Download Secondary craniosynostosis

A baby with cloverleaf
skull anomaly
R 3 羅永邦
Supervisors: Drs. 許瓊心, 林炫沛 & 邱南昌
Admission Data
黃xx之女 (張xx)
 Number: 3619275-6
 Sex: Female
 Admission Date: 94/05/30
 Chief complaints:
1. Prematurity (GA: 32 weeks)
2. Respiratory distress
3. Congenital anomaly
 Name:
Present Illness

Perinatal examinations at OBS/GYN Clinic did
not show any abnormality.

Mother was also denied of perinatal drug usage,
infection or systemic disease.

PROM was noted since 5/12 and tocolysis
performed since 5/12 at OBS/GYN Clinic.
Ampicillin Tx from 5/12 and 2 doses of Decadron
were given.
Present Illness

Due to fetal distress (HR: 80-90/min),
emergency C/S was performed.
The Apgar score 71  95.

After birth, bradycardia was noted and
endotracheal tube was inserted. Under the
diagnosis of PPROM, prematurity and
respiratory distress, she was admitted for
further treatment and evaluation.
Present Illness

Birth history:
DOB on 94/05/30 at 22:26
EDC: 94/07/20
GA: 32+ weeks, BBW: 1,910gm
Via C/S due to fetal distress
Apgar score: 7195
PPROM noted since 05/12
Prenatal ampicillin since 05/12
Prenatal steroid x2 doses
Present Illness
 Maternal
history
G1P1 healthy mother
No GDM, HTN, Toxemia, APH, PPH
URI(-), Fever(-)
HBsAg(-), HBeAg(-)
Family History
34 years old
BG: AB
電子業
28 years old
BG: AB
電子業
Physical Examination
 Blood
pressure: 56/3744/29Dopamine
used58/36
 Heart rate: 116 /min
 Respiratory rate: 60 /min
 Body temperature: 36.3C
 General appearance: acute ill looking
Physical Examination
Head: Cloverleaf skull
Frontal bone bossing
Anterior fontanel:
7.5 x 4.5cm
Mid-face hypoplasia
Eyes: not injected
Ear: suspect ear canal
obstruction
Nose: suspect left canal
Obstruction
Mouth: no cleft palate
Physical Examination
Frontal area bossing
Pseudo low set ears
Exophthalmos
Physical Examination
Thorax: symmetric expansion
no pigeon chest
Chest: breathing sound: coarse
No rale, no wheezing
Heart: RHB, no murmur or thrill
Abdomen: Soft and flat
Bowel sound: normactive
No hepatosplenomegaly
Extremities: free movable
No shortened limbs
Rectum and anus: patent
Laboratory Data (5/30)
CBC
Chemistry
Arterial
Blood Gas
Hgb: 17.9 g/dL, Hct: 53.6%, MCV: 116.5
WBC: 9,600 /uL, PLT: 320,000/uL, BG: B
Band: 0%, Neut: 23%, Eosin: 2%, Baso: 1%
Baso: 1%, Monocyte: 1%, Lym: 72%
Atypical lymphocyte: 1%
Dex: 38 mg/dl, Na: 145 mEq/L
K: 4.9 mEq/dl, Free Ca: 1.19 mmol/L
PH: 7.332, PaCO2: 45.9 mmHg, PaO2:
124.1mmHg, HCO3: 23.8 mmol/L
BE: -2.1 mmol/L
Laboratory Data (5/30)
CSF
血清病毒
Immune
Glucose: 38 mg/dL, Protein: 179 mg/dL
RBC: 58 /CMM, WBC: 2 /CMM
L:N=0:2
CRP: <0.1 mg/dL, RPR: non-reactive
Urine GBS: negative
Rubella IgM: 0.12 (<0.8)
HSV-1 IgM: 0.39 (<1)
HSV-2 IgM: 0.51 (<1)
Toxoplasma IgM: 0.09 (<0.5)
CMV IgM: 0.08 (<0.5)
Total IgM: 9 mg/dL
Laboratory Data (5/30)

CXR (5/30): Parahilar
radiating congestion
of both lungs is seen.
Slight overaeration of
bilateral lungs is seen.
 No limbs or vertebrae
abnormalities
 IMP: Retention of
lung fluid.
Impression





1. Prematurity (GA: 32+ weeks, BBW: 1910 gm)
2. PROM about 18 days
3. Respiratory distress, suspect RDS grade I
4. Hypotension
5. Congenital anomaly
r/o Crouzon syndrome
r/o Thanatophoric dysplasia
r/o Craniosynostosis
Hospital Course
 Initial
management:
1. On ETT + IMV
2. N/S challenge first, then add Dopamine
(5/30~5/31)
3. Ampicillin and gentamicin (5/30~6/06)
for suspected congenital infection
Hospital Course

Brain echo (5/31): Ventricular dilatation, bilateral;
suspect pachygyria

Renal echo (5/31): negative findings

Abdominal echo (5/31): gall bladder is visible; no
intra-abdominal mass was noted

Heart echo (5/31): PDA (left to right, 0.146 cm),
PHT (56.5 mmHg), Dysarrhythmia
Hospital Course
 His
respiratory distress improved, so
endotracheal tube was removed and
changed to O2 hood since 6/01
 DC O2 hood on 6/07
Culture
Chromosome
study
Blood culture (5/30): no growth
CSF culture (5/30): no growth
46, XX, normal
Skull PA + LAT view (6/01)
Obliteration of bilateral coronal and
Lambdoidal sutures of skull is seen.
Premature closure is considered.
Association with cloverleaf skull syndrome is considered
Hospital Course

Consult Ophthalmologist:
Incomplete regression of hyaloid vessels;
Vessels constriction of left eye
Impression:
1. Congenital abnormality of retinal vessel (OS)
2. Optic neuropathy (OS)
Suggest VEP examinations after general
condition stabilized
Hospital Course
 Add
aminophylline since 6/02
 F/U brain echo (6/03): Ventriculomegaly,
bilateral, symmetric; Suspect pachygyria;
High RI (0.94)
 Arrange brain MRI with/without contrast
on 6/03
Cavum septum
pellucidum
1. Dilatation of the lateral ventricles is noted, The 3rd
ventricle is mildly dilated. Presence of cavum septum
pellucidum and cavum vergae is noted.
2. The94.6.3
cerebral cortical sulci is broad and flattened,
pachygyria is considered.
3. Brachicephaly is noted. Trilobed skull is
demonstrated on coronal images. Cloverleaf skull
syndrome due to premature closure of multiple cranial
sutures is considered.
4. The posterior portion of the septum pellucidum is
not visualized.
Cavum vergae
Brain MRI (6/03)
1. The posterior fossa
Is small and torcular is low
Lying. Tonsillar herniation
Thru the foramen magnum
Is also noted.
2. No abnormal
enhancement is noted.
3. The pituitary gland,
cavernous sinuses and
cerebellopontine angles
appear normal and
symmetric.
Brain MRI (6/03)

Impression:
1. Cloverleaf skull syndrome, following anomalies
including acrocephalopolysyndactylies (Crouzon, Pfeiffer,
Carpenter, Apert…etc.) and type II form of thanatophoric
dysplasia should be considered in the differential
diagnosis.
2. Dilatation of the lateral ventricles and presence of
cavum septum pellucidum and cavum vergae.
3. Pachygyria.
4. Small posterior fossa and cerebellar tonsilar herniation.
5. Absent posterior septum pellucidum.
Brain CT (6/09)
1. Dilatation of the lateral ventricles and
mild dilatation of the 3rd ventricle are noted.
Presence of cavum septum pellucidum and
cavum vergae is noted.
2. The posterior septum pellucidum is not
visualized.
Brain CT (6/09)
Brain CT (6/09)
Brain CT (6/09)
1. Premature closure of multiple cranial sutures
causing trilobed appearance of skull on coronal
images and brachicephaly is seen, cloverleaf skull
syndrome is considered. Beaten copper appearance
of the skull is also noted.
2. Enlargement of the fontanelles is noted.
Brain CT (6/09)
 Impression:
1. Cloverleaf skull syndrome.
2. Dilatation of the lateral ventricles and
mild dilatation of the 3rd ventricle and
presence of cavum septum pellucidum
and cavum vergae.
3. Absent posterior septum pellucidum.
Hospital Course

Frequent bradycardia (70~80/min), apnea and
desaturation (70~80%) noted on 6/15
 No fever, no hypotension
 Head circumference increased from
27.5 cm to 29 cm

Brain echo (6/15):
Progressing ventriculomegaly, bilateral
Hydrocephalus, non-communicating type
Pachygyria, suspect lissencephaly
High RI (1.0)
Hospital Course





IICP was highly suspected, so CSF tapping was
performed, however, reddish CSF fluid was noted
Lab data (1)
Lab data (2)
CXR
Brain CT (6/15):
1. Cloverleaf skull syndrome.
2. Dilatation of the lateral ventricles and mild dilatation of
the 3rd ventricle and presence of cavum septum
pellucidum and cavum vergae.
3. Absent posterior septum pellucidum.
Hospital Course

Consult Neurosurgeon immediately
 Extraventricular device was inserted on 6/15,
then Cefamezine for post-operation prophylaxis
(6/16~6/18)
 PRBC was transfused after OP
 Luminal for preventing seizure (6/15~)
Hospital Course

Her bradycardia and desaturation improved a lot
after operation

EVD discharge: 18cc (6/16)37cc (6/17)
22.5cc (6/18)24cc (6/19)

Brain echo (6/16): Hydrocephalus, /p V-P shunt;
Decreased ventricle size, bilateral
Hospital Course

Unfortunately, her FGFR3 gene PCR showed
positive on 6/18, so Thanatophoric dysplasia
was highly suspected

Very poor prognosis was told, so her family
decided to remove EVD shunt since then

After detailed explanation of the consequence of
removing EVD shunt to her family, her EVD
shunt was removed on 6/24
Hospital Course

However, further genetic study had ruled out the
possibility of thanatophoric dysplasia
Newborn screen: normal
Tandem mass: normal
Sequencing of FGFR3 gene: normal
PCR study of FGFR2 gene: pending
Hospital Course

Brain echo (6/30):
1. Progressive bilateral ventricle dilatation
2. Suspect blood clot inside the ventricle, bilateral
3. Porencephaly at right fronto-parietal area, due to EVD
4. High RI (0.97)

Brain echo (7/06):
1. Hydrocephalus, non-communicating type, progressing
2. Porencephaly at right fronto-parietal area, progressing
3. High RI (1.0)
Hospital Course (7/07)
Hospital Course (7/07)

At this point, she
would get bradycardia
easily if you press on
her anterior fontanel
gently
Hospital Course (7/15)
Hospital Course
 This
patient was discharged on 7/16
 However, she was brought back to our ER
on 7/18 without breathing & heart beating
 Unfortunately, she died on 7/18
Discussion
Craniosynostosis
Cloverleaf skull syndrome
1.
2.
Craniosynostosis
 Primary craniosynostosis: a primary defect of
ossification
 Secondary craniosynostosis: a failure of brain
growth, more commonly
 Syndromic craniosynostosis: display other body
deformities
Craniosynostosis
 Simple craniosynostosis: only 1 suture fuses
prematurely
 Complex or compound craniosynostosis:
premature fusion of multiple sutures
Craniosynostosis






The coronal suture separates the 2
frontal bones from the parietal bones.
The metopic suture separates the
frontal bones.
The sagittal suture separates the 2
parietal bones.
The lambdoid suture separates the
occipital bone from the 2 parietal
bones.
The primary factor that keeps sutures
open is ongoing brain growth.
Normal skull growth occurs
perpendicular to each suture.
Primary craniosynostosis

When 1 or more sutures fuse prematurely, skull growth can
be restricted perpendicular to the suture. If multiple sutures
fuse while the brain is still increasing in size, intracranial
pressure can increase.

Cause: a primary defect in the mesenchymal layer
ossification in the cranial bones.

A gene locus for single suture craniosynostosis has not
been identified.
Scaphocephaly - Early fusion of the sagittal suture
Ant. plagiocephaly - Early fusion of 1 coronal suture
Post. plagiocephaly - Early closure of 1 lambdoid suture
Brachycephaly - Early bilateral coronal suture fusion
Trigonocephaly - Early fusion of the metopic suture
Secondary craniosynostosis





More frequent
Early fusion of sutures due to primary failure of brain
growth
Intracranial pressure usually is normal, and surgery seldom
is needed
Intrauterine space constraints may play a role in the
premature fusion of sutures in the fetal skull. This has been
demonstrated in coronal craniosynostosis
Microcephaly usually suggests a secondary
craniosynostosis
Secondary craniosynostosis

Endocrine
Hyperthyroidism, hypophosphatemia, vitamin D deficiency,
renal osteodystrophy, hypercalcemia, and rickets
Hematologic disorders
Which cause bone marrow hyperplasia (eg, sickle cell
disease, thalassemia)

Inadequate brain growth
Microcephaly and its causes and shunted hydrocephalus

Syndromic Craniosynostosis

Craniosynostosis sometimes is associated with sporadic
craniofacial syndromes such as Crouzon, Apert, Chotzen,
Pfeiffer, or Carpenter syndromes.

In this context, facial features, typically craniofacial
abnormalities, suture ridging, and early closure of
fontanelles, suggest the diagnosis.

Genetic mutations responsible for fibroblast growth factor
receptors 2 and 3
Craniosynostosis
 Incidence in the US: 0.04 ~ 0.1%
 2~8% had primary craniosynostosis, others were
secondary craniosynostosis
 Sagittal 50-58%, coronal 20-29%, metopic 4-10%,
and lambdoid 2-4%.
Craniosynostosis

Raised intracranial pressure is rare with fusion of a single
suture. It can occur in primary craniosynostosis when
multiple sutures fuse.

Signs include sun-setting eyes, papilledema, vomiting, and
lethargy.

Craniosynostosis of 1-2 sutures: Cosmetic defect is the
primary morbidity.
Diagnosis of Craniosynostosis
 Image studies:
1. Skull X-ray with AP, lat. and water view
2. Cranial CT scan with 3-dimensional
reconstruction
 Endocrine evaluation: Order thyroid and parathyroid
studies when associated features suggest these
diagnoses.
Treatment of Craniosynostosis
 In patients with microcephaly, investigate the cause
 Carefully monitor signs and symptoms of elevated
intracranial pressure
 Surgery typically is indicated for increased
intracranial pressure or for cosmetic reasons.
Treatment of Craniosynostosis
 Do not operate in patients without IICP until the
shape of the head does not improve by age 2-4
months, then the abnormality is unlikely to resolve
with age
 Cosmetic surgery is performed in infants aged 3-6
months in the author's practice
Cloverleaf skull
syndrome
Cloverleaf Skull Syndrome

Kleeblattschädel (ie,
cloverleaf skull) results
from fusion of all sutures
except the metopic and
squamosal sutures, giving
the head a cloverleaf
appearance
Cloverleaf Skull Syndrome
Cloverleaf Skull Syndrome
 Cloverleaf
skull or kleeblattschadel is a rare
malformation caused by synostosis of multiple
cranial sutures.
 It
can be associated with hydrocephalus, proptosis,
and hypoplasia of the midface and cranial base
Cloverleaf Skull Syndrome
 Many
syndrome present with cloverleaf skull
including most of the acrocephalopolysyndactylies
(Crouzon, Pfeiffer, Carpenter, Apert…)

It is also typical of the type II form of thanatophoric
dysplasia (another FGFR mutation).
Cloverleaf Skull Syndrome
 Differential
diagnosis
1. Crouzon syndrome
2. Apert syndrome
3. Pfeiffer syndrome
4. Carpenter syndrome
5. Thanatophoric dysplasia type II
Crouzon Syndrome
Coronal and sagittal
sutures are most
commonly involved
 Cloverleaf skull is rare and
occurs in the most
severely affected
individuals.
 Hydrocephalus
(progressive in 30%)

Crouzon Syndrome
Midface (maxillary) hypoplasia
Exophthalmos secondary to shallow orbits
Ocular hypertelorism
Nose: Beaked appearance
Mouth: Mandibular prognathism
Narrow, high, or cleft palate and bifid uvula
Crouzon Syndrome

Other skeletal features



Block fusions involving multiple vertebrae, Cervical fusion (18%),
C2-C3 and C5-C6
Subluxation of the radial heads , Ankylosis of the elbows
Skin
Approximately 5% of patients have acanthosis nigricans, which is
detectable after infancy. The hallmark of these lesions is a darkened
thickened skin with accentuated markings and a velvety feel

Central nervous system


Approximately 73% of patients have chronic tonsillar herniation.
Of these, 47% have progressive hydrocephalus.
Syringomyelia may be present.
Apert Syndrome




Coronal sutures most
commonly are involved
Large late-closing fontanels
Gaping midline defect
Rare cloverleaf skull anomaly
is found in approximately 4% of
infants
Apert Syndrome

Extremities and digits
Syndactyly involves the hands and
feet with partial-to-complete fusion
of the digits
Upper limbs are affected more
severely

Central nervous system


Intelligence varies from
normal to mental deficiency
Papilledema and optic
atrophy with loss of vision
Apert Syndrome

Skin

Hyperhidrosis (common)

Cardiovascular (10%)

ASD, PDA, VSD, PS, Overriding aorta, CoA, Dextrocardia, TOF, Endocardial
fibroelastosis

Genitourinary (9.6%)

Polycystic kidneys, Duplication of renal pelvis, etc..

Gastrointestinal (1.5%)

Pyloric stenosis, Esophageal atresia and tracheoesophageal fistula, etc..

Respiratory (1.5%)

Anomalous tracheal cartilage, Tracheoesophageal fistula, Pulmonary aplasia,
Absent right middle lobe of lung, Absent interlobular lung fissures
Pfeiffer Syndrome





Skull is prematurely fused and
unable to grow normally
Bulging wide-set eyes due to
shallow eye sockets (occular
proptosis)
Underdevelopment of the
midface
Broad, short thumbs and big
toes
Possible webbing of the hands
and feet
Carpenter's Syndrome

Head and neck: Craniosynostosis
first involving the sagittal and
lambdoid sutures later extending
to the coronal sutures. Cloverleaf
skull may occur

Mouth and oral structures: A
narrow or highly arched palate.

Hand and foot: The fingers
are short and stubby with
agenesis of the middle
phalanges and soft tissue
syndactyly, especially of the
third and fourth fingers.

Ears: Low set ears and
preauricular fistulae.

Eyes: Hypertelorism, mildly
downward slanting of the
palpebral fissures, epicanthic folds,
microcornea, corneal opacity, and
optic atrophy

Cardiovascular system:
About one third of all cases
Nose: Flat nasal bridge.

Growth and development:
Growth retardation is a
constant feature. Mental
retardation is common but not
constant.

Thanatophoric Dysplasia

Severe growth deficiency with an
average length of 40 cm at term

A macrocephalic head with a
frontal bossing, a flattened nasal
bridge, and proptotic eyes

In TD 2, a cloverleaf-shaped skull
resulting from premature closure
of the cranial sutures

Narrow thorax with small ribs

Micromelic limbs with
brachydactyly

Protuberant abdomen

Hydrocephalus and other cerebral
parenchymal abnormalities
Cloverleaf Skull Syndrome

Genetic anomalies: Most are de novo mutation of the
FGFR1-3.
ex: 1. Crouzon diseaseFGFR2
2. Thanatophoric dysplasiaFGFR3

Prognosis: When associated with hydrocephalus the
outcome is usually poor with frequent death in infancy

Surgical management: relieving the intracranial
hypertension and correcting the aesthetic appearance.