American J o u r n a l of Medical Genetics 42:346-351 (1992)
Terminal Transverse Limb Defects Associated With Familial Cavernous Angiomatosis Michele R. Filling-Katz,* Sondra W. Levin, Nicholas J. Patronas, and Norman N.K. Katz* Genetics, Exceptional Family Member Program, Department of Pediatrics, Walter Reed Army Medical Center, Washington, DC 20307 (S.W.L.), Department of Pediatrics (S.W.L.) and Division of Ophthalmology, Department of Surgery (N.N.K.K.), Uniformed Services University of the Health Sciences, Bethesda, Maryland; Warren G. Magnuson Clinical Center, Department of Radiology (N.J.P.); Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism (M.R.F.-K.), and Human Genetics Branch, National Institute of Child Health and Human Development (S.W.L.); National Institutes of Health, Bethesda Maryland (N.J.P.) Terminal transverse limb defects rarely are reported as familial. Multiple pathogenetic mechanisms, including vascular disruption, have been proposed to account for these defects. We report on a family followed over the past 6 years known to have familial cavernous angiomatosis in which 2 relatives have similar terminal transverse defects at the mid-forearm. Multiple relatives have had episodic bleeding from intracranial cavernous angiomas, a distinct finding in this disorder. Other findings in this family include retinal cavernous angiomas (2 patients), a high incidence of skin angiomas (12 patients), cavernous angiomas of the soft tissue (2 patients), and a hepatic angioma (one patient). One of the 2 individuals with the limb defect was evaluated extensively. Magnetic resonance imaging of the forearm with the terminal transverse defect using gadolinium-DTPA enhancement showed abrupt termination of all structures distal to the normal radial and ulnar heads. We propose that familial cavernous angiomatosis may be a new cause of vascular disruption resulting in terminal transverse limb defects. KEY WORDS: familial cavernous angiomatosis, angiomas, disruption, limb defect INTRODUCTION Terminal transverse limb defects (TTDs) of the forearm are reported to have an overall incidence of 1 per 25,000 live births [Birch-Jensen, 19491. These defects
are usually sporadic [Czeizel et al., 1983; Hoyme et al., 1982; Nevin et al., 1975; Robinow et al., 19781but have also occurred in some families perhaps due to a dominant trait [Bartoshesky et al., 1986; Graham et al., 1986;Hecht and Scott, 1981a; Soltan and Holmes, 19861. Autosomal recessive inheritance has also been suggested [Hecht and Scott, 1981bl and Brazilian families have been described with recessively inherited TTD of all limbs termed acheiropodia [E’reire-Maia, 19751. Some families inherit defects of the scalp and skull in conjunction with TDD (the Adams-Oliver Syndrome) [Bonafede et al., 1979; Kuster et al., 1988; Scribanu et al., 19751. Multiple pathogeneses of TTD have been proposed including amniotic band disruption sequence and vascular disruption [Bartoshesky et al., 1986; Bouwes Bavinck and Weaver, 1986; Bokesoy et al., 1983; Bouvet et al., 1978; Higginbottom et al., 1979; Hoyme et al., 1982; Soltan et al., 19861. In some instances vascular disruption has been attributed to intrauterine ischemia and secondary necrosis [Webster et al., 19871. Entities including the Hanhart syndrome, Klippel-Feil, Poland, and Mobius anomalies have been so explained [Bouwes Bavinck and Weaver, 1986; Bouvet et al., 1978; Kelln et al., 1968;Soltan and Holmes, 19861. Embryotoxic effects of maternal hyperthermia [Superneau and Wertelecki, 19851, cocaine [Hoyme et al., 19901, and meclizine hydrochloride [Bokesoy et al., 19831have also been implicated in malformation pathogenesis. We report here on a new association of familial cavernous angiomatosis, (McKusick catalogue No. 116860) an autosomal dominant disorder [Clark, 1970; Gass, 1971;Goldberget al., 1979;Hayman et al., 1982;Rigmamonti et al., 19881, with transverse terminal defects.
METHODS AND SUBJECTS The family was ascertained after the diagnosis of the Received for publication March 12,1991; revision received June proposita in January of 1984. Close relatives (marked 18, 1991. with an asterisk Table I) underwent initial evaluations *Deceased. Address reprint requests to Dr. Sondra W. Levin, Exceptional in 1984 and were followed subsequently. The extended Family Member Program, Building 38, Department of Pediatrics, family was evaluated in 1988 and the original relatives Walter Reed Army Medical Center, Washington, D.C.20307-5001. were reevaluated at that time as well (Fig. 1).History
0 1992 Wiley-Liss, Inc.
32 15 80 52 43 17 16 16
ll(V-5) 12(V-14)
13(III-3) 14(IV-3)
15(IV-7) 16(V-13) 17(V-15) 18*(V-12)
Normal
Normal
1 CAL thigh ? Bilateral CA face
Normal Normal
F F
15 36
240'1-2)
250'-9)
Normal
Normal
Normal Normal
Hepatic CA
Normal Normal
Normal Normal Normal Normal
*CA, cavernous angioma; MLH,migraine-like headache; CAL, caf6-au-lait spots; ITD,transverse terminal limb defect.
Normal
Normal Bilateral facial CA, large 6 x 4 cm CA left neck
M Normal M Normal
Hemorrhagic brainstem CA; right occipital CA; 2 hemorrhaeic left frontal EA Normal Normal
59 46
Multiple small CA forehead, hands, thigh
22(IV-4) 23(IV-6)
Small CA left eye
F
Normal Normal Normal Right parietal angioma Normal Normal
22
Normal 6 CA from 1 to 5 cm in size
5 small angiomas thorax, 1-cm CAL Normal Normal Bilateral facial CA; 2 CA hand
21*(V-l1)
19*(IV-5) 59 2O*(VI-12) 8
M Normal F Optic drusen F Normal F Normal M Normal M Large CA right eye M Normal F Normal
F Normal M Normal
Normal
Viscera Normal Normal Left old lacunar in- Normal farction; right frontal angioma Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal
CNS
Normal 3 questionable areas of hyperintensity in centrum semiovale 5 CAL of > 1 cm, 1 small angioma back Normal Normal Bilateral CA face extending into neck, Normal Normal 1 6-cm CAL abdomen Normal Normal Normal 4 small angiomas anterior chest Normal Normal
F
28
lO(V-8)
Normal
Right bulbar telangectesia, 1 angioma back 3 CAL back, 1 angioma left hip
9(V-6)
M F F M M F
M Normal
6 55 16 18 9 42
3*(VI-13) 4(IV-2) W-7) 6(VI-3) 7(vI-4) 8(V-2)
30
1 cm CA forehead Normal
Skin
Normal 3 CA right forearm and stomach Normal Normal Normal 2.5 cm CA abdomen, 1 cm CA right thigh, 1 angioma medial eyelid, multiple small angiomas back
Age Sex Retina 23 F Normal 28 F Normal Normal Normal Normal Normal Normal Normal
Patient 1(V-16) 2*(V-10)
Normal
Normal
Normal Normal
Normal Right lTD Normal
Normal Normal Normal Normal
Normal Normal
Normal Normal
Normal
Normal
Normal Normal Normal Normal Normal Normal
Bone Normal Normal
Normal MLH, multiple small soft tissue angiomas (path) Type _ _ I Waardenburg MLH
Stroke, seizure, MLH
Normal MLH
Normal MLH Normal MLH
MLH MLH, seizure
MLH MLH
MLH
Normal MLH Normal Normal Normal Soft tissue 3 x 3 cm CA, 5 p e I Waardenburg Normal
Other Normal MLH
TABLE I. Findings on Screening Examinations and Radiologic Studies in Large Familial Cavernous Angiomatosis Pedigree*
348
Filling-Katz et al.
I
I1
I11
IV V VI Fig. 1. The pedigree of the family with familial systemic cavernous angiomatosis. 0 Neurologic involvement. 0 Ocular involvement. 0 Visceral involvement. 0 Cutaneous involvement. + Examined. + Pathologic confirmation of cavernous angioma. @ Affected historically or by pedigree analysis. * lTD, not known whether associated with angioma. Skin angiomas significance unknown.
and physical and neurologic examinations including dilated ophthalmoscopy were obtained for each relative. Magnetic resonance imaging (MRI) of the central nervous system (CNS)was performed on all at-risk individuals undergoing evaluation (25 patients). Additional MRI studies were performed in selected cases including the viscera (5 patients), spine (4patients), and the limbs (2 patients). Five relatives were contacted but declined screening evaluation.
RESULTS A total of 25 individuals in this family was evaluated (Table 1). Three living individuals were found to have CNS angiomas (6 lesions) by imaging studies (Table I, Fig. 2). Two relatives have died with historical evidence of CNS angiomas and recurrent hemorrhage, one confirmed by subsequent autopsy. A fourth living individual was suspected of having a CNS lesion based on lateonset seizures (in her fifth decade) but this could not be confirmed on imaging studies. A fifth individual has questionable areas of increased intensity bilaterally seen on T2-weightedMRI in the centrum semiovale of uncertain significance. The proposita (V-11)had recurrent hemorrhage from both the brainstem and frontal cavernous angiomas, and had CNS infarction and multiple residual neurologic deficits. Both of the other individuals with CNS lesions detected by MRI had migraine-like headaches, a common complaint by 13 of the 25 relatives evaluated by us. Two individuals had retinal cavernous angiomas, both confirmed by subsequent fluorescein angiography (Fig. 3). One individual had an asymptomatic hepatic angioma discovered by abdominal computed tomography (CT) and confirmed by MRI. Two individuals had soft tissue cavernous angiomas; one was located on the palm (Fig. 4) and the second located on the chest. The first lesion was imaged by MRI and the second removed in toto after recurrent bleeding. Cav-
ernous angiomas of the skin were common (8 of 25 patients). Many other individuals had small cherry or strawberry angiomas (6of25 patients) including several who also had cavernous angiomas. Two individuals within the family had TTDs of the right mid-forearm. Only one of these 2 with the limb defect permitted evaluation (as described below).
CLINICAL REPORT A 9-year-oldwhite girl was first evaluated by us at age 4 years because of her relationship to a family with familial cavernous angiomatosis (patient 20, Table I). She was the 3,190-gproduct of a 20-year-old GlPO white woman with a 40-week pregnancy marked only by nausea and a single use of bendectin of unknown amount in the first trimester. Examination at birth showed a bloody, partially healed stump in place of the right forearm. Two small, cutaneous angiomas were present on the right leg as well. The placenta was unremarkable. At age 4 she had 4 angiomas (Fig. 5A) which were distributed over the right and left legs and torso. She had a well healed TTD at the level of the mid-forearm (Fig. 5A) without nails or digital remnants. She was otherwise normal. A contrast-enhanced CT of the head was normal. She was reevaluated at age 8 years. She had undergone normal growth and development and was performing well in the second grade. She complained of occasional migraine-like headaches. She had developed 2 new angiomas, for a total of 6, and 2 of the previous 4 had undergone interval growth proportional to body growth. MRIs of the head, abdomen, and forearm were performed prior to and after injection of gadolinium DTPA (Magnevist). The MRIs of the head and abdomen were normal. The MRI of the forearm showed an entirely normal arm terminating abruptly just below the level of the heads of the radius and ulna (Fig. 5B). The brachial artery was seen to be of normal caliber.
Limb Defects and Cavernous Angiomatosis
349
Fig. 4. Photograph of slowly growing soft tissue angioma of the left hand. MRI (not shown) was consistent with a soft tissue cavernous angioma.
350
Filling-Katz et al.
DISCUSSION We describe a family with familial cavernous angiomatosis in which 2 individuals had a severe terminal transverse limb defect. Familial cavernous angiomatosis is an autosomal dominant inherited disorder in which affected individuals have an increased risk of developing cavernous angiomas of the brain, retina, skin, and other visceral organs. Manifestations in the CNS include hemorrhage, stroke, seizure, as well as headache [Bicknell et al., 1978; Rigmamonti et al., 19883. Eye manifestations of cavernous angiomas are rare [Gass, 19711. Some predominantly Hispanic families have been described with CNS involvement alone excluding the retina [Bicknell et al., 1978; Hayman et al., 1982; Rigmamonti et al., 19881,whereas other families manifest more diffuse involvement including retina and skin [Gass, 1971; Goldberg et al., 1979; Weskamp and Cotlier, 19401.Mixed types of inherited CNS vascular malformations (arteriovenous, capillary and venous malformations) including cavernous angiomas have also been described [Takamiya et al., 1984; Zaremba et al., 19791. Thus, familial cavernous angiomatosis may not be a single disorder with incomplete penetrance and variable expression but may rather represent a heterogeneous group of disorders. The family we report is similar to families previously published with the CNS, ocular and cutaneous involvement indicative of familial cavernous angiomatosis [Gass, 1971; Goldberg et al., 1979; Weskamp and Cotlier, 19401.In addition to cavernous angiomas of the skin which were often multiple and large, small cherry or strawberry skin angiomas were also common but their significance in this family is still unclear as these angiomas are common in the general population. Other frequent symptoms in this family were migraine-like headaches, including all of those individuals known to have CNS angiomas. Since CNS angiomas are known to be associated with vascular type headaches, the occurrence of headaches in this kindred may have clinical significance; however, such headaches are also frequent in the general population and their occurrence must be interpreted with caution. Additional findings in this family not described previously in familial cavernous angioma families are the presence of terminal defects of the mid-forearm, a single hepatic angioma, and soft tissue angiomas. Also, 2 relatives have Waardenburg syndrome, inherited from a noninvolved spouse. A previous observation of one familial cavernous angioma relative with anomalies of the digits has been made in an extensively involved family [Goldberg et al., 19791. Although a few familial recurrences of limb defects have been described in otherwise normal families [BarFig. 5. (A) Photograph of proband's niece, age 4, with terminal toshesky et al., 1986; Graham et al., 19863, isolated transverse defect of the right forearm. Also visible on this photograph terminal transverse defects are, in general, sporadic are two of the cavernoue angiomas of the skin. (B) Two sequential T-1 weighted gadolinium-enhancedMRI sections ofthe right forearm dem- [Birch-Jensen, 19491. onstrating abrupt termination of the forearmjust below the level of the Thus, it seems that the two instances of TTDs in this normal radial and ulnar heads. No vascular malformation is observed. pedigree are probably not coincidental and are related to a primary diagnosis of familial cavernous angiomatosis. We feel that an acute vascular event in utero secondary to angioma formation could have produced tissue disruption and infarction leading to the observed
Limb Defects and Cavernous Angiomatosis
defect. Thus, a disruptive event may have been associated with familial cavernous angiomatosis in this one family. Prenatal ultrasound screening for TTDs [Graham et al., 19861may therefore be warranted for a t risk family members with familial cavernous angiomatosis, particularly when the cavernous angiomas do not appear limited to the CNS.
ACKNOWLEDGMENTS The views expressed in this article are those of the authors and do not reflect the official policy of the Department of the Army, Department of Defense, Department of Health and Human Services, or the United States Government.
REFERENCES Bartoshesky LE, Gans B, Goldberg M (1986): Familial occurrence of malformations possibly attributable to vascular abnormalities. J Pediatr 109:396. Bicknell JM, Carlow TJ, Kornfeld M, Stovring J , b e r P (1978): Familial cavernous angiomas. Arch Neurol35:746-749. Birch-Jensen A (1949):“Congenital Deformities ofthe Upper Extremities.” Copenhagen: Ejnar Munskgaard, pp. 11-14,141-144. Bokesoy I, Aksiiyek C, Deniz E (1983): Oromandibular limb hypogenesidHanhart’s syndrome: possible drug influence on the malformation. Clin Genet 24:47-49. Bonafede RP, Beighton P (1979): Autosomal dominant inheritance of scalp defects with ectrodactyly. Am J Med Genet 335-41. Bouvet JP, Leveque D, Bernetieres F, and Gros JJ (1978): Vascular origin of Poland syndrome? A comparative rheographic study of the vascularisation of the arms in eight patients. Eur J Pediatr 1281726. Bouwes Bavinck JNB, Weaver DD (1986): Subclavian artery supply disruption sequence: Hypothesis of a vascular etiology for Poland, Klippel-Feil and Mobius anomalies. Am J Med Genet 23:903-918. Clark JV (1970): Familial occurrence of Cavernous angioma of the brain. J Neurol Neurosurg Psych 33:871-876. Czeizel A, Bod M, Lenz W (1983): Family study on congenital limb reduction abnormalities in Hungary 1975-1977. Hum Genet 65:35-45. Freire-Maia A (1975): Genetics of acheiropodia (“the handless and footless families of Brazil”) VIII. penetrance and expressivity. Clin Genet 7:98-102. Gass JD (1971): Cavernous hemangioma of the retina: A neuro-ocular cutaneous syndrome. AJO 71:799-814. GoldbergRE, Pheasant TR, Shields JA (1979):Cavernous hemangioma of the retina: A four generation pedigree with neurocutaneous manifestations and an example of bilateral retinal involvement. Arch Ophthalmol 97:2321-2324.
351
Graham JM, Brown FE, Struckmeyer CL, Hallowell C (1986): Dominantly inherited unilateral terminal defects of the hand (adactylia) in twin sisters and one daughter. Pediatrics 78:103-106. Hayman LA, Evans RA, Ferrell RE, Fahr LH, Ostrow P, Riccardi VM (1982): Familial cavernous angiomas: natural history and genetic study over a 5 year period. Am J Med Genet 11:147-160. Hecht JT, Scott CL (1981a): Limb deficiency syndrome in half-sibs. Clin Genet 20:432-437. Hecht JT, Scott CL (1981b):Recurrent unilateral hand malformations in siblings. Clin Genet 20:225-228. Higginbottom MC, Jones KL, Hall BD, Smith DW (1979):The amniotic band disruption complex: timing of amniotic rupture and variable spectra of consequent defects. J Pediatr 95:544-549. Hovme HE. Jones KL. Van Allen MI. Saunders BS. and Benirschke K -(1982):Vascular pathogenesis of transverse limb reduction defects. J Pediatr 101:839-843. Hoyme HE, Jones KL, Dixon SD, Jewett T, Hanson JW, Robinson LK, Msall ME, Allanson J E (1990):Prenatal cocaine exposure and fetal vascular disruption. Pediatrics 85743-747. Kelln EE, Bennett CG, Klingberg WG (1968):Aglossia-adactylia Syndrome. Am J Dis Child 116:549-552. Kiister W, Lenz W, Kaiiriainen H, and Majewski F (1988):Congenital scalp defects with distal limb anomalies (Adams-OliverSyndrome): Report of ten cases and review of the literature. Am J Med Genet 31:99-115. Nevin NC, Burrows D, Allen G, Kernohan DC (1975): Aglossia-adactylia syndrome. J Med Genet 12:89-93. Rigamonti D, Hadley MN, Drayer BP, Johnson PC, Hoenig-Rigamonti K, Knight JT, Spetzler RF (1988): Cerebral cavernous malformations: Incidence and familial occurrence. N Engl J Med 319:343347. Robinow M, Marsh JL, Edgerton MT, Sabio H, Johnson GF (1978): Discordance in monozygotic twins for aglossia-adactylia and possible clues to the pathogenesis of the syndrome. BD.OAS XIV (6A):223-230. Scribanu N, Temtamy SA (1975): The syndrome of aplasia cutis congenita with terminal transverse defects of limbs. J Ped 87:79-82. Soltan HC, Holmes LB (1986): Familial occurrence of malformations possibly attributable to vascular abnormalities. J Pediatr 108:112114. Superneau DW, Wertelecki W (1985): Brief clinical report: Similarity of effects-experimental hyperthermia as a teratogen and maternal febrile illness associated with oromandibular and limb defects. Am J Med Genet 21:575-580. Takamiya Y, Takayama H, Kobayashi K, Mine T, Suzuki K (1984): Familial occurrence of multiple vascular malformations of the brain. Neurol Med Chir (Tokyo) 24:271-277. Webster WS, Lipson AH, Brown-Woodman PDC (1987): Uterine trauma and limb defects. Teratology 35:253-260. Weskamp C, Cotlier I (1940): Angioma del cerebro y de la retina con malformaciones capilares de la prel. Arch Oftalmol Buenos Aires 151-10. Zaremba J , Stepien M, Jelowicka M, Ostrowska D (1979): Hereditary neurocutaneous angioma: A new genetic entity? J Med Genet 16443-447.
Terminal Transverse Limb Defects Associated With Familial Cavernous Angiomatosis Michele R. Filling-Katz,* Sondra W. Levin, Nicholas J. Patronas, and Norman N.K. Katz* Genetics, Exceptional Family Member Program, Department of Pediatrics, Walter Reed Army Medical Center, Washington, DC 20307 (S.W.L.), Department of Pediatrics (S.W.L.) and Division of Ophthalmology, Department of Surgery (N.N.K.K.), Uniformed Services University of the Health Sciences, Bethesda, Maryland; Warren G. Magnuson Clinical Center, Department of Radiology (N.J.P.); Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism (M.R.F.-K.), and Human Genetics Branch, National Institute of Child Health and Human Development (S.W.L.); National Institutes of Health, Bethesda Maryland (N.J.P.) Terminal transverse limb defects rarely are reported as familial. Multiple pathogenetic mechanisms, including vascular disruption, have been proposed to account for these defects. We report on a family followed over the past 6 years known to have familial cavernous angiomatosis in which 2 relatives have similar terminal transverse defects at the mid-forearm. Multiple relatives have had episodic bleeding from intracranial cavernous angiomas, a distinct finding in this disorder. Other findings in this family include retinal cavernous angiomas (2 patients), a high incidence of skin angiomas (12 patients), cavernous angiomas of the soft tissue (2 patients), and a hepatic angioma (one patient). One of the 2 individuals with the limb defect was evaluated extensively. Magnetic resonance imaging of the forearm with the terminal transverse defect using gadolinium-DTPA enhancement showed abrupt termination of all structures distal to the normal radial and ulnar heads. We propose that familial cavernous angiomatosis may be a new cause of vascular disruption resulting in terminal transverse limb defects. KEY WORDS: familial cavernous angiomatosis, angiomas, disruption, limb defect INTRODUCTION Terminal transverse limb defects (TTDs) of the forearm are reported to have an overall incidence of 1 per 25,000 live births [Birch-Jensen, 19491. These defects
are usually sporadic [Czeizel et al., 1983; Hoyme et al., 1982; Nevin et al., 1975; Robinow et al., 19781but have also occurred in some families perhaps due to a dominant trait [Bartoshesky et al., 1986; Graham et al., 1986;Hecht and Scott, 1981a; Soltan and Holmes, 19861. Autosomal recessive inheritance has also been suggested [Hecht and Scott, 1981bl and Brazilian families have been described with recessively inherited TTD of all limbs termed acheiropodia [E’reire-Maia, 19751. Some families inherit defects of the scalp and skull in conjunction with TDD (the Adams-Oliver Syndrome) [Bonafede et al., 1979; Kuster et al., 1988; Scribanu et al., 19751. Multiple pathogeneses of TTD have been proposed including amniotic band disruption sequence and vascular disruption [Bartoshesky et al., 1986; Bouwes Bavinck and Weaver, 1986; Bokesoy et al., 1983; Bouvet et al., 1978; Higginbottom et al., 1979; Hoyme et al., 1982; Soltan et al., 19861. In some instances vascular disruption has been attributed to intrauterine ischemia and secondary necrosis [Webster et al., 19871. Entities including the Hanhart syndrome, Klippel-Feil, Poland, and Mobius anomalies have been so explained [Bouwes Bavinck and Weaver, 1986; Bouvet et al., 1978; Kelln et al., 1968;Soltan and Holmes, 19861. Embryotoxic effects of maternal hyperthermia [Superneau and Wertelecki, 19851, cocaine [Hoyme et al., 19901, and meclizine hydrochloride [Bokesoy et al., 19831have also been implicated in malformation pathogenesis. We report here on a new association of familial cavernous angiomatosis, (McKusick catalogue No. 116860) an autosomal dominant disorder [Clark, 1970; Gass, 1971;Goldberget al., 1979;Hayman et al., 1982;Rigmamonti et al., 19881, with transverse terminal defects.
METHODS AND SUBJECTS The family was ascertained after the diagnosis of the Received for publication March 12,1991; revision received June proposita in January of 1984. Close relatives (marked 18, 1991. with an asterisk Table I) underwent initial evaluations *Deceased. Address reprint requests to Dr. Sondra W. Levin, Exceptional in 1984 and were followed subsequently. The extended Family Member Program, Building 38, Department of Pediatrics, family was evaluated in 1988 and the original relatives Walter Reed Army Medical Center, Washington, D.C.20307-5001. were reevaluated at that time as well (Fig. 1).History
0 1992 Wiley-Liss, Inc.
32 15 80 52 43 17 16 16
ll(V-5) 12(V-14)
13(III-3) 14(IV-3)
15(IV-7) 16(V-13) 17(V-15) 18*(V-12)
Normal
Normal
1 CAL thigh ? Bilateral CA face
Normal Normal
F F
15 36
240'1-2)
250'-9)
Normal
Normal
Normal Normal
Hepatic CA
Normal Normal
Normal Normal Normal Normal
*CA, cavernous angioma; MLH,migraine-like headache; CAL, caf6-au-lait spots; ITD,transverse terminal limb defect.
Normal
Normal Bilateral facial CA, large 6 x 4 cm CA left neck
M Normal M Normal
Hemorrhagic brainstem CA; right occipital CA; 2 hemorrhaeic left frontal EA Normal Normal
59 46
Multiple small CA forehead, hands, thigh
22(IV-4) 23(IV-6)
Small CA left eye
F
Normal Normal Normal Right parietal angioma Normal Normal
22
Normal 6 CA from 1 to 5 cm in size
5 small angiomas thorax, 1-cm CAL Normal Normal Bilateral facial CA; 2 CA hand
21*(V-l1)
19*(IV-5) 59 2O*(VI-12) 8
M Normal F Optic drusen F Normal F Normal M Normal M Large CA right eye M Normal F Normal
F Normal M Normal
Normal
Viscera Normal Normal Left old lacunar in- Normal farction; right frontal angioma Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal Normal
CNS
Normal 3 questionable areas of hyperintensity in centrum semiovale 5 CAL of > 1 cm, 1 small angioma back Normal Normal Bilateral CA face extending into neck, Normal Normal 1 6-cm CAL abdomen Normal Normal Normal 4 small angiomas anterior chest Normal Normal
F
28
lO(V-8)
Normal
Right bulbar telangectesia, 1 angioma back 3 CAL back, 1 angioma left hip
9(V-6)
M F F M M F
M Normal
6 55 16 18 9 42
3*(VI-13) 4(IV-2) W-7) 6(VI-3) 7(vI-4) 8(V-2)
30
1 cm CA forehead Normal
Skin
Normal 3 CA right forearm and stomach Normal Normal Normal 2.5 cm CA abdomen, 1 cm CA right thigh, 1 angioma medial eyelid, multiple small angiomas back
Age Sex Retina 23 F Normal 28 F Normal Normal Normal Normal Normal Normal Normal
Patient 1(V-16) 2*(V-10)
Normal
Normal
Normal Normal
Normal Right lTD Normal
Normal Normal Normal Normal
Normal Normal
Normal Normal
Normal
Normal
Normal Normal Normal Normal Normal Normal
Bone Normal Normal
Normal MLH, multiple small soft tissue angiomas (path) Type _ _ I Waardenburg MLH
Stroke, seizure, MLH
Normal MLH
Normal MLH Normal MLH
MLH MLH, seizure
MLH MLH
MLH
Normal MLH Normal Normal Normal Soft tissue 3 x 3 cm CA, 5 p e I Waardenburg Normal
Other Normal MLH
TABLE I. Findings on Screening Examinations and Radiologic Studies in Large Familial Cavernous Angiomatosis Pedigree*
348
Filling-Katz et al.
I
I1
I11
IV V VI Fig. 1. The pedigree of the family with familial systemic cavernous angiomatosis. 0 Neurologic involvement. 0 Ocular involvement. 0 Visceral involvement. 0 Cutaneous involvement. + Examined. + Pathologic confirmation of cavernous angioma. @ Affected historically or by pedigree analysis. * lTD, not known whether associated with angioma. Skin angiomas significance unknown.
and physical and neurologic examinations including dilated ophthalmoscopy were obtained for each relative. Magnetic resonance imaging (MRI) of the central nervous system (CNS)was performed on all at-risk individuals undergoing evaluation (25 patients). Additional MRI studies were performed in selected cases including the viscera (5 patients), spine (4patients), and the limbs (2 patients). Five relatives were contacted but declined screening evaluation.
RESULTS A total of 25 individuals in this family was evaluated (Table 1). Three living individuals were found to have CNS angiomas (6 lesions) by imaging studies (Table I, Fig. 2). Two relatives have died with historical evidence of CNS angiomas and recurrent hemorrhage, one confirmed by subsequent autopsy. A fourth living individual was suspected of having a CNS lesion based on lateonset seizures (in her fifth decade) but this could not be confirmed on imaging studies. A fifth individual has questionable areas of increased intensity bilaterally seen on T2-weightedMRI in the centrum semiovale of uncertain significance. The proposita (V-11)had recurrent hemorrhage from both the brainstem and frontal cavernous angiomas, and had CNS infarction and multiple residual neurologic deficits. Both of the other individuals with CNS lesions detected by MRI had migraine-like headaches, a common complaint by 13 of the 25 relatives evaluated by us. Two individuals had retinal cavernous angiomas, both confirmed by subsequent fluorescein angiography (Fig. 3). One individual had an asymptomatic hepatic angioma discovered by abdominal computed tomography (CT) and confirmed by MRI. Two individuals had soft tissue cavernous angiomas; one was located on the palm (Fig. 4) and the second located on the chest. The first lesion was imaged by MRI and the second removed in toto after recurrent bleeding. Cav-
ernous angiomas of the skin were common (8 of 25 patients). Many other individuals had small cherry or strawberry angiomas (6of25 patients) including several who also had cavernous angiomas. Two individuals within the family had TTDs of the right mid-forearm. Only one of these 2 with the limb defect permitted evaluation (as described below).
CLINICAL REPORT A 9-year-oldwhite girl was first evaluated by us at age 4 years because of her relationship to a family with familial cavernous angiomatosis (patient 20, Table I). She was the 3,190-gproduct of a 20-year-old GlPO white woman with a 40-week pregnancy marked only by nausea and a single use of bendectin of unknown amount in the first trimester. Examination at birth showed a bloody, partially healed stump in place of the right forearm. Two small, cutaneous angiomas were present on the right leg as well. The placenta was unremarkable. At age 4 she had 4 angiomas (Fig. 5A) which were distributed over the right and left legs and torso. She had a well healed TTD at the level of the mid-forearm (Fig. 5A) without nails or digital remnants. She was otherwise normal. A contrast-enhanced CT of the head was normal. She was reevaluated at age 8 years. She had undergone normal growth and development and was performing well in the second grade. She complained of occasional migraine-like headaches. She had developed 2 new angiomas, for a total of 6, and 2 of the previous 4 had undergone interval growth proportional to body growth. MRIs of the head, abdomen, and forearm were performed prior to and after injection of gadolinium DTPA (Magnevist). The MRIs of the head and abdomen were normal. The MRI of the forearm showed an entirely normal arm terminating abruptly just below the level of the heads of the radius and ulna (Fig. 5B). The brachial artery was seen to be of normal caliber.
Limb Defects and Cavernous Angiomatosis
349
Fig. 4. Photograph of slowly growing soft tissue angioma of the left hand. MRI (not shown) was consistent with a soft tissue cavernous angioma.
350
Filling-Katz et al.
DISCUSSION We describe a family with familial cavernous angiomatosis in which 2 individuals had a severe terminal transverse limb defect. Familial cavernous angiomatosis is an autosomal dominant inherited disorder in which affected individuals have an increased risk of developing cavernous angiomas of the brain, retina, skin, and other visceral organs. Manifestations in the CNS include hemorrhage, stroke, seizure, as well as headache [Bicknell et al., 1978; Rigmamonti et al., 19883. Eye manifestations of cavernous angiomas are rare [Gass, 19711. Some predominantly Hispanic families have been described with CNS involvement alone excluding the retina [Bicknell et al., 1978; Hayman et al., 1982; Rigmamonti et al., 19881,whereas other families manifest more diffuse involvement including retina and skin [Gass, 1971; Goldberg et al., 1979; Weskamp and Cotlier, 19401.Mixed types of inherited CNS vascular malformations (arteriovenous, capillary and venous malformations) including cavernous angiomas have also been described [Takamiya et al., 1984; Zaremba et al., 19791. Thus, familial cavernous angiomatosis may not be a single disorder with incomplete penetrance and variable expression but may rather represent a heterogeneous group of disorders. The family we report is similar to families previously published with the CNS, ocular and cutaneous involvement indicative of familial cavernous angiomatosis [Gass, 1971; Goldberg et al., 1979; Weskamp and Cotlier, 19401.In addition to cavernous angiomas of the skin which were often multiple and large, small cherry or strawberry skin angiomas were also common but their significance in this family is still unclear as these angiomas are common in the general population. Other frequent symptoms in this family were migraine-like headaches, including all of those individuals known to have CNS angiomas. Since CNS angiomas are known to be associated with vascular type headaches, the occurrence of headaches in this kindred may have clinical significance; however, such headaches are also frequent in the general population and their occurrence must be interpreted with caution. Additional findings in this family not described previously in familial cavernous angioma families are the presence of terminal defects of the mid-forearm, a single hepatic angioma, and soft tissue angiomas. Also, 2 relatives have Waardenburg syndrome, inherited from a noninvolved spouse. A previous observation of one familial cavernous angioma relative with anomalies of the digits has been made in an extensively involved family [Goldberg et al., 19791. Although a few familial recurrences of limb defects have been described in otherwise normal families [BarFig. 5. (A) Photograph of proband's niece, age 4, with terminal toshesky et al., 1986; Graham et al., 19863, isolated transverse defect of the right forearm. Also visible on this photograph terminal transverse defects are, in general, sporadic are two of the cavernoue angiomas of the skin. (B) Two sequential T-1 weighted gadolinium-enhancedMRI sections ofthe right forearm dem- [Birch-Jensen, 19491. onstrating abrupt termination of the forearmjust below the level of the Thus, it seems that the two instances of TTDs in this normal radial and ulnar heads. No vascular malformation is observed. pedigree are probably not coincidental and are related to a primary diagnosis of familial cavernous angiomatosis. We feel that an acute vascular event in utero secondary to angioma formation could have produced tissue disruption and infarction leading to the observed
Limb Defects and Cavernous Angiomatosis
defect. Thus, a disruptive event may have been associated with familial cavernous angiomatosis in this one family. Prenatal ultrasound screening for TTDs [Graham et al., 19861may therefore be warranted for a t risk family members with familial cavernous angiomatosis, particularly when the cavernous angiomas do not appear limited to the CNS.
ACKNOWLEDGMENTS The views expressed in this article are those of the authors and do not reflect the official policy of the Department of the Army, Department of Defense, Department of Health and Human Services, or the United States Government.
REFERENCES Bartoshesky LE, Gans B, Goldberg M (1986): Familial occurrence of malformations possibly attributable to vascular abnormalities. J Pediatr 109:396. Bicknell JM, Carlow TJ, Kornfeld M, Stovring J , b e r P (1978): Familial cavernous angiomas. Arch Neurol35:746-749. Birch-Jensen A (1949):“Congenital Deformities ofthe Upper Extremities.” Copenhagen: Ejnar Munskgaard, pp. 11-14,141-144. Bokesoy I, Aksiiyek C, Deniz E (1983): Oromandibular limb hypogenesidHanhart’s syndrome: possible drug influence on the malformation. Clin Genet 24:47-49. Bonafede RP, Beighton P (1979): Autosomal dominant inheritance of scalp defects with ectrodactyly. Am J Med Genet 335-41. Bouvet JP, Leveque D, Bernetieres F, and Gros JJ (1978): Vascular origin of Poland syndrome? A comparative rheographic study of the vascularisation of the arms in eight patients. Eur J Pediatr 1281726. Bouwes Bavinck JNB, Weaver DD (1986): Subclavian artery supply disruption sequence: Hypothesis of a vascular etiology for Poland, Klippel-Feil and Mobius anomalies. Am J Med Genet 23:903-918. Clark JV (1970): Familial occurrence of Cavernous angioma of the brain. J Neurol Neurosurg Psych 33:871-876. Czeizel A, Bod M, Lenz W (1983): Family study on congenital limb reduction abnormalities in Hungary 1975-1977. Hum Genet 65:35-45. Freire-Maia A (1975): Genetics of acheiropodia (“the handless and footless families of Brazil”) VIII. penetrance and expressivity. Clin Genet 7:98-102. Gass JD (1971): Cavernous hemangioma of the retina: A neuro-ocular cutaneous syndrome. AJO 71:799-814. GoldbergRE, Pheasant TR, Shields JA (1979):Cavernous hemangioma of the retina: A four generation pedigree with neurocutaneous manifestations and an example of bilateral retinal involvement. Arch Ophthalmol 97:2321-2324.
351
Graham JM, Brown FE, Struckmeyer CL, Hallowell C (1986): Dominantly inherited unilateral terminal defects of the hand (adactylia) in twin sisters and one daughter. Pediatrics 78:103-106. Hayman LA, Evans RA, Ferrell RE, Fahr LH, Ostrow P, Riccardi VM (1982): Familial cavernous angiomas: natural history and genetic study over a 5 year period. Am J Med Genet 11:147-160. Hecht JT, Scott CL (1981a): Limb deficiency syndrome in half-sibs. Clin Genet 20:432-437. Hecht JT, Scott CL (1981b):Recurrent unilateral hand malformations in siblings. Clin Genet 20:225-228. Higginbottom MC, Jones KL, Hall BD, Smith DW (1979):The amniotic band disruption complex: timing of amniotic rupture and variable spectra of consequent defects. J Pediatr 95:544-549. Hovme HE. Jones KL. Van Allen MI. Saunders BS. and Benirschke K -(1982):Vascular pathogenesis of transverse limb reduction defects. J Pediatr 101:839-843. Hoyme HE, Jones KL, Dixon SD, Jewett T, Hanson JW, Robinson LK, Msall ME, Allanson J E (1990):Prenatal cocaine exposure and fetal vascular disruption. Pediatrics 85743-747. Kelln EE, Bennett CG, Klingberg WG (1968):Aglossia-adactylia Syndrome. Am J Dis Child 116:549-552. Kiister W, Lenz W, Kaiiriainen H, and Majewski F (1988):Congenital scalp defects with distal limb anomalies (Adams-OliverSyndrome): Report of ten cases and review of the literature. Am J Med Genet 31:99-115. Nevin NC, Burrows D, Allen G, Kernohan DC (1975): Aglossia-adactylia syndrome. J Med Genet 12:89-93. Rigamonti D, Hadley MN, Drayer BP, Johnson PC, Hoenig-Rigamonti K, Knight JT, Spetzler RF (1988): Cerebral cavernous malformations: Incidence and familial occurrence. N Engl J Med 319:343347. Robinow M, Marsh JL, Edgerton MT, Sabio H, Johnson GF (1978): Discordance in monozygotic twins for aglossia-adactylia and possible clues to the pathogenesis of the syndrome. BD.OAS XIV (6A):223-230. Scribanu N, Temtamy SA (1975): The syndrome of aplasia cutis congenita with terminal transverse defects of limbs. J Ped 87:79-82. Soltan HC, Holmes LB (1986): Familial occurrence of malformations possibly attributable to vascular abnormalities. J Pediatr 108:112114. Superneau DW, Wertelecki W (1985): Brief clinical report: Similarity of effects-experimental hyperthermia as a teratogen and maternal febrile illness associated with oromandibular and limb defects. Am J Med Genet 21:575-580. Takamiya Y, Takayama H, Kobayashi K, Mine T, Suzuki K (1984): Familial occurrence of multiple vascular malformations of the brain. Neurol Med Chir (Tokyo) 24:271-277. Webster WS, Lipson AH, Brown-Woodman PDC (1987): Uterine trauma and limb defects. Teratology 35:253-260. Weskamp C, Cotlier I (1940): Angioma del cerebro y de la retina con malformaciones capilares de la prel. Arch Oftalmol Buenos Aires 151-10. Zaremba J , Stepien M, Jelowicka M, Ostrowska D (1979): Hereditary neurocutaneous angioma: A new genetic entity? J Med Genet 16443-447.
