2. Pediatric Occipitofrontal Head Circumference (OFC): The Tale of the Tape
Kenton R. Holden, M.D.
Professor of Neurosciences (Neurology) and Pediatrics
Medical University of South Carolina , and
Senior Clinical Research Neurologist
Greenwood Genetic Center
Greenwood, South Carolina
UNITEC, HONDURAS
JAN. 2017

3. Pediatric OFC OUTLINE of CONTENT: Normal pediatric OFC/background
Historical standardized OFC growth curves
New proposed OFC growth curves
Application to microcephaly
Primary vs. acquired microcephaly
Case illustrations
Conclusions
Holden K 1/30/17

4. Pediatric OFC NORMAL OFC HEAD CIRCUMFERENCE:
A. Occipitofrontal circumference (OFC)
B. Measured above eyebrow ridges and around skull to include most prominent area of occiput
C. ± 2 standard deviations (SD) of statistical norm for age/sex
D. Range within 2 SD (2nd to 98th percentile) primarily represents normal familial and ethnic variations in somatotypes
Holden K 1/30/17

5. Pediatric OFC NORMAL OFC HEAD CIRCUMFERENCE GROWTH:
Term gestation boys: 36 cm, girls 34.5 cm at birth
Increases 0.5 to 2.5 cm per month during 1st year
Mean increase cm in first year
Greatest OFC increase in first 6 mos
Increase in OFC correlates with brain weight
Mean brain wgt 360 gm at term, 950 gm at 1 yr, and 1350 gm at adulthood
70% of final brain wgt present at 1 yr of age
Holden K 1/30/17

6. Pediatric OFC NORMAL OFC HEAD CIRCUMFERENCE:
Young child has thin scalp, thin skull & small sinuses
Head OFC primarily measures brain matter & CSF
Only one abnormal small OFC and/or significant crossing of percentiles over time indicates a possible brain abnormality and need for further evaluation
This important clinical sign is usually found on routine examination WITHOUT a parental “chief complaint”, and often unrecognized by M.D. until measured
Always consider the reference population, e.g., culturofamilial
Holden K 1/30/17

7. Pediatric OFC NORMAL OFC HEAD CIRCUMFERENCE: Term
Statistical correlation between brain size and brain volume and intelligence at 1 y.o.
As one approaches the outer limits of ± 2 SD OFC, increasing likelihood of a CNS abnormality
Childhood intelligence at 4 y and 8 y.o. associated with prenatal and infant OFC growth
Growth in brain volume > 1 y.o. usually does not compensate for lack of gray and white matter growth in first year
Premie
Premie’s OFC normally increases more rapidly during the weeks/months they are less than “term equivalent”
Premie “catch-up” OFC growth mostly complete by 6 to 9 mos; difficult to make-up for inadequate brain growth > 1 y.o.
NOTE: If not ± 2 SD at 2 yrs, unlikely to ever attain ± 2 SD
Holden K 1/30/17

8. Pediatric OFC NORMAL OFC HEAD CIRCUMFERENCE:
“STANDARDS” used over past 40+ years:
Nellhaus G 1968, 0-18 yrs, 2nd- 98th percentiles
Roche AF et al 1987, 0-18 yrs, 5th- 95th percentiles
US Centers for Disease Control & Prevention 1977& , 0-36 mos, 3rd- 97th & 5th- 95th percentiles
Gordon CC et al 1989, U.S. Army (adult) OFC data
Charting “snafus” at different ages & stages create anxiety for parents and family/doctors, etc.
Holden K 1/30/17

9. Pediatric OFC
CDC 2000
Roche et al ‘87
Female
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10. Pediatric OFC Female Gordon et al 1989 Nellhaus 1968 Roche et al 1987
Present Analysis
Holden K 1/30/17

11. Pediatric OFC NORMAL OFC HEAD CIRCUMFERENCE: Advantages Disadvantages
CDC 0-3 yr, Set 2 (3rd% – 97th%), 2000
Nellhaus 0-18 yr, (2nd% – 98th%), 1968
CDC/Nellhaus SEI & Ethnic mix good
Gordon et al: US (adult) military
Disadvantages
CDC 0-3 yr Set 1 (5th% - 95th%); 0-3 yr Set 2 (data predominately 0-2 yrs)
Roche 1987 (5th% – 95th%) non- diverse; anxiety with more normals appearing abnormal
OFC %tiles different for same ages on multiple standardized curves
Holden K 1/30/17

12. Pediatric OFC NORMAL OFC HEAD CIRCUMFERENCE:
New OFC curves for males & females from birth-21 yo
3rd – 97th percentiles, and include 10th, 25th, 50th, 75th, and 90th major %tile lines at all ages
“Smoothed” curves that include all complete data which was combined from birth-to-young adults (CDC 0-2 yrs, Roche et al, Nellhaus, and Gordon et al)
Validated in normal general pediatric population in South Carolina (n=537, from 1 to 19 yrs) males and females
Holden K 1/30/17

13. Pediatric OFC
Holden K 1/30/17

14. Pediatric OFC
Holden K 1/30/17

15. Pediatric OFC: Microcephaly
INTRODUCTION: MICROCEPHALY
Abnormal smallness of the head, usually associated with intellectual disabilities (ID)
Occipitofrontal circumference (OFC) > 2 standard deviations (SD) below the mean for age and gender
Decreased brain weight and brain volume
Rarely a parental “complaint”, and often unrecognized by M.D.
Always consider the reference population
Terminology used must be precise
Microcephaly (abnormally small OFC) necessitates micrencephaly (small brain)
Macrocephaly (abnormally large OFC) does not necessarily mean megalencephaly (large brain)
Holden K 1/30/17

16. Pediatric OFC: Microcephaly
INTRODUCTION: (continued)
You can have macrocephaly / megalocephaly and micrencephaly existing together.
Holden K 1/30/17

17. Pediatric OFC: Microcephaly
INTRODUCTION: TERMINOLOGIES (n=34)
Absolute microcephaly
Acquired microcephaly
Autosomal dominant microcephaly
Autosomal recessive microcephaly
Borderline microcephaly
Complicated microcephaly
Congenital microcephaly
Destructive microcephaly
Dysgenetic microcephaly
Environmental microcephaly
Familial microcephaly
Genetic microcephaly
Idiopathic microcephaly
Isolated microcephaly
Malformative microcephaly
Microcephaly vera
Mild microcephaly
Non-genetic microcephaly
Non-syndromal microcephaly
Postnatal microcephaly
Prenatal microcephaly
Primary microcephaly
Pure microcephaly
Recurrent microcephaly
Relative microcephaly
Secondary microcephaly
Severe microcephaly
Simple microcephaly
Symptomatic microcephaly
Syndromal microcephaly
True microcephaly
Unclassified microcephaly
Uncomplicated microcephaly
X-linked microcephaly ** *
Holden K 1/30/17

18. Pediatric OFC: Microcephaly
INTRODUCTION: (continued)
Classic clinical approach: (descriptive terminology)
Neurodevelopmental anomalies
Environmental etiologies
Metabolic-genetic etiologies
Contemporary approach: (extremely heterogeneous and classic categories blurred by “high-technology”; take each case on it’s own merits) …and include:
Neuroradiology
Biochemical analyses
Cytogenetics
Molecular genetics
Holden K 1/30/17

19. Pediatric OFC: Microcephaly
DISCUSSION:
Multiple exceptions to the rule using previous terminologies
Advancing neurometabolic-genetic testing, and neuroradiology,
Time to simplify the microcephaly terminology
Expand differential diagnosis of each new group.
More cost-effective and meaningful evaluation.
Without an etiology, empiric risk of recurrence of microcephaly is about 5%; with an specific etiology, risk of recurrence is 0-100%.
NOTE: Since the 34 terms previously used to describe microcephaly covered all the practical options, no new terms will be proposed.
Holden K 1/30/17

20. Pediatric OFC: Microcephaly
DISCUSSION: (continued)
Group I:
“Primary”: exists at birth, OFC remains small, likely prenatal etiology, if not a normal familial variant.
NOTE: “Congenital” was considered, but it implies a genetic origin.
Group II:
“Acquired”: normal OFC at birth, then crosses percentile lines to <2 SD, likely late prenatal or postnatal etiology (excluding craniosynostosis syndromes).
NOTE: “Secondary” was considered but it can be the initial presentation, and it implies an “acute” insult.
Editorial Comment: If a birth OFC can not be found in the records, one can try substituting any OFC in the neonatal period as the “baseline”.
Holden K 1/30/17

21. Pediatric OFC: Microcephaly
COMMON CAUSES FOR “PRIMARY” MICROCEPHALY:
Prenatal Factors
Small for gestational age/extreme prematurity
Prenatal Systemic Illness/Condition
Acquired immunodeficiency syndrome
Anemia
Cytomegalovirus
Coxsackie B virus
Diabetes mellitus
Malnutrition
Maternal hyperthemia/significant febrile illness
Maternal phenylketonuria
Rubella
Syphilis
Toxoplasmosis
Varicella
Prenatal Toxic Exposures
Alcohol
Anticancer
Antiepileptic
Cocaine
Heroin
Mercury
Smoking/Tobacco
Toluene
X-irradiation
Anoxia/Ischemia/Trauma
Generalized cerebral anoxia
Placental insufficiency
Porencephaly
Hydranencephaly
Chromosomal Abnormalities
Deletions and duplications
Down syndrome and other trisomies
Ring chromosomes
Sex chromosome aneuploidy
Genetic
Bloom syndrome
COFS syndrome
Coffin-Siris syndrome
Cornelia de Lange syndrome
Craniosynostosis (multi-suture)
Dubowitz syndrome
Familial
Feingold syndrome
Johanson-Blizzard syndrome
Meckel-Gruber syndrome
Mendelian
Autosomal recessive (MCPH)
Autosomal dominant
X-linked
Neu-Laxova syndrome
Nijmegen breakage syndrome
Roberts syndrome
Seckel syndrome
Smith-Lemli-Opitz syndrome
Brain Malformations
Atelencephaly (aprosencephaly)
Encephalocele
Holoprosencephaly
Lissencephaly
Polymicrogyria
Holden K 1/30/17

22. Pediatric OFC: Microcephaly
COMMON CAUSES FOR “ACQUIRED” MICROCEPHALY:
Perinatal infections
Herpes simplex virus1
Human immunodeficiency virus (HIV)
Lymphocytic choriomeningitis virus
Rubella virus1
Post meningitis
Post viral encephalitis
Syphilis1
Perinatal teratogens
Alcohol
Toluene
X-irradiation
Lead toxicity
Perinatal or postnatal insults
Anoxia/ischemia
Birth; Trauma accidental;
non-accidental trauma
Carbon monoxide poisoning
Hypoxic-ischemic encephalopathy (HIE)
Intracranial hemorrhage/thrombosis2
Porencephaly/hydranencephaly
Post status epilepticus (SE)
Chronic or systemic disease
Adrenocortical deficiency
Cardiorespiratory
Hypoglycemia
Hypopituitarism
Hypothyroidism
Malnutrition/psychosocial deprivation
Uremic encephalopathy
Structural brain anomalies2
Cerebral dysgenesis
Holoprosencephaly
Genetic
Chromosome deletions / duplications
e.g. 1p, 3p, 5p, dup 17p
Multiple malformation syndromes
Aicardi-Goutiéres syndrome
Alpha thalassemia X-linked MR syndrome
Angelman syndrome
ARX gene mutations
Christianson syndrome
Cockayne syndrome
Cohen syndrome
Marden-Walker syndrome
MCT8 gene mutations
Mowat-Wilson syndrome
Pitt-Hopkins
PPV syndrome
Rett syndrome
Rubinstein-Taybi syndrome
Sturge-Weber syndrome
Toriello-Carey syndrome
Williams syndrome
Xeroderma pigmentosa
Metabolic disorders
Amino acidurias
Congenital disorders of glycosylation
Galactosemia
Glucose transporter defect (GLUT-1)
Leukodystrophies (e.g. infantile Krabbe)
Menkes disease
Mitochondrial diseases
Neuronal ceroid-lipofuscinosis (infantile)
Organic acidurias
Pelizaeus-Merzbacher disease
Purine and pyrimidine disorders
Sulfite oxidase / Mb cofactor deficiency
1 if acquired late in pregnancy/third trimester
2 may also be of genetic etiology
Holden K 1/30/17

23. Pediatric OFC: Microcephaly
ACQUIRED MICROCEPHALY:
Evaluation:
History & exam, neonatal OFC, pedigree, familial OFCs
Ophthalmologic exam, infectious, & systemic disease review
Brain MRI prn
Chromosome microarray prn
Metabolic testing (not already done on newborn spot testing) prn
Holden K 1/30/17

24. Pediatric OFC: Microcephaly
ACQUIRED MICROCEPHALY: EVALUATION BY ALGORITHMIC APPROACH
Holden K 1/30/17

25. Pediatric OFC: Microcephaly
ACQUIRED MICROCEPHALY: PHENOTYPE OBSERVATIONS
Age of onset of acquired microcephaly related to specific etiologies.
Diagnosed postnatally by simple, inexpensive measure of OFCs over time.
New pediatric OFC charts 0-21 yrs will ease the plotting of OFCs.
Holden K 1/30/17

26. Pediatric OFC: Microcephaly
ACQUIRED MICROCEPHALY: CASE #1
E.B. 2 y.o. HM with acquired microcephaly and global neuro- developmental disabilities (NDD) including uncontrolled epilepsy on polypharmacy. H/O EEG with atypical hypsarrhythmia
Hx: Normal term gestation, ultrasds, vaginal delivery, Apgars 8 & 9.
BW = 6 lbs, length = 18.5 in, OFC = 33 cm; nl nursery course
FHx : Normal pedigree includes nl 4 y.o. brother, no consanguinity.
Develop hx: “nl 1 mo check-up ± stiffness”; “fussy & 2 mos mos: wgt = 14.5 lbs, length = 26 in, OFC = 34 cm; bilat disc pallor, follows, feeds well, rolls “half way”; infantile spasms observed.
Exam: Microcephaly, NDD, ID, spastic quad, and uncontrolled “mixed” types of epilepsy (myoclonic, tonic/atonic, atypical absences)
Labs: Nl CBC, plts, clotting studies, metabolic screen, CSF H. zoster
[photos...see next slide]
Holden K 1/30/17

27. Pediatric OFC: Microcephaly
Holden K 1/30/17

28. Pediatric OFC: Microcephaly
ACQUIRED MICROCEPHALY: EVALUATION BY ALGORITHMIC APPROACH
Holden K 1/30/17

29. Pediatric OFC: Microcephaly
ACQUIRED MICROCEPHALY: CASE #1
E.B.: Brain MRI axial & coronal views
T1-Axial 2 3 1 4
T1-Coronal 5 6
Holden K 1/30/17

30. Pediatric OFC: Microcephaly
ACQUIRED MICROCEPHALY: CASE #2
M.C. 6 y.o. WF with acquired microcephaly and global neurodevelopmental disabilities (NDD) .
NDD include ID, marked hypotonia, oropharyngeal dysfunction, and mild sensorineural hearing loss.
Hx: Normal term gestation, birth measurements nl, OFC 33 cm; by 9 mos, OFC = 41 cm.
FHx: Normal pedigree, no siblings; no consanguinity.
Developmental history: Poor feeder, global NDD with ID and severe hypotonia present by 3-6 mos. No epilepsy.
Exam: Microcephaly OFC 46.5 cm, dysmorphic/hypotonic facies, nl fundi, drooling, NDD with hypotonia
Labs: CBC, glu, LFTs, renal, T4, lead level nl. Brain MRI nl.
Holden K 1/30/17

31. Pediatric OFC: Microcephaly
ACQUIRED MICROCEPHALY: EVALUATION BY ALGORITHMIC APPROACH
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32. Pediatric OFC: Microcephaly
ACQUIRED MICROCEPHALY: CASE #2
Lab: Chromosomal microarray positive for 1p36 deletion
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33. Pediatric OFC: Microcephaly
ACQUIRED MICROCEPHALY: CASE #3
J.D. ~ 4 y.o. HM with acquired microcephaly and global neurodevelopmental delays (NDD) with ID, marked hypotonia, dystonia, and limited speech.
Hx: Nl term gestation, BW 3.6 kg, length 53 cm, and OFC 35 cm. Motor delays noticeable by 3 mos. No epilepsy,
FHx: Mat. half-brother with similar disorder, no consanguinity.
Developmental hx: Alert, NDD with ID, in stroller/non-ambulatory, gastrostomy required for nutrition.
Exam: Microcephaly, OFC = 47 cm, nondysmorphic, NDD with ID, averbal, hypotonic / myopathic facies & nl fundi.
Labs: CBC, glu, lytes, renal & LFTs, CK nl. Thyroid FT’s and brain MRI mildly abnormal but non-diagnostic.
Holden K 1/30/17

34. Pediatric OFC: Microcephaly
ACQUIRED MICROCEPHALY: CASE #3
Proband (III-3) at 3.5 years old.
Holden K 1/30/17

35. Pediatric OFC: Microcephaly
ACQUIRED MICROCEPHALY: EVALUATION BY ALGORITHMIC APPROACH
Holden K 1/30/17

36. Pediatric OFC: Microcephaly
ACQUIRED MICROCEPHALY: CASE #3
LABs: Mildly abnormal TFTs (mildly low total and free T4, mildly elevated total and free T3, with TSH normal.
Brain MRI: At 22 mos had non-diagnostic mild dysmyelination of the corpus callosum, internal capsules, and subcortical U-fibers.
Gene huntin’ after normal array studies revealed an abnormality on the X-chromosome which was identified as responsible for production of monocarboxylate transporter 8 (MCT8) which appears responsible for transporting T3 into neurons and downstream production of their mRNA.
Final Dx: X-linked MR (abnormal MCT8 gene mutation) formerly aka: Allan-Herndon-Dudley syndrome.
Reference: Holden KR et al J Child Neurol 2005;20:
Holden K 1/30/17

37. Pediatric OFC: Tale of the Tape
CONCLUSIONS:
OFC measurements are a valuable clinical tool throughout childhood; microcephaly (small head) correlates with brain size (micrencephaly); brain growth in the first year of life correlates with intelligence; and, 70% of final wgt of brain is present at 1 yr of age.
New U.S. pediatric OFC growth charts from birth to 21 years will appear in the Journal of Pediatrics, June, 2010; CDC, Roche and Nellhaus data were incorporated to produce more reliable user-friendly OFC growth charts from birth to adulthood that are smooth, continuous, and complete.
Previous terminologies for microcephaly have been jumbled by clinical, neurometabolic-genetic, and neuroradiologic studies.
Strongly suggest using “primary” microcephaly and “acquired” microcephaly to divide into groups which will facilitate cost-effective evaluations.
Holden K 1/30/17

38. Pediatric OFC: Tale of the Tape
CONCLUSIONS: (cont’d)
Obtaining the newborn OFC is crucial to this classification and in the evaluation of any patient with microcephaly.
If a newborn OFC is unavailable, any OFC in the first month of life can help document the onset of the microcephaly.
E. “Acquired” microcephaly is easily identified in most cases. The multiple etiologies and their cost-effective work-ups are manageable after a standard history, family OFCs and a pedigree, examination including funduscopy, and generally obtained investigational studies prior to elaborate neurogenetic testing.
F. “Acquired” microcephaly can exhibit a time of presentation which contributes to the cost-effective work-up and diagnosis when using this valuable clinical sign (OFC) on routine examinations.
Holden K 1/30/17

39. Pediatric OFC: Tale of the Tape
ACKNOWLEDGMENTS:
Greenwood Genetic Center
Steve A. Skinner, M.D.
Michael J. Lyons, M.D.
Laurie H. Seaver, M.D.
Jules G. Leroy, M.D.
Jonathan D. Rollins, B.S.
Julianne S. Collins, Ph.D.
Ms. Patti Broome
MUSC
Maria G. Mathews, M.D.
Zoran Rumboldt, M.D.
Honduras National Medical School
Marco R. Molinero, M.D.
Marco T. Medina, M.D.
Reyna M. Duron, M.D.
Holden K 1/30/17

40. Pediatric OFC: Tale of the Tape
REFERENCES:
Nellhaus G: Pediatrics 41:106, 1968.
Roche AF et al: Pediatrics 79:706, 1987.
National Center Health Statistics (NCHS) / CDC 2000;
CDC website:
Rollins JD, Collins JS, Holden KR: J Pediatrics 2010 Mar 19 (Epub)
Holden KR, Lyons MJ: Acquired microcephaly. In: Maria BL, ed. Current Management in Child Neurology. 4th ed. Hamilton, Ontario, Canada: BC Decker, 2009.
Hunter AG. Brain. In: Stevenson RE, Hall JG, eds. Human Malformations and Related Anomalies, 2nd ed. New York: Oxford University Press; 2006.
Jones KL. Smith’s Recognizable Patterns of Human Malformation, 6th ed. Philadelphia: WB Saunders; 2006.
Leroy JG, Frias JL. Nonsyndromic microcephaly: an overview. Adv Pediatr 2005;52:
Moeschler JB, Shevell M; American Academy of Pediatrics Committee on Genetics. Clinical genetic evaluation of the child with mental retardation or developmental delays. Pediatrics 2006; 117:
Opitz JM, Holt MC. Microcephaly: general considerations and aids to nosology. J Craniofac Genet Dev Biol 1990;10:
Rimoin DL, Connor JM, Pyeritz RE, Korf BR. Emery and Rimoin’s Principles and Practices of Medical Genetics, 4th ed. London: Churchill Livingstone; 2002.
Shevell M, Ashwal S, Donley D, et al. Practice parameter: evaluation of the child with global developmental delay: report of the Quality Standards Subcommittee of the American Academy of Neurology and The Practice Committee of the Child Neurology Society. Neurology 2003;60:
Swaiman KF, Ashwal S, Ferriero DM. Pediatric Neurology Principles and Practice, 4th ed. Philadelphia: Mosby Elsevier; 2006.
Holden K 1/30/17

41. Pediatric OFC: Tale of the Tape
PRACTITIONER AND PATIENT RESOURCES:
CDC growth charts website at:
Gene Reviews website at:
Microcephaly Support Group website at:
Online Mendelian Inheritance in Man website at:
Online Metabolic and Molecular Basis of Inherited Disease at:
Thank You!
Questions???
Holden K 1/30/17