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American Journal of Medical Genetics 87:88–90 (1999)
Letter to the Editor
Autosomal Recessive Congenital Cerebellar
Hypoplasia and Short Stature in a Large
Inbred Family
tion that, to our knowledge, has not been reported before.
To the Editor:
Nonprogressive cerebellar hypoplasia was first described by Norman [1940]. It is characterized by nonprogressive ataxia, delay in language acquisition, persistent dysarthria, strabismus, hypotonia, and mental
retardation. Neuroimaging demonstrates cerebellar atrophy affecting the vermis and/or hemispheric region.
Histologically, severe degeneration of the granular
cells with moderate to mild degeneration of the Purkinje cells is noted [Ferrer et al., 1987]. Most reported
cases have been sporadic, however, few sibs observations suggest autosomal recessive inheritance [Pascual-Castroviejo et al., 1994].
We report on a large inbred family with 12 cases of
apparent Norman disease with short stature, a condi-
Fig. 1.
Contract grant sponsor: Jérôme Lejeune Foundation.
*Correspondence to: André Mégarbané, M.D., Ph.D., Unité de
Génétique Médicale, Faculté de Médecine, Université SaintJoseph, 42, rue de Grenelle. 75007 Paris, France.
E-mail: megarban@dm.net.lb
Received 30 March 1999; Accepted 14 July 1999
© 1999 Wiley-Liss, Inc.
CLINICAL REPORTS
Members of the kindred (Fig. 1) are Christian Maronites originating from a village in the North-East of
Lebanon. All affected have nearly identical findings
and will be described together. A clinical summary of
each case is presented in Table I.
Gestation and delivery were unremarkable with no
history of exposure to pre- or perinatal environmental
toxins. Delay in psychomotor development was evident
from infancy. All patients could sit by age 3–6 years
and had a limited vocabulary by age 3–5 years. Walking began around age 9–12 years but with truncal titu-
Pedigree.
Letter to the Editor
89
TABLE I. Clinical Summary of the 12 Patients of the Family Under Study
Case
Sex
Age
OFC
(cm)
Height
(cm)
Sat at
(yr)
Walked
at (yr)
Muscle tone
Tendon reflexes
Language
(yr)
Dysarthria
VI-2
VI-4
VI-8
VI-9
VI-10
VI-15
VI-16
VI-17
VI-18
VI-21
VI-22
VI-24
F
M
M
M
M
F
M
M
M
M
M
M
25
22
37
33
23
44
42
40
37
28
27
46
53.5
53.7
54.5
56.3
56
52.3
55.7
55
57
55.5
55
55.5
148
155
160
160
148
136
163
164
162
150
154
157
5
4
5
5
4
5
4
5
5
5
4
5–6
10
9
10
11
10
12
9
12
11
11
9
13
Hypotonic
Hypotonic
Hypotonic/spastic
Hypotonic
Spastic
Hypotonic
Hypotonic/spastic
Hypotonic
Hypotonic
Hypotonic
Hypotonic
Hypotonic/spastic
Absent
Brisk
Brisk
Brisk
Brisk
Brisk
Brisk
Brisk
Brisk
Brisk
Brisk
Arms: absent, legs: brisk
5
4–5
3
4
4
5
4
5
3
4
5
4
+
+
+
+
++
+
+
+
+
+
+
+
bation when standing and needing support in walking.
At age 18–20 years ambulation was possible without
help but wide-based and mildly to severely ataxic. Only
patient VI-10 was unable to walk at age 25 years without using a walker. Speech development showed the
same pattern, but language was still moderately to severely dysarthric in all the patients.
During examination, all were cooperative and smiled
continuously. Occipito-frontal circumference (OFC)
was normal. However, stature was below the 10th centile and less than the 3rd centile in some. There were
no minor anomalies except for a defective dentition
most probably caused by an inadequate hygiene. Dermatoglyphic palm patterns were unremarkable.
Osteotendinous reflexes were increased in all cases
except for VI-2 in which absence of reflexes was noted
and case VI-24 with absence of reflexes in the upper
limbs. All had hypotonia and/or spasticity, mild fingerto-nose ataxia, slightly diminished muscle strength,
flat feet, moderate mental retardation, and defective
orientation. No seizures, sensory abnormalities, and
cranial nerve abnormalities were noted.
Magnetic resonance imaging (MRI) of the brain was
performed for cases VI-2 and VI-8 and showed pronounced cerebellar vermis and bilateral hemisphere
hypoplasia, dilated 4th ventricle, and large cisterna
magna (Fig. 2). Computed tomography scan of the
brain performed during infancy on cases VI-9 and VI24 showed hypoplasia of the cerebellum with no other
brain abnormalities.
Total body radiographs, abdominal ultrasound findings, echocardiography, electroencephalography, elec-
Fig. 2. (A) MRI of the brain of case VI-2 showing the cerebellar hypoplasia and enlargement of the 4th ventricle. (B) Sagittal view of case VI-2 showing
the large cisterna magna.
90
Mégarbané et al.
tromyogram, nerve conduction studies, evoked potentials, auditory brainstem responses, and ophthalmological evaluation carried out in some of the patients
were all unremarkable. Results of complete blood
count, hemoglobin electrophoresis, serum electrolytes,
blood glucose levels, triglycerides, cholesterol, lactate,
pyruvate, amino acid studies of plasma and urine, urinary screening for organic acids, urinalysis, thyroid,
liver and renal function tests, plasma very long chain
fatty acid, and white blood cells enzyme assays screening were all unremarkable. Chromosome study of lymphocytes with high resolution G- and R-banding for
patients VI-8 and VI-15 showed, respectively, a normal
46,XY and 46,XX karyotype.
DISCUSSION
Hereditary congenital nonprogressive cerebellar
ataxia is rare. Half of the cases associated with mental
retardation are genetically caused, mostly autosomal
recessive traits [Harding, 1992]. Although we cannot
confirm the neuropathological studies, the 12 patients
reported herein share characteristics of autosomal recessive Norman cerebellar atrophy known also as the
primary granular cell atrophy of the cerebellum (MIM
213200).
Since the first description of this entity [Norman,
1940], two different types have been defined [PascualCastroviejo et al., 1994]: one with microcephaly, severe
psychomotor retardation, seizures, and agenesis of the
corpus callosum and the other with less severe neurological abnormalities. Our patients belong to this last
group because they do not have microcephaly or gross
brain malformations with only moderate mental retardation. The delay in the acquisition of speech in sentences and ambulation without help in comparison
with other reported patients in literature may reflect
the absence of intensive speech or physical therapy
during infancy because of a delay in obtaining correct
diagnosis and the poor social situation of the family.
The short stature in these patients is rather unusual
because none of the patients reported previously have
had this additional finding. A fortuitous association is
possible; however, we think that the short stature may
be part of the patients’ syndrome. Indeed, the proportionate shortness, absence of minor anomalies, and the
normal X-ray findings of the spine and limbs eliminated a skeletal dysplasia. The mean height of the affected individuals was 154.8 ± 16.3 cm (mean ± 2 SD),
whereas that of the unaffected was 167.3 ± 10.1. The
difference was significant: t ⳱ 4.39 (P < 0.001). No
explanation for this difference in height has been
found, and it would be of value to report on further
familial cases to clarify if this is part of the syndrome or
if we are reporting on an allelic entity. The ongoing
linkage gene study in this family will also help to understand better the genesis of this pathology and to
classify the close entities allowing for appropriate management and counseling.
ACKNOWLEDGMENTS
This work was supported by grants from the Jérôme
Lejeune Foundation.
REFERENCES
Ferrer I, Sirvent J, Manresa JM, Galofré E, Fernandez-Alvarez E, Pineda
M. 1987. Primary degeneration of the granular layer of the cerebellum
(Norman type): a Golgi study. Acta Neuropathologica 75:203–208.
Harding AE. 1992. Hereditary ataxias and related disorders. In: Asbury A,
McKhann GM, McDonald WT, editors. Diseases of the nervous system:
clinical neurobiology, 2nd edition. Philadelphia: W.B. Saunders.
Norman RM. 1940. Primary degeneration of the granular layer of the cerebellum: an unusual form of familial cerebellar atrophy occuring in
early life. Brain 63:365–379.
Pascual-Castroviejo I, Guttierrez M, Morales C, Gonzales-Mediero I, Martinez-Bermejo A, Pascual-Pascual SI. 1994. Primary degeneration of
the granular layer of the cerebellum: a study of 14 patients and review
of the literature. Neuropediatrics 25: 183–190.
André Mégarbané*
Valérie Delague
Nabiha Salem
Jacques Loiselet
Unité de Génétique Médicale
Faculté de Médecine
Université Saint-Joseph
Beirut, Lebanon
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