Copyrinht 0 Munksgaard 1994 Clin Genet 1994. 45: 212-216 Printed in Denmark . All rights reserved CLINICAL GENETICS ISSN 0009-9163 Case Report Multiple coagulation defects and the Cohen syndrome , Schlichtemeier TL, Tomlinson GE, Kamen BA, Waber LJ, Wilson GN. Multiple coagulation defects and the Cohen syndrome. Clin Genet 1994: 45: 212-216. 0 Munksgaard, 1994 A 13-year-old male presented with new onset seizures, sagittal sinus , thrombosis with cerebral hemorrhage, and extensive venous thrombosis of the lower limbs. Laboratory investigation demonstrated combined de' ficiency of protein C, protein S, and antithrombin 111. He and his 17-year- old sister had a mental retardation-multiple anomaly syndrome associated with microcephaly, unusual facies, and lax connective tissue. Their dysmorphology included elongated faces with narrow forehead, arched eyebrows, large mouth with down-turned corners, malformed teeth, and furrowed tongue. Both had Marfanoid habitus with lax joints, pectus excavatum, kyphoscoliosis, and flat narrow feet. The most likely diagnosis for these siblings is the autosomal recessive Cohen syndrome of mental retardation, congenital hypotonia with Marfanoid habitus, microcephaly, pleasant affect, micrognathia, and open mouth with prominent incisors. The sagittal sinus thrombosis, left frontal intracranial hemorrhage, carotid aneurysm, tortuous descending aorta, and deep venous thrombosis suffered by the male sibling adds the Cohen syndrome to genetic vasculopa1 thies that may be associated with stroke. Genetic disorders associated with a predisposition to vasculopathy and stroke may affect the blood cells (i.e. sickle cell anemia), the clotting factors (i.e. hemophilia), the cerebral vessels (i.e. amyloidosis type VI), the connective tissue (i.e. homocystinuria), or brain metabolism (i.e. mitochondria1 encephalopathy with lactic acidosis and strokes MELAS syndrome (Natowicz & Kelley 1987). An adolescent male with cerebral hemorrhage secondary to sagittal sinus thrombosis, hypercoagulable state, and probable Cohen syndrome highlights another genetic disease that is associated with vasculopathy and stroke. Case reports Case 1 The proband is a 13-year-old black male who had been evaluated for mental retardation (IQ 50-60) but was otherwise in good health (Fig. 1). Family history showed that the mother had a prior 8-week spontaneous abortus and had undergone surgery for repair of an aortic aneurysm. Otherwise, she had a normal medical history and physical examin212 Tamml 1. Schlichtemeier', Gail E. Tomlinson2, Barton A. Kamen', Lewis J. Waber3 and Golder N. Wilsons Divisions of 'Pediatric Hematology and Oncology, 3Pediatric Genetics and Metabolism, and 'Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA Key words: Cohen syrndrome - hypercoagulability - MCA/MR syndrome - stroke Golder N. Wilson M.R, Ph.D., Division of Pediatric Genetics and Metabolism, University of Texas Southwestern Medical School, Dallas TX USA 75235-9063 Received 14 April, revised version received and accepted 30 November 1993 ation. The maternal grandmother had died of a pulmonary embolus and there was no parental consanguinity. Following acute presentation with a right-sided tonic clonic seizure, head CT scan revealed a large left frontal hemorrhage (Fig. 2) and thrombosis of the superior sagittal sinus. Physical findings included microcephaly, short stature, craniofacial dysmorphology with telecanthus and hypertelorism, and a thin body build with skeletal anomalies (Table 1). Height was 147 cm (3rd centile), weight 37 kg (3rd centile), head circumference 50 cm (50th centile for age 3 years), intercanthal distance 3.5 cm (90th centile), interpupillary distance 6.5 cm (97th centile), mean palpebral fissure length 3.4 cm (80th centile), philtrum length 0.6 cm ( < < 3rd centile), mean hand length 17.4 cm (30th centile), and mean ratio of middle finger to hand length 0.43 (75th centile). Digits 1 (right) and 1, 2 (left) had arch dermatoglyphic patterns, while the remaining digits had ulnar loops. Hospital studies included echocardiography demonstrating normal cardiac anatomy but a dilated tortuous descending aorta, cerebral angio- Cohen syndrome Fig. I. Photographs of the proband (upper panels) and his sister (lower panels). 2 13 Schlichtemeier et a). Table 1. Physical findings in the proband and his sister compared to those of Cohen syndrome Proband sister Cohen syndrome + + - + + General Congenital hypotonia Obesity Short stature Mental retardation - Cranial Microcephaly Flat occiput + Facial Hypertelorism Arched eyebrows Down-slanting eyes Ear anomalies Open mouth Prominent incisors High-arched palate Short philtrum Micrognathia gram revealing narrowed vessels with slow circulation and a small aneurysm at the left internal carotid bifurcation, and Doppler studies showing thrombotic occlusion of the deep venous system in both lower extremities. Thrombi involved the popliteal fossae with extension into the iliac veins and inferior vena cava. Normal laboratory studies included a karyotype with fragile X screening, urine screening for homocystine, erythrocyte and leucocyte counts, blood prothrombin and prothromboplastin times and liver function tests. Coagulation studies demonstrated low functional and immunologic levels of protein C, protein S , and antithrombin I11 in the proband and his sister (Table 2). The mother had a low normal functional level of protein S but normal levels of protein C and antithrombin 111. The father had normal levels of all three anticoagulant proteins. Case 2 The 17-year-old sister of the proband is also mentally retarded with similar facies (Fig. 1 ) and physical findings as summarized in Table 1. Height was 2 14 + + + - + + - + + + + + + + + + + + + + + + + + + - + + + + + + + + - + ? + - + + Genifal Cryptorchidism + + + - Trunklimbs Lax joints Pectus excavatum Kyphoscoliosis Narrow hands, long fingers Camptodactyly (R+L) Fig. 2. Head CT scan of proband showing left frontal hemorrhage. + + + + + + + Table 2. Coagulation studies Proband Sister Mother Father Protein C Immunological' Functional' No focus 32% <30% 55% 85% 95% 110% 90% Protein S ~unctiona~~ 16% 28% 60% 90% Antithrombin 118 25% 35% 100% 95% ' Normal range 70-140% based on assay with commercial antiserum. Normal range 7 5 1 7 0 % based on snake venom activation assay. Normal range based on mean*2 SD using assay as heparin cofactor activity (Camerlingo et al. 1991). 155 cm (3rd centile), weight 41 kg (3rd centile), head circumference 50 cm (50th centile for age 3'/2 years), intercanthal distance 3 cm (50th centile). interpupillary distance 7 cm (50th centile), mean palpebral fissure length 3 cm (80th centile), philtrum length 0.6 cm ( < ~ 3 r centile), d mean hand length 16.1 cm (3rd centile), and mean ratio middle finger length to hand length 0.44 (75th centile). Digits 1-2 on both hands had arch dermatoglyphic patterns, while the remaining digits had ulnar loop patterns. She has had recurrent dislocation of the patella but no history of thrombosis or hemorrhage, despite abnormal levels of coagulation fac- Cohen syndrome tors (Table 2). Like her brother before his stroke, she was striking for her euphoric affect and interactive personality. Discussion Table 1 summarizes the abnormal manifestations occurring in the two siblings and compares them with those of the Cohen syndrome (Cohen et al. 1973, Carey & Hall 1978, Norio et al. 1984). A congruent pattern of defects is shared among these siblings and patients with Cohen syndrome. The myopia in the sister, tortuous descending aorta in the proband, and the shared habitus with kyphoscoliosis and pectus excavatum suggest a disorder of connective tissue. Myopia, narrow hands with long fingers, and kyphoscoliosis are found in the Cohen syndrome, but ventricular septa1 defects and mitral valve prolapse are more characteristic than aortic anomalies (Gorlin et al. 1990). Other similarities to the Cohen syndrome include congenital hypotonia, pleasant affect, microcephaly, moderate mental retardation, short stature, open mouth, short philtrum with prominent incisors, micrognathia, and cryptorchidism (Gorlin et al. 1990). Neither sibling had retinal pathology characteristic of the Cohen syndrome (Norio et al. 1984), and neither was obese. Obesity is not a constant feature of the Cohen syndrome (Carey & Hall 1978). Homocystinuria and Fragile X syndrome were excluded by the appropriate laboratory tests, and the clinical manifestations are not consistent with other connective tissue disorders such as the Marfan or Ehlers-Danlos syndromes. An altered coagulable state was evidenced by sagittal sinus thrombosis, cerebral hemorrhage (probably secondary to sagittal sinus thrombosis) and deep venous thrombosis in the male proband. Deficient protein S, protein C, and anti-thrombin 111 levels were found in both siblings but in neither parent (except for low normal functional protein S in the mother - Table 2). Hereditary deficiencies of any one of the natural anticoagulant proteins C, S, and antithrombin I11 may predispose to recurrent thromboembolic episodes (Camerlingo et al. 1991, Israel & Seshia 1987). Heterozygous deficiency of protein C or protein S can be associated with strokes (Rick 1990, Camerlingo et al. 1991), and it is estimated that 4% of all strokes in young adults are associated with a derangement of the coagulation process (Israel & Seshia 1987). The association of strokes with the antiphospholipid antibodies syndrome is thought to be related to the inhibition of protein C by the lupus anticoagulant (Marciniak & Romond 1989). The anticoagulant proteins S and C, like the procoagulant factors 11, VII, IX, and X are syn- thesized in the liver and must undergo vitamin Kdependent carboxylation prior to function (Rick 1990). Acquired deficiencies of protein S and C occur in liver disease or in disseminated intravascular coagulation. Antithrombin I11 is also synthesized by the liver and mediates the anticoagulant effect of heparin. The apparent combined deficiency of anticoagulant proteins in these siblings may be secondary to abnormal connective tissue, aberrant carboxylation, common inhibitor, or unrecognized liver disease, but it cannot be the result of contiguous gene deletion. The genes for protein C (chromosomal band 2q13-q21), protein S ( 3 ~ 1 1 q l 1.2), and antithrombin III (lq23) are on different chromosomes, while the locus for Cohen syndrome has not been mapped (McKusick 1992). Deficiencies of protein S and C have been observed in the carbohydrate-deficient-glycoproteinsyndrome, and stroke-like episodes do occur in this disorder (Kahler et a!. 1993). While some manifestations of the siblings are compatible with this disorder, e.g. hypotonia, facial abnormalities, pectus excavatum, they do not exhibit the unusual fat distribution, hepatomegaly, retinitis pigmentosa or ataxia reported in older children. The family structure is most suggestive of autosoma1 recessive inheritance, the accepted mode of transmission for the Cohen syndrome (Cohen et al. 1973). The more severe affliction of the brother, coupled with aortic aneurysm and pulmonary embolism in female relatives, is also compatible with autosomal or X-linked dominant inheritance with variable expressivity. Cohen pointed out (Gorlin et al. 1990) the ability of adenoidal obstruction and mouth breathing to produce the open mouth and prominent incisors that are striking in these siblings. While their overall pattern of anomalies is suggestive of the Cohen syndrome (Table l), the diagnosis is obviously not secure until genetic testing is available. However, hypercoagulability with its severe complications may possibly be considered in the anticipatory management of patients with Cohen and Cohen-like syndromes. References Camerlingo M, Finazzi G, Casto L, Laffranchi C, Barbui T, Mamoli A. Inherited protein C deficiency and nonhemorrhagic arterial stroke in young adults. Neurology 1991: 41: 1371-1 373. Carey JC, Hall BD. Confirmation of the Cohen syndrome. J Pediatr 1978: 93: 239-244. Cohen MM Jr, Hall BD, Smith DW, Graham CB, Lampert KJ. A new syndrome with hypotonia, obesity, mental deficiency, and facial, oral, ocular, and limb anomalies. J Pediatr 1973: 83: 280-283. Gorlin RJ, Cohen MM Jr, Levin LS. Syndromes of the head and neck. Oxford and New York: Oxford University Press, 1990: 348-35 1. 215 Schlichterneier et al. Israel SJ, Seshia SS. Childhood strokes associated with protein C or S deficiency. J Pediatr 1987: 11 1: 562-564. Kahler SG, Van Hove JLK, Harbison MD, Macchia PA, Refetoff, S, Harrison H, Slonim AE. Carbohydrate deficient glycoprotein (CDG) syndrome: an inborn error with morphogenetic consequences. Proc Greenwood Genet Center 1993: 12: 81-82. Marciniak E, Romond EH. Impaired catalytic function of activated protein C: a new in vitro manifestation of lupus anticoagulant. Blood 1989: 74: 2426-2432. 2 16 McKusick VA. Mendelian inheritance in man, 10th edn. Baltimore and London: Johns Hopkins University Press, 1992. Natowicz M, Kelley RI. Mendelian etiologies of stroke. Ann Neurol 1987: 22: 175-192. Norio R, Raitta C, Lindahl E. Further delineation of the Cohen syndrome; report on chrorioretinal dystrophy, leukopenia and consanguinity. Clin Genet 1984: 25: 1-14. Rick ME. Protein C and protein S. Vitamin K-dependent inhibitors of blood coagulation. JAMA 1990: 263: 701-703.