Noonan Syndrome and Cavernous Hemangioma ofthe Brain

Yukichi Tanaka,1* Mitsuo Masuno,2 Hiroko Iwamoto,3 Noriko Aida,4 Rieko Ijiri,1 Shoji Yamanaka,1Kiyoshi Imaizumi,2 and Yoshikazu Kuroki2

1Department of Pathology, Kanagawa Children’s Medical Center, Yokohama, Japan2Department of Medical Genetics, Kanagawa Children’s Medical Center, Yokohama, Japan3Department of Neurology, Kanagawa Children’s Medical Center, Yokohama, Japan4Department of Radiology, Kanagawa Children’s Medical Center, Yokohama, Japan

We present two patients with multiple char-acteristics that occur in Noonan phenotypeand cavernous hemangioma of the brain.The first patient, who had been diagnosedradiographically as having a cavernoushemangioma in the left basal ganglia at age15 years, developed massive intracerebralhemorrhage, resulting in sudden death athome at 19 years. The second patient, whowas diagnosed radiographically as having acavernous hemangioma in the left parietallobe at age 17 years, is being followed care-fully (the patient is currently 18 years old).A review disclosed four cases of structuralcerebrovascular abnormalities with orwithout subsequent hemorrhage. Neitherthese four patients nor our two patients hadany severe anomalies in the heart or largevessels, which are frequently seen in pa-tients with Noonan syndrome. Cerebrovas-cular abnormalities might have a signifi-cant influence on the prognosis of patientswith Noonan syndrome, especially thosehaving no severe abnormalities in the heartor large vessels. Am. J. Med. Genet. 82:212–214, 1999. © 1999 Wiley-Liss, Inc.

KEY WORDS: Noonan syndrome; cavern-ous hemangioma; brain; sud-den death

INTRODUCTION

Noonan syndrome (NS) is a relatively common syn-drome of multiple congenital abnormalities establishedby Noonan [1968]. It is thought to be an autosomaldominant trait with a prevalence of 1/1,000 to 1/2,500

in live births. NS patients have short stature; webbedneck; hypertelorism; downward slant of palpebral fis-sures; blepharoptosis; apparently low-set ears; smallmandible; low posterior hairline; cubitus valgus; shortfifth finger with clinodactyly; wide-spaced nipples;sternal and/or vertebral deformities; mental retarda-tion; and frequently cardiovascular anomalies repre-sented by pulmonary stenosis and hypertrophic cardio-myopathy. Occasionally, the peripheral vascular sys-tem is also involved [Daoud et al., 1995], butcerebrovascular abnormalities in NS are not common.In this article we report two NS patients with cavern-ous hemangioma of the brain, which ruptured andcaused sudden death in one patient.

CLINICAL REPORTSPatient 1

The patient, a boy, was the first child of healthy non-consanguineous Japanese parents. The mother was 26years old and the father 30 years old at the time of thepatient’s birth. A healthy daughter was born threeyears later. The mother had no history of abortions orstillbirths. The patient was born at 39 weeks of gesta-tion by vacuum extraction after an uneventful preg-nancy. Apgar score was 10 at one min. The patient’sbirth weight was 4,350 g (+2.9 SD), length 52.5 cm(+1.6 SD), and OFC 38.0 cm (+3.2 SD). The patient wasfirst evaluated by us at age 2 4/12 years because ofmental retardation. His height was 80.3 cm (−2.2 SD),weight 10.9 kg (−1.1 SD), and OFC 52.0 cm (+2.2 SD).He had frontal bossing; hypertelorism; downward slantof palpebral fissures; exotropia; broad nasal bridge; an-teverted nares; high-arched palate; low-set ears;webbed neck; pectus excavatum; wide-set nipples; cu-bitus valgus; and clinodactyly of the fifth fingers. Adiagnosis of NS was made. Echocardiographic statuswas normal. He had normal chromosomes. Bleedingand clotting times were normal. Results of other labo-ratory tests, including serum chemistry, completeblood count, immunoglobulin, thyroid function, andurinalysis were normal. He lifted his head at age 6months and sat alone at 10 months. He could walkunaided at age 1 11/12 year and spoke meaningful

*Correspondence to: Yukichi Tanaka, M.D., Department of Pa-thology, Kanagawa Children’s Medical Center, Mutsukawa2-138-4, Yokohama 232, Japan.

Received 8 January 1998; Accepted 7 October 1998

American Journal of Medical Genetics 82:212–214 (1999)

© 1999 Wiley-Liss, Inc.

words at 3 8/12 years. Intelligence quotient was 40 atage 11 years. At age 15 years, electroencephalogramshowed paroxysmal spikes on the left frontal and cen-tral regions at light sleep records. Brain magnetic reso-nance imaging (proton density-weighted imaging) per-formed at age 15 years disclosed a popcorn-like, highintensity lesion in the right lentiform nucleus (Fig. 1).At 17 years the patient’s height was 146.8 cm (−4.2SD), weight 34 kg (−2.9 SD), and OFC 56.1 cm (mean).At 18 years height was 155 cm (−2.8 SD), weight 35.7kg (−2.8 SD), and OFC 56.5 cm (+0.5 SD). The findingsof neurological examinations were unremarkable. Thepatient had been doing well, but he died suddenly athome when he was 18 years old. Autopsy was per-formed about three hours after the discovery of hisdeath. There were no pathognomonic changes in thechest-abdominal viscera. The heart showed no signifi-cant structural abnormalities except high take-off coro-nary arteries. Coronal cut sections of the brain weigh-ing 1,685 g demonstrated two isolated foci of hemor-rhage in the right lentiform nucleus (Fig. 2A) and theright occipital lobe. The latter ruptured into the rightlateral ventricle, resulting in intraventricular hemor-rhage. Microscopically, the hemorrhagic foci in theright lentiform nucleus (28 × 27 × 24 mm) consisted ofruptured cavernous hemangioma, i.e., closely apposedenlarged vessels composed solely of fibrous tissue,mingled with secondary thrombosis, and dystrophiccalcification (Fig. 2B). No intervening neuroglial tissuewas observed. Disappearance of the myelin sheath andpresence of spheroid bodies were found around this le-sion. Another hemorrhagic lesion found in the rightoccipital lobe was fresh and not organized. This lesionwas considered a secondary change caused by the rup-ture of the cavernous hemangioma in the right basalganglia. No clear hemangiomatous lesions were ob-served in the other organs and tissues. Other remark-able autopsy findings included heterotopic splenic tis-sue in the pancreas tail and chronic thyroiditis, whichhas been described in NS patients.

Patient 2

This girl was the only child of a 33-year-old motherand an unrelated 39-year-old father. A previous preg-nancy had resulted in an early spontaneous abortion.The mother had had two healthy daughters with herformer husband. The patient was born at 38 weeks ofgestation after an uneventful pregnancy, labor, and de-livery. There was no neonatal asphyxia. The patient’sbirth weight was 3,300 g (+0.5 SD), length 49 cm(mean), and OFC 32.5 cm (−0.5 SD). She was firstevaluated by us at age 1 month because of a heartmurmur possibly associated with pulmonary valve ste-nosis. However, the heart murmur gradually disap-peared and no significant cardiovascular lesions weredetected. External anomalies included hypertelorism;epicanthus; blepharoptosis; downward slant of palpe-bral fissures; sparse lateral eyebrows; open mouth;low-set ears; and hyperelastic skin. Chromosomalanalysis demonstrated a 46,XX karyotype. A diagnosisof NS was made. The patient lifted her head at age 10months and was able to sit unaided at age 3 years. Shecould walk without support at age 4 2/12 years andspoke meaningful words at 5 years. She has sufferedfrom frequent vomiting since age 6 years. At 13 yearsshe was admitted to our hospital because of hematem-

Fig. 1. Brain magnetic resonance imaging (proton density-weighted im-aging; TR/TE: 2000/38) of Patient 1 at age 15 years. A popcorn-like high-intensity lesion is seen in the right lentiform nuclei.

Fig. 2. Autopsy findings of Patient 1. A: A coronal cut section of thebrain of Patient 1, demonstrating a well-defined hemorrhagic lesion in-volving the right basal ganglia, and intraventricular hemorrhage. B: His-tology of the lesion, showing proliferating vessels with a thin wall and focalcalcification (HE stain, × 150).

Noonan Syndrome With Cerebral Hemangioma 213

esis and convulsions due to hyponatremia. A perforatedduodenal ulcer was found and subtotal gastrectomywas performed. The first seizure, a generalized tonicconvulsion, occurred at age 17 years. Electroencepha-logram showed frequent positive spikes, phantomspikes, and wave bursts at both awake and very lightsleep records. Anticonvulsant therapy was adminis-tered thereafter. Computed tomography of the headshowed a faint calcified lesion in the left parietal lobe.Magnetic resonance imaging of the head showed a lowsignal hemosiderin rim on T2-weighted images thatsurrounded a well-defined core of mixed signal inten-sities on T1-weighted images. These findings werecompatible with a diagnosis of cavernous hemangiomawith old hemorrhage. Platelet number, activated par-tial thromboplastin time, and prothrombin time werenormal. Coagulation factor activities (VIII:C, 135.2%;XI:C, 137.3%) were normal, but a partial factor XII:Cdeficiency (45.0%) was detected. Results of other labo-ratory tests, including serum chemistry, completeblood count, immunoglobulin, and urinalysis, were nor-mal. On imaging, the lesion was found to measure lessthan 15 mm at its greatest dimension. The patient hasbeen followed carefully, and surgery is being consid-ered. At 17 years the patient had her first menstrua-tion. Her intelligence is moderately retarded. The find-ings on neurological examinations were unremarkable.Her height was 129.4 cm (−5.7 SD), weight 30.4 kg(−3.2 SD), and OFC 55.0 cm (mean). She is doing wellat present.

DISCUSSION

Apart from mental retardation, several neurologicaldeficits and structural abnormalities of the nervoussystem have been described in NS patients. To date,four NS cases with structural cerebrovascular abnor-malities have been reported [Hara et al., 1993; Hin-nant, 1995; McAnena et al., 1984; Schon et al., 1992].Schon et al. [1992] described a 35-year-old man with‘‘severe cerebral arteriovenous malformation,’’ andMcAnena et al. [1984] presented a 36-year-old manwith ‘‘posterior communicating artery aneurysm.’’Hara et al. [1993] documented a 19-year-old man withvarious vascular anomalies on angiography, includinga small aneurysm that resulted in subarachnoid hem-orrhage. Hinnant [1995] reported a 15-year-old girlwith thromboembolic infarcts and probable hypoplasiaof the posterior cerebral vessels. In addition, Robertsonet al. [1997] reported a 10-month-old boy with no struc-tural cerebral abnormality who suffered two episodesof cerebral infarction. There have been no reports men-tioning cavernous hemangioma occurring in NS pa-tients.

Both of our patients had a solitary cavernous hem-angioma in the cerebrum. Radiographic and histopath-ological findings of the left basal ganglia in Patient 1mostly favored ruptured cavernous hemangioma withboth old and fresh hemorrhage. Fresh hemorrhage inthe right posterior lobe seemed secondary to the rup-ture of the cavernous hemangioma in the left basalganglia, although the presence of posterior circulationabnormality, which has been demonstrated by McAn-ena et al. [1984] and Hinnant [1995], cannot completelybe ruled out as a factor. Radiographic finding of thelesion in the left parietal lobe in Patient 2 was consis-tent with cavernous hemangioma. A review, combinedwith our two cases, suggests that cerebrovascular ab-normalities are more common in NS patients thanthought previously. Like hypertrophic cardiomyopa-thy, pulmonary valve stenosis, and manifestations ofcutaneous vasculature, including hemangioma, lymph-angioma, and lymphedema [Daoud et al., 1995], cere-brovascular abnormalities support the suggestion ofvascular dysgenesis based on mesenchymal disorder inNS patients.

As pointed out by Ball and Peiris [1982], neurologicalcomplications due to structural lesions might be under-reported in NS patients because the associated mentalretardation may conceal neurological symptoms andsigns, and because clinical course can be influenced toa great extent by the presence and degree of cardiovas-cular disease, which might result in death at an earlyage before neurological problems become apparent. Ce-rebrovascular abnormalities should be investigatedcarefully in NS patients, because they might have asignificant influence on the prognosis of these patients,especially those lacking severe cardiac abnormalities,as shown in our Patient 1.

REFERENCESBall MJ, Peiris A. 1982. Chiari (type I) malformation and syringomyelia in

a patient with Noonan’s syndrome. J Neurol Neurosurg Psychiatry45:753–754.

Daoud MS, Dahl PR, Su DWP. 1995. Noonan syndrome. Seminar Dermatol14:140–144.

Hara T, Sasaki T, Miyauchi H, Takakura K. 1993. Noonan phenotypeassociated with intracerebral hemorrhage and cerebral vascularanomalies: case report. Surg Neurol 39:31–36.

Hinnant CA. 1995. Noonan syndrome associated with thromboembolicbrain infarcts and posterior circulation abnormalities. Am J Med Genet56:241–244.

McAnena O, Padilla JR, Buckley TF. 1984. Intracranial aneurysm in as-sociation with Noonan’s syndrome. Ir Med J 77:140–141.

Noonan JA. 1968. Hypertelorism with Turner phenotype. A new syndromewith associated congenital heart disease. Am J Dis Child 116:373–380.

Robertson S, Tsang B, Aftimos S. 1997. Cerebral infarction in Noonansyndrome. Am J Med Genet 71:111–114.

Schon F, Bowler J, Baraitser M. 1992. Cerebral arteriovenous malforma-tion in Noonan’s syndrome. Postgrad Med J 68:37–40.

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