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A form of X-linked mental retardation with marfanoid habitus.

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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.
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