1. A baby with cloverleaf skull anomaly R 3 羅永邦 Supervisors: Drs. 許瓊心, 林炫沛 & 邱南昌

2. Admission Data  Name: 黃 xx 之女 ( 張 xx)  Number: 3619275-6  Sex: Female  Admission Date: 94/05/30  Chief complaints: 1. Prematurity (GA: 32 weeks) 1. Prematurity (GA: 32 weeks) 2. Respiratory distress 2. Respiratory distress 3. Congenital anomaly 3. Congenital anomaly

3. 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.

4. Present Illness  Due to fetal distress (HR: 80-90/min), emergency C/S was performed. The Apgar score 7 1  9 5. The Apgar score 7 1  9 5.  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. further treatment and evaluation.

5. Present Illness  Birth history: DOB on 94/05/30 at 22:26 DOB on 94/05/30 at 22:26 EDC: 94/07/20 EDC: 94/07/20 GA: 32 + weeks, BBW: 1,910gm GA: 32 + weeks, BBW: 1,910gm Via C/S due to fetal distress Via C/S due to fetal distress Apgar score: 7 1  9 5 Apgar score: 7 1  9 5 PPROM noted since 05/12 PPROM noted since 05/12 Prenatal ampicillin since 05/12 Prenatal ampicillin since 05/12 Prenatal steroid x2 doses Prenatal steroid x2 doses

6. Present Illness  Maternal history G1P1 healthy mother G1P1 healthy mother No GDM, HTN, Toxemia, APH, PPH No GDM, HTN, Toxemia, APH, PPH URI(-), Fever(-) URI(-), Fever(-) HBsAg(-), HBeAg(-) HBsAg(-), HBeAg(-)

7. Family History 28 years old BG: AB 電子業 34 years old BG: AB 電子業

8. 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

9. 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

10. Physical Examination Frontal area bossing Pseudo low set ears Exophthalmos

11. 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

12. Laboratory Data (5/30) CBC 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% Chemistry Dex: 38 mg/dl, Na: 145 mEq/L K: 4.9 mEq/dl, Free Ca: 1.19 mmol/L Arterial Blood Gas PH: 7.332, PaCO2: 45.9 mmHg, PaO2: 124.1mmHg, HCO3: 23.8 mmol/L BE: -2.1 mmol/L

13. Laboratory Data (5/30) CSF Glucose: 38 mg/dL, Protein: 179 mg/dL RBC: 58 /CMM, WBC: 2 /CMM L : N = 0 : 2 血清病毒 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) Immune Total IgM: 9 mg/dL

14. 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.

15. 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 Crouzon syndrome r/o Thanatophoric dysplasia r/o Thanatophoric dysplasia r/o Craniosynostosis r/o Craniosynostosis

16. Hospital Course  Initial management: 1. On ETT + IMV 1. On ETT + IMV 2. N/S challenge first, then add Dopamine (5/30~5/31) 2. N/S challenge first, then add Dopamine (5/30~5/31) 3. Ampicillin and gentamicin (5/30~6/06) for suspected congenital infection 3. Ampicillin and gentamicin (5/30~6/06) for suspected congenital infection

17. 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

18. 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 Blood culture (5/30): no growth CSF culture (5/30): no growth Chromosome study 46, XX, normal

19. 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

20. Hospital Course  Consult Ophthalmologist:  Incomplete regression of hyaloid vessels;  Incomplete regression of hyaloid vessels; Vessels constriction of left eye Vessels 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

21. 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 on 6/03

22. 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.

23. Brain MRI (6/03)

24. 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.

26. 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. 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. 2. Dilatation of the lateral ventricles and presence of cavum septum pellucidum and cavum vergae. 3. Pachygyria. 3. Pachygyria. 4. Small posterior fossa and cerebellar tonsilar herniation. 4. Small posterior fossa and cerebellar tonsilar herniation. 5. Absent posterior septum pellucidum. 5. Absent posterior septum pellucidum.

27. 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.

28. Brain CT (6/09)

30. 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.

31. Brain CT (6/09)  Impression: 1. Cloverleaf skull syndrome. 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. 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. 3. Absent posterior septum pellucidum.

32. 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 27.5 cm to 29 cm  Brain echo (6/15): Progressing ventriculomegaly, bilateral Progressing ventriculomegaly, bilateral Hydrocephalus, non-communicating type Hydrocephalus, non-communicating type Pachygyria, suspect lissencephaly Pachygyria, suspect lissencephaly High RI (1.0) High RI (1.0)

33. Hospital Course  IICP was highly suspected, so CSF tapping was performed, however, reddish CSF fluid was noted  Lab data (1) Lab data (1) Lab data (1)  Lab data (2) Lab data (2) Lab data (2)  CXR CXR  Brain CT (6/15): 1. Cloverleaf skull syndrome. 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. 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. 3. Absent posterior septum pellucidum.

34. Laboratory Data (6/15) CBC Hgb: 13.6 g/dL, Hct: 40.2% WBC: 10,600/uL, Platelet: 313,000/uL Band: 0%, Neut: 38%, Eosin: 1% Baso: 0%, Monocyte: 8%, Lym: 53% 血清病毒 CRP: <0.1 mg/dL Arterial blood gas PH: 7.469, PaCO2: 25.7 mmHg PaO2: 66.5 mmHg, HCO3: 18.2 mmol/L B.E ： -5.5 mmol/L

35. Laboratory Data (6/16) CSF Glucose: 42 mg/dL, Protein: 65 mg/dL RBC: 37/CMM, WBC: 1/CMM, L : N =1:0 Chemistry Glucose: 54 mg/dL, Na: 141 mEq/L K: 5.4 mEq/L, Cl: 109 mEq/L, Ca: 10.1 mg/dL Coagulation PT: 10.8 sec (control: 11.0) APTT: 39.2 sec (control: 30.0), INR: 0.96 (<2) Culture Blood culture: no growth CSF culture: no growth Throat & rectal virus cultures: no growth yet

36. CXR (6/15)  CXR (6/15): The follow up chest condition shows stable as compared with the last exam. with the last exam.

37. 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~)

38. 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

39. 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

40. Hospital Course  However, further genetic study had ruled out the possibility of thanatophoric dysplasia  Newborn screen: normal  Newborn screen: normal  Tandem mass: normal  Tandem mass: normal  Sequencing of FGFR3 gene: normal  Sequencing of FGFR3 gene: normal  PCR study of FGFR2 gene: pending  PCR study of FGFR2 gene: pending

41. 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)

42. Hospital Course (7/07)

43.  At this point, she would get bradycardia easily if you press on her anterior fontanel gently

44. Hospital Course (7/15)

45. 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

46. Discussion 1. Craniosynostosis 2. Cloverleaf skull syndrome

47. Craniosynostosis  Primary craniosynostosis: a primary defect of ossification  Secondary craniosynostosis: a failure of brain growth, more commonly  Syndromic craniosynostosis: display other body deformities

48. Craniosynostosis  Simple craniosynostosis: only 1 suture fuses prematurely  Complex or compound craniosynostosis: premature fusion of multiple sutures

49. 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.

50. 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.

51. Scaphocephaly - Early fusion of the sagittal suture

52. Ant. plagiocephaly - Early fusion of 1 coronal suture Post. plagiocephaly - Early closure of 1 lambdoid suture

53. Brachycephaly - Early bilateral coronal suture fusion

54. Trigonocephaly - Early fusion of the metopic suture

55. 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

56. Secondary craniosynostosis  Endocrine Hyperthyroidism, hypophosphatemia, vitamin D deficiency, renal osteodystrophy, hypercalcemia, and rickets Hyperthyroidism, hypophosphatemia, vitamin D deficiency, renal osteodystrophy, hypercalcemia, and rickets  Hematologic disorders Which cause bone marrow hyperplasia (eg, sickle cell disease, thalassemia) Which cause bone marrow hyperplasia (eg, sickle cell disease, thalassemia)  Inadequate brain growth Microcephaly and its causes and shunted hydrocephalus Microcephaly and its causes and shunted hydrocephalus

57. 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

58. 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%.

59. 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.

60. Diagnosis of Craniosynostosis  Image studies: 1. Skull X-ray with AP, lat. and water view 1. Skull X-ray with AP, lat. and water view 2. Cranial CT scan with 3-dimensional reconstruction 2. Cranial CT scan with 3-dimensional reconstruction  Endocrine evaluation: Order thyroid and parathyroid studies when associated features suggest these diagnoses.

61. 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.

62. 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

63. Cloverleaf skull syndrome

64. 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

65. Cloverleaf Skull Syndrome

66.  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

67. 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).

68. Cloverleaf Skull Syndrome  Differential diagnosis 1. Crouzon syndrome 1. Crouzon syndrome 2. Apert syndrome 2. Apert syndrome 3. Pfeiffer syndrome 3. Pfeiffer syndrome 4. Carpenter syndrome 4. Carpenter syndrome 5. Thanatophoric dysplasia type II 5. Thanatophoric dysplasia type II

69. 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%)

70. 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

71. Crouzon Syndrome  Other skeletal features Block fusions involving multiple vertebrae, Cervical fusion (18%), C2-C3 and C5-C6 Block fusions involving multiple vertebrae, Cervical fusion (18%), C2-C3 and C5-C6 Subluxation of the radial heads, Ankylosis of the elbows 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 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. Approximately 73% of patients have chronic tonsillar herniation. Of these, 47% have progressive hydrocephalus. Syringomyelia may be present. Syringomyelia may be present.

72. 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

73. Apert Syndrome  Extremities and digits Syndactyly involves the hands and feet with partial-to-complete fusion of the digits Syndactyly involves the hands and feet with partial-to-complete fusion of the digits Upper limbs are affected more severely Upper limbs are affected more severely  Central nervous system Intelligence varies from normal to mental deficiency Papilledema and optic atrophy with loss of vision

74. Apert Syndrome  Skin Hyperhidrosis (common) Hyperhidrosis (common)  Cardiovascular (10%) ASD, PDA, VSD, PS, Overriding aorta, CoA, Dextrocardia, TOF, Endocardial fibroelastosis ASD, PDA, VSD, PS, Overriding aorta, CoA, Dextrocardia, TOF, Endocardial fibroelastosis  Genitourinary (9.6%) Polycystic kidneys, Duplication of renal pelvis, etc.. Polycystic kidneys, Duplication of renal pelvis, etc..  Gastrointestinal (1.5%) Pyloric stenosis, Esophageal atresia and tracheoesophageal fistula, etc.. 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 Anomalous tracheal cartilage, Tracheoesophageal fistula, Pulmonary aplasia, Absent right middle lobe of lung, Absent interlobular lung fissures

75. 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

76. Carpenter's Syndrome  Head and neck: Craniosynostosis first involving the sagittal and lambdoid sutures later extending to the coronal sutures. Cloverleaf skull may occur  Ears: Low set ears and preauricular fistulae.  Eyes: Hypertelorism, mildly downward slanting of the palpebral fissures, epicanthic folds, microcornea, corneal opacity, and optic atrophy  Nose: Flat nasal bridge.  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.  Cardiovascular system: About one third of all cases  Growth and development: Growth retardation is a constant feature. Mental retardation is common but not constant.

77. 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

78. Head & Neck Extremities Crouzon Syndrome Apert syndrome Coronal sutures most commonly are involved Pfeiffer syndrome Carpenter's Syndrome Sagittal and lambdoid sutures later extending to the coronal sutures Thanatophoric dysplasia type II

79. Craniosynostosis Crouzon Syndrome Apert syndrome Pfeiffer syndrome Carpenter's Syndrome sagittal and lambdoid sutures later extending to the coronal sutures Thanatophoric dysplasia type II

80. Cause Crouzon Syndrome Apert syndrome Pfeiffer syndrome Carpenter's Syndrome Thanatophoric dysplasia type II

81. Cloverleaf Skull Syndrome   Genetic anomalies: Most are de novo mutation of the FGFR 1-3. 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.