10.1038/ng1196-357. PMID: 8896572.
Pubmed Web link
Mutations in the human Sonic Hedgehog gene cause holoprosencephaly - PubMed (nih.gov)
Taylor MD, Northcott PA, Korshunov A, Remke M, Cho YJ, Clifford SC, Eberhart CG, Parsons DW,
Rutkowski S, Gajjar A, Ellison DW, Lichter P, Gilbertson RJ, Pomeroy SL, Kool M, Pfister SM.
Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol. 2012
Apr;123(4):465-72. doi: 10.1007/s00401-011-0922-z. Epub 2011 Dec 2. PMID: 22134537; PMCID:
PMC3306779.
Pubmed Web link
Molecular subgroups of medulloblastoma: the current consensus - PubMed (nih.gov)
Myotonic dystrophy
Answers:
A. Somatic
B. Mitochondrial
C. Autosomal recessive
D. Autosomal dominant
E. X-linked
Autosomal dominant
Discussion:
Duchenne’s muscular dystrophy is transmitted in an X-linked fashion. Myotonic dystrophy is
transmitted in an autosomal dominant fashion.
References:
Therapeutic developments for Duchenne muscular dystrophy.
Verhaart IEC, Aartsma-Rus A.
Nat Rev Neurol. 2019 Jul;15(7):373-386. doi: 10.1038/s41582-019-0203-3.
PMID: 31147635
Congenital Muscular Dystrophy and Congenital Myopathy.
Butterfield RJ.
Continuum (Minneap Minn). 2019 Dec;25(6):1640-1661. doi: 10.1212/CON.0000000000000792.
PMID: 31794464
Which of the following features of café au lait spots in neurofibromatosis type 1 is correct?
Answers:
A. Having more than ten suggests the diagnosis
B. They typically appear in adulthood
C. They are typically raised
D. Having more than six suggests the diagnosis
E. They are frequently painful
Having more than six suggests the diagnosis
Discussion:
Cafe au lait spots are typically flat (macules), painless, and appear in childhood. Having more than
six is one of the diagnostic criteria for neurofibromatosis type 1. Neurofibromatosis-1 (NF1) is one
of the most common genetic disorders and involves mutations/deletion of the neurofibromin gene
on 17q. This gene acts as a tumor suppressor by negatively regulating the Ras oncogene pathway.
It is inherited in an autosomal dominant manner, though almost 50% of cases arise sporadically
from new mutations. In an attempt to reflect the diverse nature of the disease, the NIH released
consensus criteria for the diagnosis of NF1 and NF2. These diagnostic criteria for NF1 are met if a
person has two or more of the following:
1) Six or more cafe-au-lait macules that have a maximum diameter of greater than 5 mm in
prepubertal patients and greater than 15 mm in post pubertal patients
2) Two or more neurofibromas of any type, or one plexiform neurofibroma
3) Freckling in the axillary or inguinal region
4) Optic glioma
5) Two or more Lisch nodules
6) A characteristic osseous lesion, such as sphenoid wing dysplasia or thinning of long bone
cortex
7) A first-degree relative with NF1 by the above criteria
Tuberous sclerosis is commonly associated with pervasive developmental delays; imaging
demonstrates subependymal giant cell astrocytoma (SEGA) and multiple tubers. Von Hippel
Lindau is associated with development of hemangioblastomas and endolymphatic sac tumors.
Neurofibromatosis type 2 is associated with bilateral vestibular schwannomas and meningiomas.
Ocular abnormalities in NF2 include juvenile sublenticular opacity (cataract).
References:
Nowak CB. The phakomatoses: dermatologic clues to neurologic anomalies. Semin Pediatr
Neurol. 2007 Sep;14(3):140-149.Farrell CJ, Plotkin SR. Genetic causes of brain tumors:
neurofibromatosis, tuberous sclerosis, von Hippel-Lindau, and other syndromes. Neurol Clin. 2007
Nov;25(4):925-946.Verhagen MM, Abdo WF, Willemsen MA, et al. Clinical spectrum of ataxiatelangiectasia in adulthood. Neurology. 2009 Aug 11;73(6):430-437. Epub 2009 Jun 17.
A male newborn is diagnosed with achondroplasia. Which of the following is the most common
disorder for which he should be screened?
Answers:
A. Fibrous dysplasia
B. Foramen magnum stenosis
C. Craniosynostosis
D. Os odontoideum
E. Parietal foramina
Foramen magnum stenosis
Discussion:
Foramen magnum stenosis is common in achondroplasia. It is frequently asymptomatic and, if so,
can be observed since the natural history is for improvement over time. The other bony anomalies
listed are not typical features of achondroplasia.
References:
J Neurosurg Pediatr
2009 Oct;4(4):297-306. doi: 10.3171/2009.3.PEDS08344.
Neurosurgical implications of achondroplasia
James A J King 1, Shobhan Vachhrajani, James M Drake, James T Rutka
PMID: 19795959
Am J Med Genet A
2016 Jan;170A(1):42-51. doi: 10.1002/ajmg.a.37394. Epub 2015 Sep 23.
Best practices in the evaluation and treatment of foramen magnum stenosis in achondroplasia
during infancy
Klane K White 1 , Viviana Bompadre 1 , Michael J Goldberg 1 , Michael B Bober 2 , Jeffrey W
Campbell 3 , Tae-Joon Cho 4 , Julie Hoover-Fong 5 , William Mackenzie 6 , Shawn E Parnell 7 ,
Cathleen Raggio 8 , David M Rapoport 9 , Samantha A Spencer 10 , Ravi Savarirayan 11
PMID: 26394886
The microscopic section shown was obtained from a lesion that is a chief manifestation of
Answers:
A. Tuberous sclerosis complex
B. Gorlin syndrome
C. Von Recklinghausen’s disease
D. Cowden syndrome
E. Von Hippel-Lindau disease
Von Hippel-Lindau disease
Discussion:
The figure shows a hemangioblastoma containing endothelial cells lining capillary spaces, and
vacuolated stromal cells. The latter contain vacuoles filled with lipids and thus appear clear after
H&E stain. About 25% of hemangioblastomas are associated with von Hippel-Lindau disease
(reference 1).
Von Recklinghausen’s disease, or neurofibromatosis type 1 (NF1), is commonly associated with
neurofibromas of the peripheral nerves. These benign lesions are comprised of cells with thin,
spindly nuclei intermixed with collagen bundles. Optic pathway gliomas are another common tumor
seen in NF1 (15% of children with NF1). These are generally WHO grade 1 pilocytic astrocytomas
characterized by bipolar-appearing cells with hairlike cytoplasmic processes along with Rosenthal
fibers and eosinophilic granular bodies.
Tuberous sclerosis complex presents with subependymal giant cell astrocytomas in about 5-15%
of patients. Histology will generally show large atypical astrocytes with abundant eosinophilic
cytoplasm. These cells can resemble gemistocytes.
Gorlin syndrome, or nevoid basal cell carcinoma syndrome, patients are at risk of developing
medulloblastomas. The desmoplastic medulloblastoma subtype has been reported more
commonly in Gorlin syndrome. H&E sections show areas of small, densely packed cells with
hyperchromatic nuclei interspersed by less cellular areas composed of reticulin and collagen.
Dysplastic cerebellar gangliocytomas are highly associated with Cowden syndrome. These tumors
are more commonly seen in adults. Histopathology shows enlarged dysplastic ganglionic cells
infiltrating the internal granular layer of the cerebellar cortex causing thickened cerebellar folia.
References:
Conway JE, Chou D, Clatterbuck RE, Brem H, Long DM, Rigamonti D. Hemangioblastomas of the
central nervous system in von Hippel-Lindau syndrome and sporadic disease. Neurosurgery. 2001
Jan;48(1):55-62; discussion 62-3. doi: 10.1097/00006123-200101000-00009. PMID: 11152361.
Pubmed Web link
https://pubmed.ncbi.nlm.nih.gov/11152361/
Tadros S, Kondrashov A, Namagiri S, Chowdhury A, Banasavadi-Siddegowda YK, Ray-Chaudhury
A. Pathological Features of Tumors of the Nervous System in Hereditary Cancer Predisposition
Syndromes: A Review. Neurosurgery. 2021 Mar 8:nyab019. doi: 10.1093/neuros/nyab019. Epub
ahead of print. PMID: 33693933.
Pubmed Web link
https://pubmed.ncbi.nlm.nih.gov/33693933/
For Krabbe disease, select the enzyme most likely to be deficient
Answers:
A. Hexosaminidase A
B. Galactocerebrosidase
C. Glucocerebrosidase
D. Arylsulfatase A
E. Sphingomyelinase
Galactocerebrosidase
Discussion:
Globoid cell dystrophy or Krabbe leukodystrophy is an autosomal recessive lysosomal lipid storage
disorder caused by deficiency of the enzyme galactocerebrosidase (GALC). GALC is responsible
for catabolism of certain glycolipids, including the toxic compound galactosylsphingosine
(psychosine). Accumulation of this toxic compound results in rapid widespread myelin loss in the
peripheral and central nervous system. This causes progressive neurological deterioration,
seizures, motor deterioration, and eventually death in infants.
Metachromatic leukodystrophy is caused by recessive mutations of arylsulfatase A (ARSA).
Glucocerebrosidase deficiency causes Gaucher disease.
Hexosaminidase A enzyme deficiency causes Tay-Sachs disease.
Sphingomyelinase deficiency is seen in Niemann-Pick disease.
References:
History, genetic, and recent advances on Krabbe disease Adriana Carol Eleonora Graziano,
Venera Cardile
Gene. 2015 Jan 15;555(1):2-13.
Pubmed Web link
https://pubmed.ncbi.nlm.nih.gov/25260228/
Krabbe disease: One Hundred years from the bedside to the bench to the bedside
David A Wenger, Mohammad A Rafi, Paola Luzi
J Neurosci Res. 2016 Nov;94(11):982-9.
Pubmed Web link
https://pubmed.ncbi.nlm.nih.gov/27638583/
Which of the following is the most likely set of findings in a patient with Crouzon disease?
Answers:
A. Bicoronal craniosynostosis, normal intelligence, and midface hypoplasia
B. Bicoronal craniosynostosis, syndactyly, and midface hypoplasia
C. Poikiloderma, craniosynostosis, and radial ray deficiency
D. Bicoronal craniosynostosis, abnormal intelligence, and midface hypoplasia
E. Hypertelorism, pollex varus, and hallux varus
Bicoronal craniosynostosis, normal intelligence, and midface hypoplasia
Discussion:
Crouzon syndrome is a rare autosomal dominant disorder caused by mutations in FGFR2 and
FGFR3. It is characterized by multisuture craniosynostosis (classically bicoronal), hypertelorism
and exorbitism, midfacial hypoplasia and mandibular prognathism. Patients with Crouzon have
normal intelligence.
Bicoronal craniosynostosis, abnormal intelligence, syndactyly and midface hypoplasia are seen in
Apert syndrome.
Hypertelorism, pollex varus and hallux varus are seen with Pfeiffer syndrome.
Poikiloderma, craniosynostosis and radial ray deficiency is seen in Baller-Gerold syndrome.
References:
Apert and Crouzon syndromes: clinical findings, genes and extracellular matrix Francesco Carinci,
Furio Pezzetti, Paola Locci, Ennio Becchetti, Friedrick Carls, Anna Avantaggiato, Alessio
Becchetti, Paolo Carinci, Tiziano Baroni, Maria Bodo
J Craniofac Surg. 2005 May;16(3):361-8.
Pubmed Web link
https://pubmed.ncbi.nlm.nih.gov/15915098/
Classification of Subtypes of Crouzon Syndrome Based on the Type of Vault Suture Synostosis
Xiaona Lu, Rajendra Sawh-Martinez, Antonio Jorge Forte, Robin Wu, Raysa Cabrejo, Alexander
Wilson, Derek M Steinbacher, Michael Alperovich, Nivaldo Alonso, John A Persing J Craniofac
Surg. May/Jun 2020;31(3):678-684.
Pubmed Web link
https://pubmed.ncbi.nlm.nih.gov/32068731/
Which of the following hereditary diseases is most frequently carried by a recessive gene?
Answers:
A. Ataxia-telangiectasia
B. Von Hippel-Lindau
C. Huntington’s disease
D. Tuberous sclerosis
E. Neurofibromatosis type 1
Ataxia-telangiectasia
Discussion:
Ataxia-telangiectasia is transmitted in an autosomal recessive pattern. The others are autosomal
dominant. Ataxia-telangiectasia (AT), unlike the other neurocutaneous syndromes, exhibits
autosomal recessive inheritance. The ATM gene, which has been linked to chromosome 11q22-23,
encodes the ATM protein kinase, which plays a pivotal role in the cellular response to DNA doublestrand breaks by inducing either DNA repair or apoptotic cell death.AT occurs rarely, in roughly 1
per 40,000 births, but the prevalence of heterozygotes ranges from 0.5-2%.AT patients have a
propensity to develop multiple cancer types, particularly of the lymphoreticular system. However,
CNS lesions have also been linked to AT. Multiple case reports have linked AT with astrocytoma,
medulloblastoma, and even craniopharyngioma.Meningiomas, too, have been shown to have both
positive and negative associations with certain ATM haplotypes.Recent evidence does not,
however, suggest a primary role for the ATM gene in the oncogenesis of medulloblastoma. The
surgical management of AT-associated intracranial lesions does not necessarily differ from that of
sporadic lesions. An important consideration, though, is that the extreme sensitivity of AT patients
to ionizing radiation necessitates judicious use of radiation therapy as an adjunctive treatment, with
lower than standard dose regimens perhaps optimizing the balance between maximizing
effectiveness and minimizing risk. Neurofibromatosis Type I (aka von Recklinghausen disease or
NF1) is the most common neurocutaneous syndrome, having a prevalence of 1 in 2,190-7,800.
The NF1 gene encodes the protein neurofibromin; the NF1 mutation responsible for NF1 features
autosomal dominant inheritance with complete penetrance but variable expression, though roughly
half of cases appear sporadically, likely secondary to new mutations. Neurofibromatosis Type II, or
NF2, is a disorder of autosomal dominant inheritance affecting 1 in 33,000-40,000 individuals, with
99% penetrance by age 60. Von Hippel Lindau (VHL), like the other syndromes so far reviewed, is
inherited in an autosomal dominant fashion. Its genetic locus, the VHL gene, is located on
chromosome 3p. VHL acts as a tumor suppressor gene, and most patients inherit one defective
copy of the gene and one wild-type copy; according to the two-hit hypothesis, inactivation of both
VHL alleles leads to tumorigenesis.Tuberous sclerosis (TS), like the other neurocutaneous
syndromes so far discussed, is transmitted in an autosomal dominant fashion, though sporadic
cases outnumber inherited cases. The overall incidence of this disorder is 1 in 30,000, with a birth
incidence of 1 in 5,800.
References:
Nowak CB. The phakomatoses: dermatologic clues to neurologic anomalies. Semin Pediatr
Neurol. 2007 Sep;14(3):140-9. Farrell CJ, Plotkin SR. Genetic causes of brain tumors:
neurofibromatosis, tuberous sclerosis, von Hippel-Lindau, and other syndromes. Neurol Clin. 2007
Nov;25(4):925-46. Verhagen MM, Abdo WF, Willemsen MA, Hogervorst FB, Smeets DF, Hiel JA,
Brunt ER, van Rijn MA, Majoor Krakauer D, Oldenburg RA, Broeks A, Last JI, van’t Veer LJ,
Tijssen MA, Dubois AM, Kremer HP, Weemaes CM, Taylor AM, van Deuren M. Clinical spectrum of
ataxia-telangiectasia in adulthood. Neurology. 2009 Aug 11;73(6):430-7
Which of the following is a feature of tuberous sclerosis?
Answers:
A. Adenoma sebaceum
B. Cafe-au-lait spots
C. Port-wine stain (nevus flammeus)
D. Axillary freckles
E. Melanoblastosis cutis linearis (pigmented dermatitis)
Adenoma sebaceum
Discussion:
Tuberous sclerosis classically presents with seizures, developmental delay, and adenoma
sebaceum – angiofibromas appearing as red papules on the face. Associated hydrocephalus may
be caused by subependymal giant cell astrocytoma (SEGA), a WHO grade I tumor. Port-wine stain
or nevus flammeus, a capillary malformation on the skin, may be observed in Sturge-Weber
Syndrome. Melanoblastosis cutis linearis, a type of pigmented dermatitis, is associated with
incontinentia pigmenti, another neurocutaneous disorder. Café-au-lait spots and axillary freckles
are seen in neurofibromatous type I.
References:
Cross JH. Neurocutaneous syndromes and epilepsy-issues in diagnosis and management.
Epilepsia. 2005;46 Suppl 10:17-23. Islam MP et al. Tuberous sclerosis complex. Handb Clin
Neurol 2015;132:97-109.
Which of the following is a characteristic of achondroplasia?
Answers:
A. Foramen magnum stenosis
B. Fibrous dysplasia
C. Parietal foramina
D. Os odontoideum
E. Craniosynostosis
Foramen magnum stenosis
Discussion:
Foramen magnum stenosis is common in achondroplasia. It is frequently asymptomatic and, if so,
can be observed since the natural history is for improvement over time. The other bony anomalies
listed are not typical features of achondroplasia.
References:
J Neurosurg Pediatr
2009 Oct;4(4):297-306. doi: 10.3171/2009.3.PEDS08344.
Neurosurgical implications of achondroplasia
James A J King 1, Shobhan Vachhrajani, James M Drake, James T Rutka
PMID: 19795959
Am J Med Genet A
2016 Jan;170A(1):42-51. doi: 10.1002/ajmg.a.37394. Epub 2015 Sep 23.
Best practices in the evaluation and treatment of foramen magnum stenosis in achondroplasia
during infancy
Klane K White 1 , Viviana Bompadre 1 , Michael J Goldberg 1 , Michael B Bober 2 , Jeffrey W
Campbell 3 , Tae-Joon Cho 4 , Julie Hoover-Fong 5 , William Mackenzie 6 , Shawn E Parnell 7 ,
Cathleen Raggio 8 , David M Rapoport 9 , Samantha A Spencer 10 , Ravi Savarirayan 11
PMID: 26394886
Digital fusion anomalies are most common in patients with which of the following syndromes?
Answers:
A. Cleidocranial dysplasia
B. Apert syndrome
C. Antley-Bixler syndrome
D. Crouzon syndrome
E. Muenke syndrome
Apert syndrome
Discussion:
Apert and Crouzon syndrome commonly present with multiple cranial suture involvement and
midface hypoplasia. Syndactyly, however, is typical in Apert syndrome and presents only rarely in
Crouzon syndrome. Hydrocephalus and developmental delay are present in the majority of
children with Apert syndrome, compared to only approximately 1/3 of those with Crouzon
syndrome. Patients with Apert syndrome often have some degree of ventriculomegaly but without
progressive hydrocephalus. Chiari malformations are present in a very high percentage of patients
with syndromic craniosynostosis while arachnoid cysts are rare. Apert and Crouzon syndrome
have an autosomal dominant inheritance pattern, and most patients with either disease appear to
have mutations in fibroblast growth factor receptor genes.
References:
Collmann H, Sorensen N, Krauss J: Hydrocephalus in craniosynostosis: a review. Childs Nerv
Syst. Oct;21(10):902-12. 2005. Cinalli G, Spennato P, Sainte-Rose C, Arnaud E, Aliberti F,
Brunelle F, Cianciulli E, Renier D: Chiari malformation in craniosynostosis. Childs Nerv Syst. 2005
Oct;21(10):889-901. Carinci F, Pezzetti F, Locci P, Becchetti E, Carls F, Avantaggiato A, Becchetti
A, Carinci P, Baroni T, Bodo M: Apert and Crouzon syndromes: clinical findings, genes and
extracellular matrix. J Craniofac Surg. 2005 May;16(3):361-8
The pathologic lesion associated with Huntington disease is found in which of the following?
Answers:
A. Zona incerta
B. Internal globus pallidus
C. Pulvinar
D. Dorsal striatum
E. Nucleus accumbens
Dorsal striatum
Discussion:
Huntington disease is a disorder caused by an accumulation of mutant huntingtin protein within
neurons. While this process occurs in all regions of the brain, it leads to early degeneration within
the dorsal striatum, including the caudate nucleus and putamen. This pattern of atrophy causes
significant volume loss along the walls of the frontal horns of the lateral ventricles, giving patient
brains the classic “box car ventricle” appearance on imaging and gross inspection.
Other regions prominently impacted in Huntington disease include the mesial temporal lobe and
calcarine cortex.
The nucleus accumbens and globus pallidus interna are relatively spared in Huntington disease,
though careful inspection in later stages of the disease will still show huntingtin-related inclusion
bodies within affected neurons.
Likewise, the pulvinar and zona incerta, while subject to degeneration over the course of the
disease, do not suffer degeneration as consistently or to the degree that the dorsal striatum does.
References:
Johnson EB, Ziegler G, Penny W, Rees G, Tabrizi SJ, Scahill RI, Gregory S. Dynamics of Cortical
Degeneration Over a Decade in Huntington’s Disease. Biol Psychiatry. 2020 Nov
18:S0006-3223(20)32069-2. doi: 10.1016/j.biopsych.2020.11.009. Epub ahead of print. PMID:
33500176.
Pubmed Web link
Dynamics of Cortical Degeneration Over a Decade in Huntington’s Disease - PubMed (nih.gov)
Tan B, Shishegar R, Poudel GR, Fornito A, Georgiou-Karistianis N. Cortical morphometry and
neural dysfunction in Huntington’s disease: a review. Eur J Neurol. 2021 Apr;28(4):1406-1419. doi:
10.1111/ene.14648. Epub 2020 Dec 6. PMID: 33210786.
Pubmed Web link
Cortical morphometry and neural dysfunction in Huntington’s disease: a review - PubMed (nih.gov)
A 9-month-old boy is noted to have a misshapen skull. On the basis of the three-dimensional
CT scan shown, which of the following is the most immediate issue for the craniofacial surgery
team?
Answers:
A. Chiari malformation
B. Patent anterior fontanel
C. Pointed occiput
D. Increased ICP
E. Hypotelorism
Increased ICP
Discussion:
This child has premature closure of the sagittal and proximal bilateral lambdoid sutures which is
relatively rare but does occur. The shape is typically described as posterior trigonocephaly or
sometimes as a “Mercedes sign” after the automobile emblem. Multisuture craniosynostosis such
as this has a higher likelihood of causing increased intracranial pressure than single suture
craniosynostosis. The thin or dehiscent areas of skull seen on the scan may be indicative of this as
the cerebral gyri imprint themselves on the inner table of bone (known as copper beaten skull). In
addition, a large fontanel and splaying of the patent coronal sutures is seen also consistent with
possible increased intracranial pressure.
References:
Craniosynostosis.
Governale LS.
Pediatr Neurol. 2015 Nov;53(5):394-401. doi: 10.1016/j.pediatrneurol.2015.07.006. Epub 2015 Jul
22. PMID: 26371995
Identifying the Misshapen Head: Craniosynostosis and Related Disorders.
Dias MS, Samson T, Rizk EB, Governale LS, Richtsmeier JT; SECTION ON NEUROLOGIC
SURGERY, SECTION ON PLASTIC AND RECONSTRUCTIVE SURGERY.
Pediatrics. 2020 Sep;146(3):e2020015511. doi: 10.1542/peds.2020-015511.
PMID: 32868470
Intraventricular hemorrhage in very low-birth-weight infants usually originates in which of the
following?
Answers:
A. Choroid plexus
B. Massa intermedia
C. Tapetum
D. Germinal matrix
E. Hippocampus
Germinal matrix
Discussion:
In most infants, involution of the germinal matrix is complete by 35-36 weeks gestation. The
thalamostriate groove usually contains the thickest area of germinal matrix prior to involution.
Germinal matrix hemorrhage, or intraventricular hemorrhage of prematurity is the most common
cause of hydrocephalus in the preterm infant. It is believed to occur due to alterations of cerebral
blood flow through the germinal matrix. The vessels of the germinal matrix do not seem to have
the usual components that comprise the blood-brain barrier. Intraventricular hemorrhage and the
resulting injury is a major cause of neurodevelopmental deficits.
References:
Morioka T, Hashiguchi K, Nagata S, Miyagi Y, Mihara F, Hikino S, et al: Fetal germinal matrix and
intraventricular hemorrhage. Pediatr Neurosurg 42:354-361, 2006. Volpe JJ: Intraventricular
hemorrhage and brain injury in the premature infant. Neuropathology and pathogenesis. Clin
Perinatol 16:361-386, 1989
Patients with Pfeiffer syndrome can be distinguished from those with Apert syndrome by the
presence of which of the following signs?
Answers:
A. Hypertelorism
B. Syndactyly
C. Midface hypoplasia
D. Broad thumbs
E. Hearing loss
Broad thumbs
Discussion:
Broad shape and medial deviation of the thumbs and great toes may be seen in Pfeiffer syndrome
but is not a typical feature of Apert syndrome. The other listed signs may be seen in either
syndrome.
References:
Craniosynostosis.
Governale LS.
Pediatr Neurol. 2015 Nov;53(5):394-401. doi: 10.1016/j.pediatrneurol.2015.07.006. Epub 2015 Jul
22. PMID: 26371995
Identifying the Misshapen Head: Craniosynostosis and Related Disorders.
Dias MS, Samson T, Rizk EB, Governale LS, Richtsmeier JT; SECTION ON NEUROLOGIC
SURGERY, SECTION ON PLASTIC AND RECONSTRUCTIVE SURGERY.
Pediatrics. 2020 Sep;146(3):e2020015511. doi: 10.1542/peds.2020-015511.
PMID: 32868470
A 5-year-old boy has had seizures since infancy. On examination, he shows cognitive delay,
hemiparesis, glaucoma, and choroidal hemangioma. Which of the following is the most likely
diagnosis?
Answers:
A. Neurofibromatosis type 1
B. Von Hippel-Lindau
C. Sturge-Weber
D. Tuberous sclerosis
E. Ataxia-telangiectasia
Sturge-Weber
Discussion:
Sturge-Weber is neurocutaneous syndrome affecting the development of blood vessels. It is
classically described by the triad of port-wine facial birthmark, leptomeningeal angioma, and
glaucoma. Due to insufficient blood flow through affected intracranial blood vessels, patients are
more prone to ischemic events, cerebral atrophy, intracranial calcifications, hemiparesis, seizures,
and cognitive delay. However, phenotype will vary in severity from patient to patient.
Neurofibromatosis type 1 (NF1) is an autosomal dominant neurocutaneous disorder caused by
a defect in the neurofibromin gene on chromosome 17. Patients can be identified by the presence
of 2 or more of the following: > 5 café au lait spots, > 1 dermal neurofibroma or at least 1 plexiform
neurofibroma, osseous lesions, a first-degree family member with NF1, Lisch nodules, axillary or
inguinal freckling, and/or an optic pathway glioma.
Von Hippel-Lindau is caused by mutations in the VHL tumor suppressor gene on chromosome 3. It
is characterized by a propensity for angiomatosis (particularly in the retina), pheochromocytomas,
renal cell carcinomas, and hemangioblastomas.
Tuberous sclerosis is an autosomal dominant disorder characterized by seizures, intellectual
disability, and facial angiofibromas. Additionally, these patients will form cortical “tubers” and
subependymal giant-cell astrocytomas. Manifestations outside of the central nervous system
include renal angiomyolipomas, Shagreen patches, and cardiac rhabdomyomas. Glaucoma is not
a typical finding associated with tuberous sclerosis.
Ataxia-telangiectasia is a recessive disorder caused by mutations in the ATM gene, a
serine/threonine kinase important for DNA repair. Individuals with ataxia-telangiectasia develop
telangiectasias over the sclera of the eyes, ataxia, recurrent respiratory infections, and
hematologic cancers.
References:
Kongkham P, Rutka JT. Chapter 108: Neurocutaneous Syndromes. In: Berger M, Prados M, eds.
Textbook of Neuro-Oncology. New York: McGraw Hill, Inc.; 2004:
818-831.http://emedicine.medscape.com/article/1177523-overview
Ruggieri M, Polizzi A, Marceca GP, Catanzaro S, Praticò AD, Di Rocco C. Introduction to
phacomatoses (neurocutaneous disorders) in childhood. Childs Nerv Syst. 2020
Oct;36(10):2229-2268. doi: 10.1007/s00381-020-04758-5. Epub 2020 Sep 17. PMID: 32940773.
Pubmed Web link
Introduction to phacomatoses (neurocutaneous disorders) in childhood - PubMed (nih.gov)
The familial form of cavernous malformation is transmitted through which of the following genetic
inheritance patterns?
Answers:
A. X-linked recessive
B. Autosomal dominant
C. Mitochondrial
D. Autosomal recessive
E. X-linked dominant
Autosomal dominant
Discussion:
Cerebral cavernous malformations (CCM) appear as ”popcorn” lesions on T2 and display
prominent blooming on susceptibility-weighted imaging (SWI). It is possible that small lesions may
only be identified on SWI. Twenty percent of patients present with multiple lesions. CCM may be
sporadic or familial. Familial forms follow an autosomal dominant inheritance pattern. They are
caused by mutations in CCM1 (KRIT1), CCM2 (MGC4607) or CCM3 (PDCD10) genes.
References:
1. Neurosurgery. 2017 May 1;80(5):665-680. doi: 10.1093/neuros/nyx091. Synopsis of Guidelines
for the Clinical Management of Cerebral Cavernous Malformations: Consensus Recommendations
Based on Systematic Literature Review by the Angioma Alliance Scientific Advisory Board Clinical
Experts Panel. Akers A, Al-Shahi Salman R, A Awad I, Dahlem K, Flemming K, Hart B, Kim H,
Jusue-Torres I, Kondziolka D, Lee C, Morrison L, Rigamonti D, Rebeiz T, Tournier-Lasserve E,
Waggoner D, Whitehead K. 2. J Neurosurg Sci. 2015 Sep;59(3):211-20. Epub 2015 Apr 22.
Genetics of cerebral cavernous malformations: current status and future prospects. Choquet H,
Pawlikowska L, Lawton MT, Kim H. 3. ScientificWorldJournal. 2015;2015:808314. doi:
10.1155/2015/808314. Epub 2015 Jan 5. Management of cerebral cavernous malformations: from
diagnosis to treatment. Mouchtouris N, Chalouhi N, Chitale A, Starke RM, Tjoumakaris SI,
Rosenwasser RH, Jabbour PM.
An otherwise healthy 15-year-old girl is evaluated because of new-onset seizures. Workup reveals
multiple intracranial vascular abnormalities, as well as pulmonary vascular abnormalities. Digital
subtraction angiograms are shown. Which of the following is the most likely diagnosis?
Answers:
A. Familial cerebral cavernous malformations
B. Hereditary hemorrhagic telangiectasia
C. Von Hippel-Lindau disease
D. Sturge-Weber syndrome
E. Granulomatosis with polyangiitis
Hereditary hemorrhagic telangiectasia
Discussion:
This case depicts a young patient with multiple cerebral AVMs seen on the angiogram as well as a
pulmonary AVM. This constellation of vascular malformations is highly suggestive of hereditary
hemorrhagic telangiectasia (HHT), also called Osler-Weber-Rendu syndrome. HHT is an
autosomal dominant inheritable disorder with variable penetrance that affects 1 in 5,000-8,000
persons. The HHT causing genes encode proteins that modulate transforming growth factor
(TGF)-β signaling superfamily in vascular endothelial cells leading to development of abnormal
vascular structures with weak vessel walls. Cerebral arteriovenous malformations occur in 10% of
HHT patient and arteriovenous malformations in other body systems are very common including,
pulmonary (~50%), hepatic (~30%), spinal (~1%). Nosebleeds are very common from
mucocutaneous telangiectasia (~90%) and up to 1/3 of HHT patients are anemic from chronic GI
bleeding.
Cavernous malformations are not visible on cerebral angiogram while Sturge-Weber syndrome is
typified by a unilateral port wine stain on the forehead and eyelid with abnormal intracranial pial
vessels and cerebral calcification (“tram-track sign”) and loss of cerebral cortex. Von Hippel-Lindau
disease patients often harbor cerebral hemangioblastomas which can have similar appearance to
the small AVMs seen in this case on catheter angiogram but are more commonly located in the
cerebellum. Granulomatosis polyangiitis (formerly known as Wegener’s granulomatosis) is an
inflammatory granulomatous condition that can present with hemoptysis and renal dysfunction. It is
associated with CNS vasculitis and intracranial granulomatous lesions.
References:
Govani FS, Shovlin CL. Hereditary haemorrhagic telangiectasia: a clinical and scientific review.
European Journal of Human Genetics. 2009;17(7):860-871. doi:10.1038/ejhg.2009.35.
McDonald, J., Bayrak-Toydemir, P., & Pyeritz, R. E. (2011). Hereditary hemorrhagic telangiectasia:
an overview of diagnosis, management, and pathogenesis. Genetics in medicine, 13(7), 607
Which of the following hereditary disorders is transmitted via chromosomal DNA?
Answers:
A. Kearns–Sayre syndrome (KSS)
B. L1CAM syndrome (LS)
C. Myoclonic epilepsy with ragged red fibers (MERRF)
D. Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS)
E. Leber hereditary optic neuropathy (LHON)
L1CAM syndrome (LS)
Discussion:
L1CAM syndrome (LS) is caused by L1CAM gene mutations located on the X chromosome. The
other disorders are caused by mutations located in the mitochondrial DNA.
References:
Infantile hydrocephalus: a review of epidemiology, classification and causes.
Tully HM, Dobyns WB.
Eur J Med Genet. 2014 Aug;57(8):359-68. doi: 10.1016/j.ejmg.2014.06.002. Epub 2014 Jun 13.
PMID: 24932902
The genetic landscape of familial congenital hydrocephalus.
Shaheen R, Sebai MA, Patel N, Ewida N, Kurdi W, Altweijri I, Sogaty S, Almardawi E, Seidahmed
MZ, Alnemri A, Madirevula S, Ibrahim N, Abdulwahab F, Hashem M, Al-Sheddi T, Alomar R,
Alobeid E, Sallout B, AlBaqawi B, AlAali W, Ajaji N, Lesmana H, Hopkin RJ, Dupuis L, MendozaLondono R, Al Rukban H, Yoon G, Faqeih E, Alkuraya FS.
Ann Neurol. 2017 Jun;81(6):890-897. doi: 10.1002/ana.24964.
PMID: 28556411
A 25-year-old man has had progressive ataxia since age 9 years. Examination shows loss of
position sense in the lower extremities, absence of lower extremity reflexes, and mild muscle
wasting and weakness in the lower extremities. There is a strong family history of similar
symptoms. Which of the following is the most likely genetic inheritance pattern of the disorder?
Answers:
A. X-linked
B. Somatic
C. Autosomal recessive
D. Autosomal dominant
E. Mitochondrial
Autosomal recessive
Discussion:
This man has Friedreich’s Ataxia, an autosomal recessive condition caused by an unstable GAA
trinucleotide repeat in a gene for a mitochondrial protein named frataxin. Patients develop
symptoms of gait instability and lower extremity sensory disturbance in adolescence. Symptoms
progress, eventually involving the arms. 50% have skeletal deformities, including pes cavus and
scoliosis. 60% can have a hypertrophic cardiomypopathy. Other symptoms can include deafness,
optic atrophy, and diabetes mellitus. Pathologic changes are characterized by demyelination and
degeneration of the posterior columns, spinocerebellar, and pyramidal tracts in the spinal cord.
Similar changes are seen in the cerebellar dentate nuclei, dorsal root ganglia, and peripheral
nerves (loss of large myelinated fibers). Diagnosis is by genetic confirmation of the mutation on
chromosome 9. Care is supportive. Life expectancy is typically 35-40 years from onset.
References:
Delatycki MB. Evaluating the progression of Friedreich ataxia and its treatment. J Neurol. 2009
Mar;256 Suppl 1:36-41. SECOND REFERENCE:https://pubmed.ncbi.nlm.nih.gov/12150575/
