Alobar Holoprosencephaly: Report of Two Cases with Unusual

Case Report
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Alobar Holoprosencephaly:
Report of Two Cases with Unusual Findings
Li-Hsiung Chang, MD
Holoprosencephaly, a disorder resulting from failure of cleavage or incomplete differentiation of the forebrain structures at various levels or to various degrees, is related to hereditary factors, chromosomal anomalies, cytogenetic abnormalities, and environmental teratogenic factors. We report on 2 cases of alobar holoprosencephaly, with similar physical findings, including microcephaly, microphthalmia, cebocephalus, choanal atresia, pseudo cleft
palate, distended abdomen, and acrocyanosis. The brain echogram of these 2 patients
demonstrated fused thalami and a single large U-shaped ventricular cavity. Chromosome
studies of these 2 patients were normal. The findings of the autopsies confirmed the clinical
presentations. One of our cases had a clinical picture similar to that of holoprosencephalypolydactyly syndrome. The other had the rare anatomical finding of a polylobuated spleen.
Because of the poor prognosis of alobar holoprosencephaly, early prenatal diagnosis is recommended. (Chang Gung Med J 2003;26:700-6)
Key words: alobar holoprosencephaly, polydactyly, polysplenia.
I
n 1963, Demyer and Zeman(1) proposed the term
holoprosencephaly which is a disorder resulting
from failure of septation, cleavage, or differentiation
of the midline forebrain structures at various levels
or to various degrees. Defects in development of the
midfacial region frequently coexist. The disease
affects both components of the forebrain: the telencephalon and the diencephalon. Demyer et al. divided the pathological characteristics of the forebrain
into 4 categories: lobar (presence of an interhemispheric fissure but the cingulate gyrus and the lateral
ventricles are fused, and there is no septum pellucidum), semilobar (posterior partial formation of the
interhemispheric fissure, with only a single ventricle), variant (heterotopic gray matter), and alobar
(absence of the interhemispheric fissure, falx cerebri,
the third ventricle, and fused thalami, and often
absence of neurohypophysis and olfactory tracts)
ones according to the graded degrees of failed differentiation.(1) The various holoprosencephalic abnormalities of the face include cyclopia, proboscis, ethmocephalus, cebocephaly, premaxilla agenesis,
median cleft palate/lip, and other less-severe facial
dysmorphism.
Holoprosencephaly is an extremely heterogeneous disease, whose origin can be related to chromosomal, monogenic, and environmental teratogenic
factors and which may be associated with other
anomalies.
We present the clinical, cytogenetic, and pathological findings of 2 newborn babies. One who possessed preaxial polydactyly had clinical presentations similar to those of holoprosencephaly-polydactyly syndrome; the other had the rare finding of a
polylobulated spleen.
From the Department of Pediatrics, Taichung Hospital, Department of Health, Executive Yuan, Taichung.
Received: Sep. 25, 2002; Accepted: Mar. 4, 2003
Address for reprints: Dr. Li-Hsiung Chang, Department of Pediatrics, Taichung Hospital, Department of Health, Executive Yuan.
199, San-Min Road, Sec. 1, Taichung 400, Taiwan, R.O.C. Tel.: 886-4-22294411 ext. 2276; Fax: 886-4-22585806; E-mail:
63053@mail.taic.tpg.gov.tw
Li-Hsiung Chang
Alobar holoprosencephaly
CASE REPORT
Case 1
This was the second pregnancy of non-consanguineous parents, aged 33 and 35 years, respectively.
A
C
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The first pregnancy of the mother had ended with a
spontaneous abortion. There was a history of neither
hereditary disease nor chromosome disorders in
either family. The mother had received no regular
B
D
Fig. 1 Case 1. (A) Anterior view of the face; (B) brain sonogram; (C) single large ventricle without septation; and (D) polylobulated spleen.
Chang Gung Med J Vol. 26 No. 9
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Li-Hsiung Chang
Alobar holoprosencephaly
prenatal checkups, including ultrasound examination,
during the entire course of the pregnancy; hence, no
diagnosis was made during the prenatal stage. In the
38th week of gestational age, a female baby weighing 3200 g was born via cesarean section due to premature rupture of the membrane for 8 hours.
General cyanosis and delayed initial crying occurred
immediately after delivery. The Apgar scores were 5
at 1 min and 7 at 5 min. She was immediately
admitted to the neonatal intensive care unit. Physical
examinations showed lethargy, microcephaly (less
than the 3rd percentile), short stature (less than the
3rd percentile), microphthalmia, hypotelorism, cebocephalus, choanal atresia, pseudo cleft palate, a moderately distended abdomen, and acrocyanosis. The
newborn died on the third day of life. A brain
A
C
echogram performed on the first day of admission
showed a fused thalamus and a single large U-shaped
ventricular cavity. The chromosomal analysis
showed a 46,XX, normal karyotype.
An autopsy was performed with the parents'
consent. The abnormal findings of the autopsy
included: (1) a single large ventricle with an opening
to the posterior part of the brain, (2) the absence of
olfactory and optic nerves, (3) dysgenesis of the
hypopituitary, thyroid, and adrenal glands, (4)
choanal atresia, (5) no lobulation of the left lung, and
(6) polylobulation of the spleen.
Case 2
This female baby was born to 34- and 31-yearold, non-consanguineous parents who had suffered
B
D
Fig. 2 Case 2. (A) Anterior view of the face; (B) brain sonogram; (C) preaxillary polydactyly; and (D) single large ventricle without septation.
Chang Gung Med J Vol. 26 No. 9
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Li-Hsiung Chang
Alobar holoprosencephaly
from infertility for 3 years. The primigravida was
transferred to our obstetric department for confirmation of hydrocephalus which was suspected during
the last month of pregnancy by local medical clinics.
Fetal ultrasonography at 37 weeks of gestation
revealed oligohydramnios, microcephaly, a single
large ventricle, a fused thalamus, and hypotelorism.
A tentative prenatal diagnosis of alobar holoprosencephaly was made. A child weighing 2900 g was
born at 38 weeks of gestation by cesarean section
due to breech presentation. A delay of initial crying
was found after delivery. The Apgar scores were 4 at
1 min and 6 at 5 min. There were similar abnormal
physical findings as those of case 1, including microcephaly, microphalmia, hypotelorism, cebocephalus,
a pseudo cleft palate, and choanal atresia; preaxial
polydactyly of the left hand was an additional finding. The results of a postnatal brain echogram were
the same as those of the prenatal stage. She died at
30 hours of age. The karyotype of the patient was
46,XX. The abnormal findings by autopsy included:
(1) a single large ventricle with an opening to the
posterior part of the brain and a fused thalamus, (2)
the absence of olfactory and optic nerves, (3) dysgenesis of the hypopituitary, thyroid, and adrenal
glands, (4) choanal atresia, and (5) polydactyly.
DISCUSSION
During the third week of embryonic life, the
prechordal mesoderm migrates into the area prior to
the notochord and affects midline facial development; hence, before 4 weeks of embryonic age, the
varying degrees of loss or disruption in the development of prechordal mesoderm cause abnormal forebrain development and midfacial defects.(2)
Holoprosencephaly, the most common structural
anomaly of the developing forebrain and midface in
humans, is a disorder in which the cephalic neural
tube fails to develop and does not divide into right
and left lobes. Holoprosencephalon is the term used
to describe a single, unpaired forebrain.
The epidemiology of holoprosencephaly was
poorly described before, partly due to the inclusion
of only small case numbers and there being no basal
population; on the other hand, there is marked natural loss of the fetus, while milder forms may go
unrecognized. Consequently, the prevalence rate differs in various study groups. During early embryo-
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genesis, it is about 1 in 250; due to the high rate of
spontaneous abortion, the prevalence rate in live
births ranges from 1: 14,736 to 1: 26,730.(3) The first
population-based survey of holoprosencephaly
prevalence provided by Bullen et al. representing the
total prevalence (including pregnancy termination)
was 1.2 cases per 10,000 registered births, and the
birth prevalence (affected live births and stillbirths at
> 24 weeks' gestation) was 0.49 cases per 10,000
births.
The etiology of holoprosencephaly indicates
interactions with both genetic and environmental factors, including chromosomal anomalies, gene
rearrangements, mendelian mutations, and teratogens, and it can usually be determined.
Although it is extremely heterogeneous, there
may be a common final pathway for the abnormal
development of the forebrain and face. The majority
of holoprosencephaly cases are sporadic; cases of
familial holoprosencephaly are reported to be autosomal dominant, autosomal recessive, or X-linked in
inheritance. Nearly 50% of all holoprosencephaly
cases have cytogenetic abnormalities, and approximately 18%-25% of patients of holoprosencephaly
have a documented monogenic syndrome.(4,5) To the
present, there are at least 12 known loci which may
contain genes critical for normal brain development
on 11 chromosomes. Trisomy 13 is the most commonly identified cause; others include trisomy 18,
HPE1(21q22.3), HPE2(2p21,SIX3), HPE3(7q36,
SHH,SonicHedgehog), HPE4(18p11.3,TGIF), (6)
HPE5(13q32,ZIC2), HPE6(3p24-pter), HPE7
(13q12-q14), HPE8(14q13), HPE9(20p13), HPE10
(1q42-qter), HPE11(5p), HPE12(6q26-qter), (7)
t(7;13)(q21.2;q33), 3q22 deletion,13q33, q34 or 35qter deletion, 7q36-qter deletion, and 14q22 deletion,del(14) (q11.1q13).(8) Environmental teratogens
reported to induce holoprosencephaly include maternal diabetics (with a reported 200-fold increase in the
incidence of holoprosencephaly in infants of diabetic
mothers over infants of non-diabetic mothers), (9)
steroid alkaloids, thanol, and retinoic acid. (10)
Syndromatic associations include Martin syndrome,
Steinfeld syndrome, CHARGE association, MeckelGruber syndrome, Kallmann syndrome, HallPallister syndrome, Vasidi syndrome,(11) Smith-LemliOpitz syndrome, holoprosencephaly-polydactyly
syndrome, (12) and Rubenstein-Taybi syndrome.
Associated abnormalities include microcephaly,
Chang Gung Med J Vol. 26 No. 9
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Li-Hsiung Chang
Alobar holoprosencephaly
hydrocephalus, agenesis of the corpus callosum, posterior fossa abnormality, cerebellar vermis aplasia,
myelomingocele, absence of an olfactory bulb, a
cleft lip/palate, adrenal hypoplasia, renal dysplasia,
renal cysts, omphalocele, cardiovascular malformations, intestinal abnormalities, club foot,
sirenomelia, (13) spina bifida, and endocrinopathies
(pituitary gland dysplasia, growth hormone deficiency, and diabetes insipidus).(14) Knowing the etiologies of holoprosencephaly is important for establishing the risk of recurrence.
One of our cases with a normal karyotype, who
possessed polydactyly, and adrenal and thyroid gland
dysgenesis, is compatible with the clinical picture of
holoprosencephaly-polydactyly syndrome, a moreneutral term recommended by Verloes et al.(12) to substitute for the previous term of pseudotrisomy 13
syndrome suggested by Hewitt et al.(15) The characteristics of the polydactyly in our patient was of the
preaxial type, in comparison to the postaxial polydactyly in all reported cases of holoprosencephalypolydactyly syndrome. Most cases of holoprosencephaly-polydactyly syndrome are sporadic, but
autosomal recessive and autosomal dominant modes
of inheritance have also been reported. The hypothesis is that a chromosomal rearrangement or duplication occurs between 13q31 and 13q34. In 1991,
Raoul suggested the use of the descriptive name of
autosomal recessive holoprosencephaly, heart defect,
and postaxial polydactyly syndrome. (16) In 1993,
Lurie and Wulfsberg suggested the use of an
eponymic name, such as the Cohen-Gorlin syndrome, because they found that neither holoprosencephaly nor polydactyly was an obligatory manifestation of this disease entity.(17) One of our patients
had polysplenia which is a rare finding in holoprosencephaly cases.
The phenotypic expression of holoprosencephaly varies widely. "The face predicts the brain"
as recommended by DeMyer et al. in 1963(1) is correct in about 70%-80% of cases, but not in all children with holoprosencephaly. The craniofacial anomalies include cyclopia (a single eye or partially divided eyes in a single orbit with a proboscis above the
eye), ethmocephaly (severe hypotelorism and a proboscis between the eyes), cebocephaly
(hypotelorism, a single nostril, and a blind-ended
nose), premaxillary agenesis, arhinencephalia (the
absence of olfactory bulbs and tracts), agenesis of the
Chang Gung Med J Vol. 26 No. 9
September 2003
corpus callosum. Facial-only phenotypes include
midface hypoplasia, hypotelorism, coloboma,
microphthalmia, unilateral or bilateral clefts, solitary
central incisor and/or pyriform aperture stenosis,
hypotelorism, the absence of nasal bones or a flat
nose, and the absence of the upper lip midline frenulum. Milder forms may be unrecognized if imaging
studies of the brain are not arranged.
Patients with severe forms of holoprosencephaly
usually die during the first year of life.(19) Both of our
cases who were diagnosed to be of the alobar type
expired within 3 days after birth. The less-severe
forms, i.e., semilobar or lobar holoprosencephaly,
may allow longer life spans if other associated
abnormalities are not life threatening. But all survivors have the inability to smell, developmental
delay, profound intellectual impairment, and
seizures.(19) Other problems include (1) increased
muscle tone to the point of spasticity, poor control of
muscles, and contractures; (2) fluctuating behavior
between calmness and irritability, with sudden
changes in mood; (3) hoarse, barking, or a highpitched voice; (4) difficulty with swallowing, choking spells and gagging during feedings, spitting up,
frank vomiting, risk of aspiration, and constipation;
(5) growth delays, (6) sleep disturbances; (7) periodic brain stem and/or hypothalamus dysfunction with
irregular breathing, heart rhythm, and heart rate, and
unstable temperature control; and (8) pituitary and/or
thyroid gland dysfunction.(18) The cause of death is
usually abnormal brain stem function, especially
superimposed with infection, diabetes insipidus causing severe dehydration, or intractable seizures.
Early detection by sonography offers a better
and earlier diagnostic procedure than amniocentesis.
The earliest gestational age at the time of diagnosis
was 14 weeks. Because of the short life span and
ominous outcome in all patients with alobar holoprosencephaly, genetic counseling and prenatal diagnosis by ultrasound (transabdominal or transvaginal
scanning) are of great importance for early detection
and allows earlier termination of the pregnancy.(19)
In summary, we report on 2 cases of alobar
holoprosencephaly with the special findings of polysplenia in case 1 and preaxial polydactyly in case 2.
The variety of clinical pictures and the complexity of
genetics in holoprosencephaly require further investigations in clinical, radiological, pathological, genetic, embryological, and teratogenic fields.
Li-Hsiung Chang
Alobar holoprosencephaly
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