American Journal of Medical Genetics 82:194–198 (1999)
Previously Apparently Undescribed Autosomal
Recessive MCA/MR Syndrome With Light Fixation,
Retinal Cone Dystrophy, and Seizures:
The M Syndrome
Anita Rauch,1,2 Karla A. Feindt,2 Claire O. Leonard,2 Joel A. Thompson,3 Robert O. Hoffman,4
Donnell J. Creel,5 and John M. Opitz2*
1
Institut für Humangenetik, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Nürnberg, Germany
2
Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, Utah
3
Division of Neurology, University of Utah, Salt Lake City, Utah
4
Division of Pediatric Ophthalmology and Strabismus, University of Utah, Salt Lake City, Utah
5
Department of Anatomy, University of Utah, Salt Lake City, Utah
We report on two sisters from healthy fami-
lies with a syndrome of severe developmen-
tal delay, ataxia, impaired social interac-
tion, a seizure disorder with early onset but
without epileptiform electroencephalogram
changes, and a striking light-fixating behav-
ior which was associated with retinal cone
dystrophy. Additionally, they have minor
anomalies including peripheral iris hypo-
plasia, bluish sclerae, mild anteversion of
nostrils, micrognathia, ear anomalies, broad
halluces and thumbs, hypoplastic toenails,
short perineal body, ‘‘Mongolian spots,’’
mild hirsutism, hypoplastic ridges in the hy-
pothenar area, and distal axial triradii.
Growth and general health are normal in
both, but one also had tetralogy of Fallot
and vesicoureteral reflux. Because this con-
dition appears to be previously undescribed
we postulate a new autosomal recessive dis-
order with light-fixating behavior and reti-
nal cone dystrophy as leading symptom. Am.
J. Med. Genet. 82:194–198, 1999.
© 1999 Wiley-Liss, Inc.
KEY WORDS: autosomal recessive; MCA
syndrome; mental retarda-
tion; seizures; light fixation;
retinal dystrophy
*Correspondence to: J.M. Opitz, Suite 2100, Primary Chil-
dren’s Medical Center, 100 N. Medical Drive, Salt Lake City, UT
84113-1100.
Received 21 January 1998; Accepted 27 September 1998
© 1999 Wiley-Liss, Inc.
INTRODUCTION
We report on two sisters with a previously appar-
ently undescribed multiple anomalies/mental retarda-
tion (MCA/MR) syndrome characterized by a remark-
able behavior of staring at bright lights associated with
abnormal cone function, peripheral iris hypoplasia,
broad halluces and thumbs, developmental delay with
ataxia and seizure disorder, but with normal growth
and health.
CLINICAL DATA
The girls are the only children of their healthy, noncon-
sanguineous Brazilian parents with unremarkable family
histories. Clinical findings are listed in Tables I and II.
Patient 1
During the second month of pregnancy there was a
bloody discharge and possible decrease of fetal move-
ment, but ultrasound findings were normal. The girl
was delivered at 38 weeks by Cesarean section and had
Apgar scores of 9 and 10. With reference to normal
Brazilian girls, birth measurements reflected mild pre-
natal growth deceleration. The newborn infant had
substantial congenital hypotonia and was described as
a quiet baby who cried little. Reduced visual contact
suggested hearing loss, but results of audiography
were normal. Tetralogy of Fallot was discovered in in-
fancy and was repaired successfully at the age of 1
year. She also has had grade II vesicoureteral reflux
with urinary tract infections being treated with Keflex.
At 2 months the infant developed apparent myoclonic
jerks and a febrile seizure after immunizations. She
has been treated with valproic acid and phenobarbital
with good control. However, all electroencephalogram
(EEG), computed tomographic (CT), and magnetic
resonance imaging (MRI) scan results were normal.
Without fever she appears to experience some ab-
sences. Gross motor development was delayed and the
girl has not learned to play well. She has had numerous
 M Syndrome 195

TABLE I. Clinical Findings in the Affected Sisters*

Patient 1 Patient 2
Age of last investigation 4 years 2 years
Pregnancy Bleeding during 2nd month, Bleeding during 2nd month
decreased fetal movement
Birth
Weeks of pregnancy 38 40
Birth weight (g) 2890 3550
Birth length (cm) 47 50
OFC at birth (cm) 32.5 36
Apgar scores 9/10 9/10
Congenital hypotonia + −
Congenital heart disease Tetralogy of Fallot −
Urogenital system Vesicoureteral reflux II° R>L −
Growth
Height (centile) 50th >98th
Weight (centile) 50th 98th
OFC (centile) 50th 98th
Neurology
First walked (assisted) 24 months −
First words − −
Toilet trained − −
Social interaction Minimal Minimal
Muscle tone Hypotonic Hypotonic
Deep tendon reflexes Brisk with crossed adductor reflexes Brisk
Superficial reflexes Absent Absent
Seizures Myoclonic jerks with fever, absences Myoclonic jerks, absences (1st at 1
(1st at 2 months) month)
Ataxia + +
EEG Diffuse slowing of background Normal for age
CT Normal Normal
MRI Normal Mild atrophy
Light fixation + +
Morning temperature peaks + −
Intermittent periods of happiness + +
and laughter
Craniofacial
Skull shape Dolichocephalic Dolichocephalic
Metopic suture Normal Slight prominence
Epicanthus − Mild, bilaterally
Sclerae Mildly grayish-bluish, pigmented Mildly grayish-bluish, pigmented
spots spots
Exophthalmos − Mild
Iris Peripheral hypoplasia Peripheral hypoplasia
Eye function Fine rotary nystagmus, convergent Nystagmus; myopia (−5 dpt.)
strabismus, alternating esotropia;
hyperopia (+5 dpt.)
Retinal function Abnormal cone function Abnormal cone function
Ears R tragus bifid, helices somewhat Bil. slightly underdeveloped tragus,
hypoplastic bil. prominent helix
Hearing Normal Normal
Nose Anteversion of nostrils Mild anteversion of nostrils
Cheeks Normal Prominent
Mouth Normal Anterior mordex apertus
Micrognathia Mild Mild
Trunk
Hirsutism Mild, mainly back Mild, mainly back
Perineal body Short Short
Sacral region Faint Mongolian spot Mongolian spots
Limbs
Broad thumbs + +
Broad halluces + +
*Table continued on following page.

metabolic studies and cytogenetic analyses with nor-
mal results.
At 4 years (Fig. 1) this healthy, well-nourished child
manifested severe developmental delay with minimal
interaction, ataxia, hypotonia, and brisk reflexes, but
with normal strength. She was being treated with val-
proic acid. There was a striking light-fixating behavior
with normal fundi. Abnormal cone function was de-
tected on the basis of decreased flicker-following re-
sponse, low normal response to a single bright flash,
and decreased visual-evoked responses bilaterally.
However, on the basis of this testing it was not possible
196 Rauch et al.

TABLE I. Clinical Findings in the Affected Sisters (Continued)

Patient 1 Patient 2
Brachydactyly Bil. Dubois sign −
Nail hypoplasia Small, short toenails Broad, short toenails
Lymphedema Mild Pronounced
Heel cord Mild contracture Normal
Normal test results
Chromosomes (HRB) ✓
Acylcarnitine profile ✓
Urine organic acids ✓
CSF glycine, glucose, lactate, ✓
protein
Quantitative serum amino acids ✓
Quantitative urine amino acids ✓
Very long chain fatty acids ✓
Urinalysis ✓ 1 + protein
Urine culture ✓ Pseudomonas aeruginosa
Liver function tests ✓ Mild elevation of GGT consistent with
effects of valproic acid
Complete blood count ✓ Mild anemia (Hct 29%) with normal
red cell indices
Serum electrolytes, ammonia
Lactate, glucose and creatinine ✓ ✓
EEG Diffuse slowing, no epileptic focus Diffuse slowing, no epileptic focus

to distinguish between a cone dystrophy or diffuse reti-
nal dysfunction with more cone than rod involvement.
Occasionally, in the morning there were temperature
spikes of a low-grade nature ranging from 38.0 to
38.1°C. However, no infectious source was found in the
upper airway system, blood, urine, or cerebrospinal
fluid. Metabolic studies including acyl carnitine profile
(for organic acid disorders and disorders of fatty acid
metabolism), quantitative serum amino acids, urine or-
ganic acids, quantitative urine amino acids, very long
chain fatty acids, and cerebrospinal fluid glycine, espe-
cially to rule out biotinidase deficiency, argininosuc-
cinic aciduria, argininemia and Leigh disease, failed to
show any abnormalities. Results of high-resolution
chromosome analysis, fluorescent in situ hybridization
for 22q11.2 deletion (probe D22S75), and DNA studies
for Angelman syndrome (methylation-specific polymer-
ase chain reaction for SNRPN) were normal.
Patient 2
As in Patient 1 there was spotting during the second
month of pregnancy but fetal movements were consid-
ered normal. The girl was delivered by elective Cesar-
ean section at 40 weeks with Apgar scores of 9 and 10
and normal birth measurements. After her first immu-
nization at 1 month she developed myoclonic jerks and
has been treated since then with valproic acid. Without
fever there were some absences. At age 2 years (Fig. 2)
the girl appeared, like her sister, a healthy, well-
nourished child with severe developmental delay,
ataxia, hypotonia, and brisk reflexes but with normal
strength. Her fundi were normal; however, she also

TABLE II. Dermatoglyphics

Patient 1 Patient 2 Mother Father
R L R L R L R L
Palmar creases n n Sydney n n n n n
t/palm ratio 17.2 21.5 12.9;64.3 11.3;59.6 11.5 11.7 13.1 5.0
Axial triradii t⬘ t⬘ t, t⬙ t, t⬙ t t t t
Thenar pattern − − − − − − − −
Hypothenar pattern − − LU LU − − − −
Digital triradii abcd abcd abcd abcd abcd abcd abcd abcd
Interdigital pattern I4 VRd I4 VRd − I4 V I3 V I4 VRd I 4 Ld I4 V
Pattern
I U 16 U 10 WTL 14;6 U 12 WTL 18;9 U 10 U 19 U9
II R4 R4 WCP 11;7 U9 WCP 12;5 U9 R5 R5
III U 12 U 12 U 13 U 18 U 12 U 11 U 12 A
IV U 10 WCP 12;9 WCP 13;6 ULP 13 ULP 13 ULP 13 U 17 U 14
V U7 U5 ULP 14 ULP 14 U9 U 10 U 12 U7
AFRC 101 150 131 100
TFRC 92 138 117 10
atd angle 42° 41.5° 40.5°; 122° 43°; 98° 34° 34° 40° 35°
a-b ridge count 46 49 44 46 47 42 43 44
White lines ↑ ↑ ↑ ↑ n n n n
Hypoplastic ridges in + + + + (+) (+) (+) (+)
hypothenar area

Fig. 1.
manifested the same striking light-fixating behavior
and had a form of retinal dysplasia on electrophysi-
ological studies. EEG, CT, and MRI scan, chromosome
analysis, and DNA studies for Angelman syndrome
and metabolic screening were normal. She had coinci-
dental urinary tract infection with Pseudomonas aeru-
ginosa and dermatosis due to scabies. Electrolytes, glu-
cose, and creatinine were normal, but liver function
test showed mild elevation of GGT consistent with ef-
fects of valproic acid. There was also mild anemia (he-
matocrit 29%) with normal red cell indices.
DISCUSSION
The sisters we describe have a syndrome of severe
developmental delay with ataxia and minimal social
Fig. 2.
M Syndrome 197
Patient 1 at 4 years.
interaction, seizure disorder with onset at age 1 to 2
months but without epileptiform EEG changes, and
striking light-fixating behavior which may be related
to the abnormal cone function found in both. Addition-
ally, they have minor anomalies in common such as
peripheral iris hypoplasia, bluish sclerae, mild ante-
version of nostrils, mild micrognathia, mild ear anoma-
lies, broad halluces and thumbs, hypoplastic toenails,
short perineal body, ‘‘Mongolian spots,’’ and mild hir-
sutism. Growth and general health are normal. A gross
malformation was evident only in Patient 1 and con-
sisted of tetralogy of Fallot; she also had vesicoureteral
reflux. To our knowledge, this presumably autosomal
recessive condition has not been described previously.
A tempting diagnosis was the disorder of X-linked fe-
Patient 2 at 2 years.
198 Rauch et al.
male-restricted epilepsy with mental retardation
(EFMR) [Juberg and Hellman, 1971; Ryan et al., 1997],
which is associated with normal development until age
4 to 18 months and subsequent developmental regres-
sion presumably secondary to the grand mal convulsive
disorder. However, there was no evidence of regression
in our patients and family history was otherwise unre-
markable. Hyperreflexia is absent in the EFMR syn-
drome and all patients have remained ambulatory.
Furthermore, cone dystrophy or light-staring behavior
has not been described in EFMR syndrome patients.
The girls do not have the Angelman syndrome, al-
though they have a happy nature, nor was there any
evidence of periventricular heterotopias [Fink et al.,
1997] in repeated MRI studies.
We would like to draw attention to the light-staring
behavior and apparent retinal cone dystrophy as a
leading symptom to determine if this condition has
been observed in other patients.
ACKNOWLEDGMENTS
We are most grateful to the D/M family for the privi-
lege of studying their daughters, and to the staff of
Primary Children’s Medical Center for their care of
this family, for providing Portuguese language exper-
tise, and to all of the professional colleagues, house
staff, and medical students who provided consultation
and care. The critical review and comments of Drs.
Richard I. Kelley and William B. Dobyns are greatly
appreciated.
REFERENCES
Fink JM, Dobyns WB, Guerrini R, Hirsch BA. 1997. Identification of a
duplication of Xq28 associated with bilateral periventricular nodular
heterotopia. Am J Hum Genet 61:379–387.
Juberg RC, Hellman CD. 1971. A new familial form of convulsive disorder
and mental retardation limited to females. J Pediatr 79:726–732.
Ryan SG, Chance PF, Zou C-H, Spinner NB, Golden JA, Smietana S. 1997.
Epilepsy and mental retardation limited to females: an X-linked dom-
inant disorder with male sparing. Nat Genet 17:92–95.