American Journal of Medical Genetics 17:311-322 (1984) A FORM OF X-LINKED MENTAL RETARDATION WITH MARFANOID HABITUS J. Enrique Lujan Mary Esther Carlin Herbert A. Lubs From t h e Division of Genetics, Department of Pediatrics, University of Miami School of Medicine, Miami, Florida ABSTRACT A kindred has been studied in which mental retardation and marfanoid clinical f e a t u r e s are present in several individuals. The pedigree is consistent with X-linked recessive inheritance. Four a f f e c t e d males aged 12-18 years and four obligate carriers have been identified. Clinical findings in t h e 4 a f f e c t e d males included a tall slender habitus (3) (the Xourth was tall but muscular), a long-narrow face (3), large head (4), highly arched p a l a t e (4), small mandible (41, abnormal speech (41, hypernasal voice (31, joint hyperextensibility (3), borderline to large testes (31, pectus excavatum (21, a t r i a l septa1 d e f e c t (I), and a double row of t e e t h (1). Mental retardation (4) ranged from mild to severe; abnormal behavior included hyperactive and aggressive behavior (21, autistic-like (1) and jovial behavior (1). One and possibly two, males had absence of t h e corpus callosum. Chromosome studies on a l l were normal; no marker X was observed. W e believe this family probably represents a new form of X-linked mental r e tar da t ion. Key Words : X-linked recessive inheritance, mental retardation, mar fanoid habitus. Address reprint requests to: Enrique Lujan, M.D. P.O. Box 016820 Miami, FL 33101 0 1984 Alan R. Liss, Inc. 312 Lujan, Carlin, and Lubs INTRODUCTION The excess of males with retardation is thought to be due to X-linked genes. About one third to one half of families with Xlinked mental retardation have a marker->( chromosome (Turner, 1980). Since t h e r e is no laboratory test for t h e remaining entities, t h e s e must b e delineated on clinical grounds or on t h e basis of linkage studies. The t e n t a t i v e classification provided by Opitz and Sutherland in t h e present issue, which includes 12 t o 13 entities, a g r e e s surprisingly well with t h e prior e s t i m a t e s of both Morton et a1 (1977) of up t o 18 genes and Herbst and Miller (1980) of 7-19 such entities. Because of interest in t h e marker->( chromosome, most recent studies have not focused on t h e markerX negative families and progress is only now being made in recognizing and describing these entities. In t h e authors' current series, which includes 20 marker->( negative families, only 2 entities have so f a r been identified. One was a family with t h e Renpenning syndrome. Recently patients with this syndrome were restudied by Fox et a1 (1980) and found to be marker->( negative. The second is t h e present family, which is clinically distinct from any of those summarized in this issue by Opitz and Sutherland, and w e think may represent a new entity. METHODS All families in t h e present study were referred for mental retardation. When 2 or more males with mental retardation were identified in a family and t h e occurrence of MR in t h e family was consistent with X-linked inheritance, other studies were instituted; informed consent was obtained for a l l procedures, either from t h e patients or their parents. In t h e present kindred (Fig. I) 4 retarded males had been born to 3 sisters. W e examined t h e 4 a f f e c t e d males and their parents. Psychological d a t a were obtained on 2 of t h e affected males, and cytogenetic information was obtained in all affected males and one carrier. Psychological Tests In t h e 2 males tested, intellectual functioning was assessed using t h e Revised Wechsler Adult Intelligence Scale (WISC-R), Stanford Binet, Peabody Picture Vocabulary and Auditory Comprehension of Language (TACL) tests. X-Linked Inheritance 313 I II + I 111 1 IV 2 5 6 * 11 12 15 Fig 1 Pedigree Male, mental retardation and Marfanoid habitus Male, mental retardation only 0 Obligate carrier Q Tall with recessed mandible Cytogenetic Studies Chromosomes studies from leukocyte cultures were done using 0.4 ml heparinized blood, cultured for 72 hr in 10 ml of medium 199 (GIBCO) with 5% and 2% f e t a l calf serum (FCS)to which 0.2 ml of PHA (Burroughs reagent grade phytohemagglutinin) were added. One hundred GTG banded cells were analyzed in 3 males and one female. 50 cells w e r e analyzed for t h e marker X using t h e s a m e medium by Dr. Park Gerald (Boston) in individual IV-9; in none of t h e cells analyzed on any patient were we able to demonstrate t h e marker X. Testes Testicular size was measured using a m e t a l ruler and t h e Prader Orchidometer. Testicular volume was calculated as follows: !d/6 x L x W 2 and compared to t h e values published by Zachmann et a1 (1974). 314 Lujan, Carlin, and Lubs CLINICAL REPORTS Patient 1 (Tables I, 11) IV-2 (Fig. 2) DOB: 5/9/65 17 years at last examination BW: 2.33 kg He was born at t e r m a f t e r a difficult vaginal delivery. He had perinatal jaundice and a general delay in psychomotor development. He developed seizures a t 9 years with EEG characteristics of focal major motor seizures, f o r which he has taken 500 m g of Mysoline R and 300 mg of Dilantin R daily. A CT scan showed agenesis of t h e corpus callosum. He has hyperactivity and aggressiveness, and abnormal speech. At 14 10/12 years, h e scored at 7% years using t h e Peabody Picture Vocabulary Test, and at 6% years on Auditory Comprehension of Language Test (TACL). His full scale I.Q. was less than 40 using t h e WISC-R. On t h e Fisher-Longemann Test of Articulation Competence he demonstrated multiple articulation distortions and sorne substitutions. Hearing was normal, as were results of a n amino acid and mucopolysacchar ide screen of t h e urine. On examination (Fig. 2) he was tall for age (80th centile), had a normal weight, large head, a long, thin, narrow face with apparently low-set, posteriorly-rotated, protruding ears; highly arched, narrow palate; double row of t e e t h in t h e upper dental arch; small mandible; mild pectus excavatum and generalized joint hyperextensibility. Hands and fingers were long and thin; testes were estimated as normal but were not measured. (He was not available for restudy). Neurologically h e was normal. H e is presently attending a school for educably mentally retarded students. Patient 2 (Tables I, 11) IV-5 (Fig. 3) DOB: 12/5/70 12 years at last examination BW: 3.43 kg He was born at t e r m pregnancy, a f t e r a difficult vaginal delivery; h e also developed neonatal jaundice. Gestational history was unremarkable. He also had generally delayed psychomotor development. At 6 years a murmur was noted and a diagnosis was made of a small a t r i a l septa1 defect. A t 7 years he was diagnosed and t r e a t e d for hyperactivity; however, his hyperactivity increased and t h e medication was discontinued. At age 9 3/12 years, a Stanford Binet test showed a n I.Q. of 56. A Peabody Picture Vocabulary Test was scored at 6 2/12 years, and an 315 X-Linked Inheritance Table I CLINICALMANIFEWA~ONS PEDIGREE I N-2 N-5 IV-9 N-11 Age(yrs) 17 I1 18 21 19 Sex M M M F M Hyperactive, aggressive Hyperactive Hyperactive, aggressive Normal Jovial I.Q. 40 56 Low Agenesis of corpus callosum + -+ Tall thin Tall thin 75-90 75 Behavior Habitus and limbs Height k e n t i l e ) N-12 Normal Low Not studied Not studied Tall husky Tall Tall thin 90 90 90 + Pectus excavatum + Long thin hands + + + Large forehead + + + Narrow f a c e + Head circumference kentile) 75 + 98 95 92 + + + + Palate High arch; double row of t e e t h High arch narrow High arch High arch narrow High arch narrow Speech High-pitched hypernasal distorted High-pitched nasal vowel substitutions omission of several phonemes Minimal to absent High-pitched nasal High-pitched nasal Low-set Normal Normal Low-set Small mandible Ears Short, apparently low-set & antever ted & anteverted 12 19 21 10 18 19 IV-11 IV- 12 4 8 9 12 9 14 15 (years) AGE IV-9 IV-5 IV-2 PEDIGREE # (90,<90) 50.5/29.4 N/A b-90) 24/27.5 (>90) 8.3/5.2 ? TESTICULAR SIZE (ml) k e ntile) 149 (95) 190 (>99) 190 (>99) 172 (92) 160 (90) 104 (70) 132 (75) 137 (75) 142 (92) 164 (75) 172 (75) HEIGHT (cm) k e ntile) Table U GROWTH 57 (95) 56 (95) 56 (90) 58 (95) 30.45 (30) 56.81 (10) 57.72 (12) 56 (98) 54 (75) 53 (75) 56 (>98) 58 (>98) 59 (>98) HEAD CIRCUMFERENCE (cm) (centile) 65.90 (80) 31.81 (>90) 16.36 (40) 25 (30) 27.72 (30) 33.18 (50) (60) 50 53.18 (50) (centile) (kd WEIGHT 5r F Ea "5' 9 0 Y r E. X-Linked Inheritance 317 Auditory Comprehension of Language Test (TACL) at 5 4/12 years. A Fisher-Longemann Test of Articulation Competence showed t h a t he had multiple vowel substitutions and omission of phonemes r, I, j, s, and v. His hearing was evaluated to be normal. A CT scan was read as a suggesting absence of t h e corpus callosum with mild lateral ventricle enlargement. Figure 2. IV-2 at 14% years. recessed mandible. Note high bridge of nose and Figure 3. IV-5 at 9h years. Note high forehead, high nasal bridge and posteriorly angulated ears. 318 Lujan, Carlin, and Lubs Examination (Fig. 3) at 12 9/12 years: height 75%, weight 33%, and OFC at t h e 75%. He had a prominent forehead; thin, narrow face, with a small, recessed mandible; apparently low-set, protruding ears; highly arched palate; pectus excavatum; systolic h e a r t murmur (2/6) diagnosed as an a t r i a l septa1 defect, and generalized joint hyperextensibility. Testicular size was borderline large on t h e right (Table 11). Figure 4. IV-9 at 18 years. Note high bridge of nose and recessed mandible. Patient 3 (Tables I, 11) IV-9 (Fig. 4) DOB: 9/7/64 18 years at last examination BW: 3.68 kg He was born vaginally at t e r m with no apparent pre- or postnatal problems. Psychomotor development was delayed, h e had a hyperactive, aggressive, autistic-like behavior without speech. However, a n initial diagnosis of autism was not confirmed. Hearing was normal. No expressive language was elicited and a severe cognitive delay with f l a t affect was diagnosed. He cries and sucks his thumb frequently. His behavior is consistent with t h a t of a 2 year old. At 12 years results of a n electroencephalogram, and urine amino acid and mucopolysaccharide screen were normal. At 13 years pneumoencephalography and a skull film were normal. Examination (Fig. 4): height at 90th centile, weight > 95%; he had a large forehead and highly arched palate, and normal ears, mandible and chest. His hands were short and stocky with multiple excoriations and bite marks on t h e dorsum of t h e hands. Uric acid level is pending. There was no hyperextensibility; t h e testes were large (Table 11). No focal neurological abnormalities were present. X-Linked Inheritance 319 Patient 4 (Tables I, 11) IV-11 DOB: 10/16/61 21 years at last examination B.W.: 3.21 kg She was born vaginally at t e r m with normal pre-, peri-, and postnatal periods. Psychomotor development was normal and her medical history is unremarkable. She finished 12th grade and is presently working as a cashier in a grocery store. She has had no psychological, hearing, or CNS testing. She is a 172 cm, tall, cooperative young woman, with OFC of 57 c m (95%), with a generally normal facial appearance and normal eyes and ears. She had a highly arched palate, slightly small, recessed mandible and a mildly high-pitched nasal voice. She was without a h e a r t murmur o r joint hyperextensibility and was neurologically normal. Her father was 190 c m and was t h e only parent of t h e a f f e c t e d males who was over 177 cm. Patient 5 (Tables I, 11) IV-12 (Fig. 5 ) DOB: 5/23/64 19 years at last examination BW: 3.72 kg He was born vaginally at t e r m without prenatal problems, and was considered normal until 7 months, when his parents noticed a delay in development (he was unable to lift his head or roll over). He had a seizure associated with f e v e r around 8 years. Figure 5. IV-12 at 19 years. Note prominent forehead, high nasal bridge and recessed mandible. 320 Lujan, Carlin, and Lubs Since 8 months, h e has been in several training-rehabilitative programs. However, he has continued to show generalized developmental delay, but is toilet-trained, c a n dress himself, help with simple tasks around t h e house, and reads slowly. This year h e graduated from a Vocational Training C e n t e r for Special Children. His behavior is jovial, and no hyperactivity has been reported . Examination (Fig. 5 ) at 19 years: height 190 c m , h e was slender and had a n O F C of 58.5 cm; broad forehead and high nasal bridge; apparently low-set, posteriorly angulated ears; highly arched palate; "recessed" mandible; mild malar hypoplasia and pectus excavatum. One testis was large and t h e other borderline (Table 11). Limbs were long and thin with generalized joint hyperextensibility. There was no h e a r t murmur or abnormality of t h e spine. Figure 6 . Individuals IV-2(a), IV-S(b) and IV- 12(c) respectively at 14 10/12 years, 9 years, and 19 years; n o t e facial appearance, tall, thin habitus and pectus excavatum. X-Linked Inheritance 321 DISCUSSION The clinical manifestations in t h e 4 a f f e c t e d males (Tables I and 11) included a tall slender habitus (3) (the fourth was t a l l but muscular), a long-narrow f a c e (3), large head (41, highly arched palate (41, small mandible (41, abnormal speech (41, hypernasal voice (31, joint hyperextensibility (31, borderline to large testes (31, pectus excavatum (21, a t r i a l septa1 d e f e c t (11, and a double row of t e e t h (1). Mental retardation (4) ranged from mild to severe; abnormal behavior included hyperactive and aggressive behavior (21, autistic-like (1) and jovial behavior (1). Various examinations of t h e CNS showed a n absent corpus callosum (11, possible partial absence of t h e corpus callosum with mild enlargement of lateral ventricles (1) and a normal intraventricular system (I). As in other X-linked disorders with MR (XLMR), t h e phenotype was variable and recognition in a sporadic case with minimal findings may be difficult. Although some manifestations of a connective tissue disorder may be seen in other XLMR disorders, none of t h e e n t i t i e s listed by Opitz and Sutherland include a large head and a tall, thin habitus with borderline or slightly large testes. Clearly, t h e inheritance, lack of e y e findings and presence of mental retardation suggest a n entity distinct from Marfan syndrome. The use of t h e phrase "Marfan-like" or "Marfanoid" serves to distinguish t h e condition in this farnily from other XLMR e n t i t i e s and to foster recognition of other families and individuals with this possible syndrome. I t is of g r e a t importance to identify such XLMR syndromes so t h a t linkage and other more definitive studies can be carried out. Acknowledgements Supported in p a r t by NICHD Grant HD 13898. W e thank Patricia A. Lujan for her help in t h e peparation of this manuscript. REFERENCES Fox P, Fox D, and Gerrard J W (1980). X-linked mental retardation: Renpenning revisited. Am J Med Genet 7:491-495. 322 Lujan, Carlin, and Lubs Herbst DS and Miller J R (1980). Nonspecific X-linked mental retardation. 11. The frequency in British Columbia. Am J Med Genet 7: 46 1-464. Morton NE, Rao DC, Lang-Brown H, MacLean CJ, Bart RC, and Lew R (1977). Colchester revisited: A genetic study of mental defect. J Med Genet 14:l-9. Opitz J, Sutherland G (1983). History, nosology and bibliography of X-linked mental retardation. Am J Med Genet. (Present issue). X-linked mental Turner G, Daniel A, and Frost M (1980). retardation, macro-orchidism, and Xq27 fragile site. J Pediatr 96~837-841. Zachmann M, Prader A, Kind HP, Hafliger H, and Budliger H (1974). Testicular volume during adolescence. Helv Paediat Acta 29:61-72. EDITOR'S COFIMEPIT I did n o t include t h i s e n t i t y in the nosologic l i s t in Opitz and Sutherland (elsewhere i n t h i s issue of the Journal) because I remain unconvinced t h a t i t i s d i f f e r e n t from the FIBS with rather more pronounced connective tissue dysplasia. B u t the paper i s printed here because Lujan e t a1 make a good point - namely t h a t phenotypic v a r i a b i l i t y may in f a c t represent causal heterogeneity which issue i s best resolved with linkage studies; a l s o , agenesis of corpus callosurn i s n o t a known component of the FIBS, hence L u j a n e t a1 may be dealing with a genuinely d i f f e r e n t e n t i t y . However, without coronal sections t h i s i s a d i f f i c u l t diagnosis t o make with CT scanning. Edited by John M. Opitz Received for publication September 19, 1983; revision received November 1, 1983.