A baby with cloverleaf skull anomaly

A baby with cloverleaf A baby with cloverleaf skull anomalyskull anomaly

R 3 R 3 羅永邦羅永邦Supervisors: Drs. Supervisors: Drs. 許瓊心許瓊心 , , 林炫沛林炫沛 & & 邱南昌邱南昌

Admission DataAdmission Data

Name: Name: 黃黃 xxxx 之女之女 (( 張張 xx)xx) Number: 3619275-6Number: 3619275-6 Sex: FemaleSex: Female Admission Date: 94/05/30Admission Date: 94/05/30 Chief complaints: Chief complaints: 1. Prematurity (GA: 32 weeks)1. Prematurity (GA: 32 weeks) 2. Respiratory distress2. Respiratory distress 3. Congenital anomaly3. Congenital anomaly

Present IllnessPresent Illness Perinatal examinations at OBS/GYN Clinic did Perinatal examinations at OBS/GYN Clinic did

not show any abnormality. not show any abnormality.

Mother was also denied of perinatal drug usage, Mother was also denied of perinatal drug usage, infection or systemic disease. infection or systemic disease.

PROM was noted since 5/12 and tocolysis PROM was noted since 5/12 and tocolysis performed since 5/12 at OBS/GYN Clinic. performed since 5/12 at OBS/GYN Clinic. Ampicillin Tx from 5/12 and 2 doses of Decadron Ampicillin Tx from 5/12 and 2 doses of Decadron were given. were given.

Present IllnessPresent Illness Due to fetal distress (HR: 80-90/min), Due to fetal distress (HR: 80-90/min),

emergency C/S was performed. emergency C/S was performed. The Apgar score 7The Apgar score 71 1 9 955. .

After birth, bradycardia was noted and After birth, bradycardia was noted and endotracheal tube was inserted. Under the endotracheal tube was inserted. Under the diagnosis of PPROM, prematurity and diagnosis of PPROM, prematurity and respiratory distress, she was admitted for respiratory distress, she was admitted for

further treatment and evaluation.further treatment and evaluation.

Present IllnessPresent Illness

Birth history: Birth history: DOB on 94/05/30 at 22:26DOB on 94/05/30 at 22:26 EDC: 94/07/20EDC: 94/07/20 GA: 32GA: 32++ weeks, BBW: 1,910gm weeks, BBW: 1,910gm Via C/S due to fetal distressVia C/S due to fetal distress Apgar score: 7Apgar score: 7119955

PPROM noted since 05/12PPROM noted since 05/12 Prenatal ampicillin since 05/12Prenatal ampicillin since 05/12 Prenatal steroid x2 dosesPrenatal steroid x2 doses

Present IllnessPresent Illness

Maternal historyMaternal history

G1P1 healthy motherG1P1 healthy mother

No GDM, HTN, Toxemia, APH, PPHNo GDM, HTN, Toxemia, APH, PPH

URI(-), Fever(-)URI(-), Fever(-)

HBsAg(-), HBeAg(-)HBsAg(-), HBeAg(-)

Family HistoryFamily History

28 years oldBG: AB電子業

34 years oldBG: AB電子業

Physical ExaminationPhysical Examination

Blood pressure: 56/37Blood pressure: 56/3744/2944/29Dopamine Dopamine usedused58/3658/36

Heart rate: 116 /minHeart rate: 116 /min Respiratory rate: 60 /minRespiratory rate: 60 /min Body temperature: 36.3CBody temperature: 36.3C General appearance: acute ill lookingGeneral appearance: acute ill looking


Head: Cloverleaf skullFrontal bone bossing

Anterior fontanel: 7.5 x 4.5cm

Mid-face hypoplasia

Eyes: not injectedEar: suspect ear canal

obstructionNose: suspect left canal

ObstructionMouth: no cleft palate


Frontal area bossingPseudo low set ears

Exophthalmos


Thorax: symmetric expansion no pigeon chest

Chest: breathing sound: coarseNo rale, no wheezing

Heart: RHB, no murmur or thrillAbdomen: Soft and flat

Bowel sound: normactiveNo hepatosplenomegalyExtremities: free movable

No shortened limbsRectum and anus: patent

Laboratory Data (5/30)Laboratory Data (5/30)

CBCCBC

Hgb: 17.9 g/dL, Hct: 53.6%, MCV: 116.5Hgb: 17.9 g/dL, Hct: 53.6%, MCV: 116.5

WBC: 9,600 /uL, PLT: 320,000/uL, BG: BWBC: 9,600 /uL, PLT: 320,000/uL, BG: B

Band: 0%, Neut: 23%, Eosin: 2%, Baso: 1% Band: 0%, Neut: 23%, Eosin: 2%, Baso: 1% Baso: 1%, Monocyte: 1%, Lym: 72%Baso: 1%, Monocyte: 1%, Lym: 72%

Atypical lymphocyte: 1%Atypical lymphocyte: 1%

ChemistryChemistryDex: 38 mg/dlDex: 38 mg/dl, Na: 145 mEq/L, Na: 145 mEq/L

K: 4.9 mEq/dl, Free Ca: 1.19 mmol/LK: 4.9 mEq/dl, Free Ca: 1.19 mmol/L

Arterial Arterial Blood GasBlood Gas

PH: 7.332, PaCO2: 45.9 mmHg, PaO2: PH: 7.332, PaCO2: 45.9 mmHg, PaO2: 124.1mmHg, HCO3: 23.8 mmol/L124.1mmHg, HCO3: 23.8 mmol/L

BE: -2.1 mmol/LBE: -2.1 mmol/L


CSFCSF

Glucose: 38 mg/dL, Protein: 179 mg/dLGlucose: 38 mg/dL, Protein: 179 mg/dL

RBC: 58 /CMM, WBC: 2 /CMM RBC: 58 /CMM, WBC: 2 /CMM

L : N = 0 : 2L : N = 0 : 2

血清病毒血清病毒

CRP: <0.1 mg/dL, RPR: non-reactiveCRP: <0.1 mg/dL, RPR: non-reactive

Urine GBS: negativeUrine GBS: negative

Rubella IgM: 0.12 (<0.8)Rubella IgM: 0.12 (<0.8)

HSV-1 IgM: 0.39 (<1)HSV-1 IgM: 0.39 (<1)

HSV-2 IgM: 0.51 (<1)HSV-2 IgM: 0.51 (<1)

Toxoplasma IgM: 0.09 (<0.5)Toxoplasma IgM: 0.09 (<0.5)

CMV IgM: 0.08 (<0.5)CMV IgM: 0.08 (<0.5)

ImmuneImmune Total IgM: 9 mg/dLTotal IgM: 9 mg/dL


CXR (5/30): Parahilar CXR (5/30): Parahilar radiating congestion radiating congestion of both lungs is seen. of both lungs is seen. Slight overaeration of Slight overaeration of bilateral lungs is bilateral lungs is seen.seen.

No limbs or vertebrae No limbs or vertebrae abnormalitiesabnormalities

IMP: Retention of IMP: Retention of lung fluid.lung fluid.

ImpressionImpression

1. 1. Prematurity (GA: 32+ weeks, BBW: 1910 gm)Prematurity (GA: 32+ weeks, BBW: 1910 gm) 2. PROM about 18 days2. PROM about 18 days 3. Respiratory distress, suspect RDS grade I3. Respiratory distress, suspect RDS grade I 4. Hypotension4. Hypotension 5. Congenital anomaly5. Congenital anomaly

r/o Crouzon syndromer/o Crouzon syndrome

r/o Thanatophoric dysplasiar/o Thanatophoric dysplasia

r/o Craniosynostosisr/o Craniosynostosis

Hospital CourseHospital Course

Initial management: Initial management:

1. On ETT + IMV1. On ETT + IMV

2. N/S challenge first, then add Dopamine 2. N/S challenge first, then add Dopamine (5/30~5/31)(5/30~5/31)

3. Ampicillin and gentamicin (5/30~6/06) 3. Ampicillin and gentamicin (5/30~6/06) for suspected congenital infectionfor suspected congenital infection


Brain echo (5/31): Ventricular dilatation, bilateral; Brain echo (5/31): Ventricular dilatation, bilateral; suspect pachygyriasuspect pachygyria

Renal echo (5/31): negative findingsRenal echo (5/31): negative findings

Abdominal echo (5/31): gall bladder is visible; no Abdominal echo (5/31): gall bladder is visible; no intra-abdominal mass was notedintra-abdominal mass was noted

Heart echo (5/31): PDA (left to right, 0.146 cm), Heart echo (5/31): PDA (left to right, 0.146 cm), PHT (56.5 mmHg), DysarrhythmiaPHT (56.5 mmHg), Dysarrhythmia

Hospital Course Hospital Course

His respiratory distress improved, so His respiratory distress improved, so endotracheal tube was removed and endotracheal tube was removed and changed to O2 hood since 6/01changed to O2 hood since 6/01

DC O2 hood on 6/07DC O2 hood on 6/07

CultureCulture Blood culture (5/30): no growthBlood culture (5/30): no growth

CSF culture (5/30): no growthCSF culture (5/30): no growth

Chromosome Chromosome studystudy

46, 46, XX, normalXX, normal

Skull PA + LAT view (6/01)Skull PA + LAT view (6/01)

Obliteration of bilateral coronal and Obliteration of bilateral coronal and Lambdoidal sutures of skull is seenLambdoidal sutures of skull is seen. .

Premature closure is considered. Premature closure is considered. Association with Association with cloverleaf skull syndromecloverleaf skull syndrome is considered is considered


Consult Ophthalmologist: Consult Ophthalmologist:

Incomplete regression of hyaloid vessels;Incomplete regression of hyaloid vessels;

Vessels constriction of left eyeVessels constriction of left eye

Impression: Impression:

1. Congenital abnormality of retinal vessel (OS) 1. Congenital abnormality of retinal vessel (OS)

2. Optic neuropathy (OS)2. Optic neuropathy (OS)

Suggest VEP examinations after general Suggest VEP examinations after general

condition stabilized condition stabilized


Add aminophylline since 6/02Add aminophylline since 6/02 F/U brain echo (6/03): Ventriculomegaly, F/U brain echo (6/03): Ventriculomegaly,

bilateral, symmetric; Suspect pachygyria; bilateral, symmetric; Suspect pachygyria; High RI (0.94) High RI (0.94)

Arrange brain MRI with/without contrast Arrange brain MRI with/without contrast

on 6/03on 6/03

94.6.3

Cavum septum pellucidum

Cavum vergae

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. The 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.

Brain MRI (6/03)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 andsymmetric.

Brain MRI (6/03)Brain MRI (6/03)

Impression:Impression: 1. Cloverleaf skull syndrome, following anomalies 1. Cloverleaf skull syndrome, following anomalies

including acrocephalopolysyndactylies (Crouzon, including acrocephalopolysyndactylies (Crouzon, Pfeiffer, Carpenter, Apert…etc.) and type II form of Pfeiffer, Carpenter, Apert…etc.) and type II form of thanatophoric dysplasia should be considered in the thanatophoric dysplasia should be considered in the differential diagnosis. differential diagnosis.

2. Dilatation of the lateral ventricles and presence of 2. Dilatation of the lateral ventricles and presence of cavum septum pellucidum and cavum vergae.cavum septum pellucidum and cavum vergae.

3. Pachygyria.3. Pachygyria. 4. Small posterior fossa and cerebellar tonsilar 4. Small posterior fossa and cerebellar tonsilar

herniation.herniation. 5. Absent posterior septum pellucidum.5. Absent posterior septum pellucidum.

Brain CT (6/09)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)


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.


Impression: Impression:

1. Cloverleaf skull syndrome.1. Cloverleaf skull syndrome.

2. Dilatation of the lateral ventricles and 2. Dilatation of the lateral ventricles and mild dilatation of the 3rd ventricle and mild dilatation of the 3rd ventricle and presence of cavum septum pellucidum presence of cavum septum pellucidum and cavum vergae.and cavum vergae.

3. Absent posterior septum pellucidum.3. Absent posterior septum pellucidum.

Hospital CourseHospital Course Frequent bradycardia (70~80/min), apneaFrequent bradycardia (70~80/min), apnea and and

desaturation (70~80%) noted on 6/15desaturation (70~80%) noted on 6/15 No fever, no hypotensionNo fever, no hypotension Head circumference increased from Head circumference increased from 27.5 cm to 29 cm27.5 cm to 29 cm

Brain echo (6/15): Brain echo (6/15): Progressing ventriculomegaly, bilateralProgressing ventriculomegaly, bilateral Hydrocephalus, non-communicating typeHydrocephalus, non-communicating type Pachygyria, suspect lissencephalyPachygyria, suspect lissencephaly High RI (1.0)High RI (1.0)


IICP was highly suspected, so CSF tapping was IICP was highly suspected, so CSF tapping was performed, however, reddish CSF fluid was notedperformed, however, reddish CSF fluid was noted

Lab data (1) Lab data (1) Lab data (2)Lab data (2) CXRCXR Brain CT (6/15): Brain CT (6/15): 1. Cloverleaf skull syndrome.1. Cloverleaf skull syndrome. 2. Dilatation of the lateral ventricles and mild dilatation of 2. Dilatation of the lateral ventricles and mild dilatation of

the 3rd ventricle and presence of cavum septum the 3rd ventricle and presence of cavum septum pellucidum and cavum vergae.pellucidum and cavum vergae.

3. Absent posterior septum pellucidum.3. Absent posterior septum pellucidum.


Consult Neurosurgeon immediatelyConsult Neurosurgeon immediately Extraventricular device was inserted on 6/15, Extraventricular device was inserted on 6/15,

then Cefamezine for post-operation prophylaxis then Cefamezine for post-operation prophylaxis (6/16~6/18)(6/16~6/18)

PRBC was transfused after OPPRBC was transfused after OP Luminal for preventing seizure (6/15~)Luminal for preventing seizure (6/15~)


Her bradycardia and desaturation improved a lot Her bradycardia and desaturation improved a lot after operationafter operation

EVD discharge: 18cc (6/16)EVD discharge: 18cc (6/16)37cc (6/17) 37cc (6/17) 22.5cc (6/18)22.5cc (6/18)24cc (6/19)24cc (6/19)

Brain echo (6/16): Hydrocephalus, /p V-P shunt; Brain echo (6/16): Hydrocephalus, /p V-P shunt; Decreased ventricle size, bilateralDecreased ventricle size, bilateral


Unfortunately, her Unfortunately, her FGFR3 gene PCR showed FGFR3 gene PCR showed positive on 6/18positive on 6/18, so Thanatophoric dysplasia , so Thanatophoric dysplasia was highly suspectedwas highly suspected

Very poor prognosis was told, so her family Very poor prognosis was told, so her family decided to remove EVD shunt since thendecided to remove EVD shunt since then

After detailed explanation of the consequence of After detailed explanation of the consequence of removing EVD shunt to her family, her EVD removing EVD shunt to her family, her EVD shunt was removed on 6/24shunt was removed on 6/24


However, further genetic study had ruled out the However, further genetic study had ruled out the possibility of thanatophoric dysplasiapossibility of thanatophoric dysplasia

Newborn screen: normalNewborn screen: normal

Tandem mass: normal Tandem mass: normal

Sequencing of FGFR3 gene: normalSequencing of FGFR3 gene: normal

PCR study of FGFR2 gene: pendingPCR study of FGFR2 gene: pending

Hospital CourseHospital 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 At this point, she would get bradycardia would get bradycardia easily if you press on easily if you press on her anterior fontanel her anterior fontanel gently gently


This patient was discharged on 7/16This patient was discharged on 7/16 However, she was brought back to our ER However, she was brought back to our ER

on 7/18 without breathing & heart beatingon 7/18 without breathing & heart beating Unfortunately, she died on 7/18Unfortunately, she died on 7/18

DiscussionDiscussion

1.1. CraniosynostosisCraniosynostosis

2.2. Cloverleaf skull syndromeCloverleaf skull syndrome

CraniosynostosisCraniosynostosis

Primary craniosynostosisPrimary craniosynostosis: a primary defect of : a primary defect of ossificationossification

Secondary craniosynostosisSecondary craniosynostosis: a failure of brain : a failure of brain growth, more commonlygrowth, more commonly

Syndromic craniosynostosisSyndromic craniosynostosis: display other body : display other body deformitiesdeformities


Simple craniosynostosisSimple craniosynostosis: only 1 suture fuses : only 1 suture fuses prematurelyprematurely

Complex or compound craniosynostosisComplex or compound craniosynostosis: : premature fusion of multiple suturespremature fusion of multiple sutures

CraniosynostosisCraniosynostosis The coronal suture separates the 2 The coronal suture separates the 2

frontal bones from the parietal bones. frontal bones from the parietal bones. The metopic suture separates the The metopic suture separates the

frontal bones. frontal bones. The sagittal suture separates the 2 The sagittal suture separates the 2

parietal bones. parietal bones. The lambdoid suture separates the The lambdoid suture separates the

occipital bone from the 2 parietal occipital bone from the 2 parietal bones. bones.

The primary factor that keeps sutures The primary factor that keeps sutures open is ongoing brain growth.open is ongoing brain growth.

Normal skull growth occurs Normal skull growth occurs perpendicular to each suture.perpendicular to each suture.

Primary craniosynostosisPrimary craniosynostosis

When 1 or more sutures fuse prematurely, skull growth can When 1 or more sutures fuse prematurely, skull growth can be restricted perpendicular to the suture. If multiple sutures be restricted perpendicular to the suture. If multiple sutures fuse while the brain is still increasing in size, fuse while the brain is still increasing in size, intracranial intracranial pressurepressure can increase. can increase.

Cause: a primary defect in the mesenchymal layer Cause: a primary defect in the mesenchymal layer ossification in the cranial bones. ossification in the cranial bones.

A gene locus for single suture craniosynostosis has not A gene locus for single suture craniosynostosis has not been identified.been identified.

ScaphocephalyScaphocephaly - Early fusion of the - Early fusion of the sagittalsagittal suture suture

Ant. plagiocephalyAnt. plagiocephaly - Early fusion of 1 - Early fusion of 1 coronal suturecoronal suture

Post. plagiocephalyPost. plagiocephaly - Early closure of 1 - Early closure of 1 lambdoid suturelambdoid suture

BrachycephalyBrachycephaly - Early bilateral - Early bilateral coronal suturecoronal suture fusion fusion

TrigonocephalyTrigonocephaly - Early fusion of the - Early fusion of the metopic suturemetopic suture

Secondary craniosynostosisSecondary craniosynostosis

More frequentMore frequent Early fusion of sutures due to Early fusion of sutures due to primary failure of brain growth primary failure of brain growth Intracranial pressure usually is normal, and surgery seldom Intracranial pressure usually is normal, and surgery seldom

is neededis needed Intrauterine space constraints may play a role in the Intrauterine space constraints may play a role in the

premature fusion of sutures in the fetal skull. This has been premature fusion of sutures in the fetal skull. This has been demonstrated in coronal craniosynostosis demonstrated in coronal craniosynostosis

MicrocephalyMicrocephaly usually suggests a secondary usually suggests a secondary craniosynostosiscraniosynostosis

Secondary craniosynostosisSecondary craniosynostosis EndocrineEndocrine Hyperthyroidism, hypophosphatemia, vitamin D deficiency, Hyperthyroidism, hypophosphatemia, vitamin D deficiency,

renal osteodystrophy, hypercalcemia, and ricketsrenal osteodystrophy, hypercalcemia, and rickets

Hematologic disordersHematologic disorders Which cause bone marrow hyperplasia (eg, sickle cell Which cause bone marrow hyperplasia (eg, sickle cell

disease, thalassemia)disease, thalassemia)

Inadequate brain growthInadequate brain growth Microcephaly and its causes and shunted hydrocephalusMicrocephaly and its causes and shunted hydrocephalus

Syndromic CraniosynostosisSyndromic Craniosynostosis

Craniosynostosis sometimes is associated with sporadic Craniosynostosis sometimes is associated with sporadic craniofacial syndromes such as craniofacial syndromes such as Crouzon, Apert, Chotzen, Crouzon, Apert, Chotzen, Pfeiffer, or Carpenter syndromes.Pfeiffer, or Carpenter syndromes.

In this context, facial features, typically In this context, facial features, typically craniofacial craniofacial abnormalities, suture ridging, and early closure of abnormalities, suture ridging, and early closure of fontanellesfontanelles, suggest the diagnosis., suggest the diagnosis.

Genetic mutations responsible for Genetic mutations responsible for fibroblast growth factor fibroblast growth factor receptors 2 and 3receptors 2 and 3


Incidence in the US: Incidence in the US: 0.04 ~ 0.1%0.04 ~ 0.1%

2~8%2~8% had primary craniosynostosis, others were had primary craniosynostosis, others were secondary craniosynostosissecondary craniosynostosis

Sagittal 50-58%Sagittal 50-58%, coronal 20-29%, metopic 4-10%, , coronal 20-29%, metopic 4-10%, and lambdoid 2-4%. and lambdoid 2-4%.


Raised intracranial pressure is rare with fusion of a single Raised intracranial pressure is rare with fusion of a single suture. It can occur in primary craniosynostosis when suture. It can occur in primary craniosynostosis when multiple sutures fuse. multiple sutures fuse.

Signs include sun-setting eyes, papilledema, vomiting, and Signs include sun-setting eyes, papilledema, vomiting, and lethargy. lethargy.

Craniosynostosis of 1-2 sutures: Cosmetic defect is the Craniosynostosis of 1-2 sutures: Cosmetic defect is the primary morbidity.primary morbidity.

Diagnosis of CraniosynostosisDiagnosis of Craniosynostosis

Image studies:Image studies: 1. Skull X-ray with AP, lat. and water view1. Skull X-ray with AP, lat. and water view 2. Cranial CT scan with 3-dimensional 2. Cranial CT scan with 3-dimensional

reconstructionreconstruction

Endocrine evaluation: Order thyroid and parathyroid Endocrine evaluation: Order thyroid and parathyroid studies when associated features suggest these studies when associated features suggest these diagnoses.diagnoses.

Treatment of CraniosynostosisTreatment of Craniosynostosis

In patients with microcephaly, investigate the causeIn patients with microcephaly, investigate the cause

Carefully monitor signs and symptoms of elevated Carefully monitor signs and symptoms of elevated intracranial pressureintracranial pressure

Surgery typically is indicated for increased Surgery typically is indicated for increased intracranial pressure or for cosmetic reasons.intracranial pressure or for cosmetic reasons.

Treatment of CraniosynostosisTreatment of Craniosynostosis

Do not operate in patients without IICP until Do not operate in patients without IICP until the the shape of the head does not improve by shape of the head does not improve by age 2-4 age 2-4 monthsmonths, then the abnormality is unlikely to resolve , then the abnormality is unlikely to resolve with agewith age

Cosmetic surgery is performed in infants Cosmetic surgery is performed in infants aged 3-6 aged 3-6 monthsmonths in the author's practice in the author's practice

Cloverleaf skull Cloverleaf skull syndromesyndrome

Cloverleaf Skull SyndromeCloverleaf Skull Syndrome

Kleeblattschädel (ie, Kleeblattschädel (ie, cloverleaf skull)cloverleaf skull) results results from fusion of all sutures from fusion of all sutures except the except the metopic and metopic and squamosal suturessquamosal sutures, giving , giving the head a cloverleaf the head a cloverleaf appearanceappearance


Cloverleaf skull or kleeblattschadel is a rare Cloverleaf skull or kleeblattschadel is a rare malformation caused by synostosis of multiple malformation caused by synostosis of multiple cranial sutures. cranial sutures.

It can be associated with It can be associated with hydrocephalus, proptosis, hydrocephalus, proptosis, and hypoplasia of the midface and cranial baseand hypoplasia of the midface and cranial base


Many syndrome present with cloverleaf skull Many syndrome present with cloverleaf skull including most of the acrocephalopolysyndactylies including most of the acrocephalopolysyndactylies (Crouzon, Pfeiffer, Carpenter, Apert…)(Crouzon, Pfeiffer, Carpenter, Apert…)

It is also typical of the type II form of thanatophoric It is also typical of the type II form of thanatophoric dysplasia (another FGFR mutation).dysplasia (another FGFR mutation).


Differential diagnosisDifferential diagnosis

1. Crouzon syndrome1. Crouzon syndrome

2. Apert syndrome2. Apert syndrome

3. 3. Pfeiffer syndromePfeiffer syndrome 4. Carpenter syndrome4. Carpenter syndrome 5. Thanatophoric dysplasia type II5. Thanatophoric dysplasia type II

Crouzon SyndromeCrouzon Syndrome

Coronal and sagittal Coronal and sagittal sutures are most sutures are most commonly involved commonly involved

Cloverleaf skull is rare and Cloverleaf skull is rare and occurs in the most occurs in the most severely affected severely affected individuals. individuals.

Hydrocephalus Hydrocephalus (progressive in 30%) (progressive in 30%)

Crouzon SyndromeCrouzon 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 SyndromeCrouzon Syndrome Other skeletal featuresOther skeletal features

Block fusions involving multiple vertebrae, Cervical fusion (18%), Block fusions involving multiple vertebrae, Cervical fusion (18%), C2-C3 and C5-C6 C2-C3 and C5-C6

Subluxation of the radial heads , Ankylosis of the elbowsSubluxation of the radial heads , Ankylosis of the elbows Skin Skin Approximately 5% of patients have Approximately 5% of patients have acanthosis nigricansacanthosis nigricans, which is , which is

detectable after infancy. The hallmark of these lesions is a darkened detectable after infancy. The hallmark of these lesions is a darkened thickened skin with accentuated markings and a velvety feelthickened skin with accentuated markings and a velvety feel

Central nervous systemCentral nervous system Approximately Approximately 73% of patients have chronic tonsillar herniation73% of patients have chronic tonsillar herniation. .

Of these, 47% have progressive hydrocephalus.Of these, 47% have progressive hydrocephalus. Syringomyelia may be present.Syringomyelia may be present.

Apert SyndromeApert Syndrome

Coronal sutures most Coronal sutures most commonly are involved commonly are involved

Large late-closing fontanels Large late-closing fontanels Gaping midline defect Gaping midline defect Rare cloverleaf skull anomaly is Rare cloverleaf skull anomaly is

found in approximately found in approximately 4%4% of of infants infants

Apert SyndromeApert Syndrome

Extremities and digitsExtremities and digits SyndactylySyndactyly involves the hands and involves the hands and

feet with partial-to-complete fusion feet with partial-to-complete fusion of the digits of the digits

Upper limbsUpper limbs are affected more are affected more severely severely

Central nervous systemCentral nervous system Intelligence varies from Intelligence varies from

normal to mental deficiencynormal to mental deficiency Papilledema and optic Papilledema and optic

atrophy with loss of vision atrophy with loss of vision

Apert SyndromeApert Syndrome SkinSkin

Hyperhidrosis (common) Hyperhidrosis (common)

Cardiovascular (10%)Cardiovascular (10%) ASD, PDA, VSD, PS, Overriding aorta, CoA, Dextrocardia, TOF, Endocardial ASD, PDA, VSD, PS, Overriding aorta, CoA, Dextrocardia, TOF, Endocardial

fibroelastosisfibroelastosis

Genitourinary (9.6%)Genitourinary (9.6%) Polycystic kidneys, Duplication of renal pelvis, etc..Polycystic kidneys, Duplication of renal pelvis, etc..

Gastrointestinal (1.5%)Gastrointestinal (1.5%) Pyloric stenosis, Esophageal atresia and tracheoesophageal fistula, etc..Pyloric stenosis, Esophageal atresia and tracheoesophageal fistula, etc..

Respiratory (1.5%)Respiratory (1.5%) Anomalous tracheal cartilage, Tracheoesophageal fistula, Pulmonary aplasia, Anomalous tracheal cartilage, Tracheoesophageal fistula, Pulmonary aplasia,

Absent right middle lobe of lung, Absent interlobular lung fissuresAbsent right middle lobe of lung, Absent interlobular lung fissures

Pfeiffer Syndrome Pfeiffer Syndrome

Skull is prematurely fused and Skull is prematurely fused and unable to grow normallyunable to grow normally

Bulging wide-set eyes due to Bulging wide-set eyes due to shallow eye sockets (shallow eye sockets (occular occular proptosis)proptosis)

Underdevelopment of the Underdevelopment of the midface midface

Broad, short thumbs and big Broad, short thumbs and big toestoes

Possible webbing of the hands Possible webbing of the hands and feetand feet

Carpenter's Syndrome Carpenter's Syndrome Head and neck:Head and neck: Craniosynostosis Craniosynostosis

first involving the first involving the sagittal and sagittal and lambdoidlambdoid sutures later extending sutures later extending to the coronal sutures. Cloverleaf to the coronal sutures. Cloverleaf skull may occurskull may occur

Ears:Ears: Low set ears and Low set ears and preauricular fistulae.preauricular fistulae.

Eyes:Eyes: Hypertelorism, mildly Hypertelorism, mildly downward slanting of the downward slanting of the palpebral fissures, epicanthic palpebral fissures, epicanthic folds, microcornea, corneal folds, microcornea, corneal opacity, and optic atrophyopacity, and optic atrophy

Nose:Nose: Flat nasal bridge. Flat nasal bridge.

Mouth and oral structures:Mouth and oral structures: A A narrow or highly arched palate.narrow or highly arched palate.

Hand and foot:Hand and foot: The fingers are The fingers are short and stubby with agenesis short and stubby with agenesis of the middle phalanges and of the middle phalanges and soft tissue soft tissue syndactylysyndactyly, , especially of the third and fourth especially of the third and fourth fingers. fingers.

Cardiovascular system:Cardiovascular system: About About one third of all cases one third of all cases

Growth and development:Growth and development: Growth retardation is a constant Growth retardation is a constant featurefeature. Mental retardation is . Mental retardation is common but not constant.common but not constant.

Thanatophoric DysplasiaThanatophoric Dysplasia Severe growth deficiency with an Severe growth deficiency with an

average length of 40 cm at termaverage length of 40 cm at term

A macrocephalic head with a frontal A macrocephalic head with a frontal bossing, a flattened nasal bridge, bossing, a flattened nasal bridge, and proptotic eyesand proptotic eyes

In TD 2, a In TD 2, a cloverleaf-shaped skullcloverleaf-shaped skull resulting from premature closure of resulting from premature closure of the cranial suturesthe cranial sutures

Narrow thorax with small ribsNarrow thorax with small ribs

Micromelic limbs with brachydactylyMicromelic limbs with brachydactyly

Protuberant abdomenProtuberant abdomen

Hydrocephalus and other cerebral Hydrocephalus and other cerebral parenchymal abnormalitiesparenchymal abnormalities


Genetic anomalies: Most are de novo mutation of the FGFR1-3.

ex: 1. Crouzon diseaseFGFR2 2. Thanatophoric dysplasiaFGFR3

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.

A baby with cloverleaf skull anomaly

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