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Prenatal ultrasound diagnosis of holoprosencephaly and associated anomalies

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Hemang D Chaudhari
Hemang D Chaudhari
Hemang D Chaudhari
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Gurudatt Thakkar at Sakalchand Patel University,Visnagar
Gurudatt Thakkar
  • Sakalchand Patel University,Visnagar
Parth Darji
Parth Darji
Pratik Khokhani
Pratik Khokhani
Pratik Khokhani
  • This person is not on ResearchGate, or hasn't claimed this research yet.
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Abstract and Figures

Holoprosencephaly is a rare spectrum of cerebral and facial malformations resulting from incomplete division of the embryonic forebrain (prosencephalon) into distinct lateral cerebral hemisphere. Holoprosencephaly spectrum in the fetus is often associated with other anomalies, particularly of the face and extremities. Here we present three different cases of patients with holoprosencephaly who failed to attain routine sonography during 11-20 weeks owing to some unavoidable circumstances. Two of them were diagnosed during the third trimester and one in the late second trimester. Ultrasound findings of associated anomalies were confirmed after a clinical examination of the delivered fetuses.
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Rare disease
Prenatal ultrasound diagnosis of holoprosencephaly
and associated anomalies
Hemang D Chaudhari, Gurudatt Thakkar, Parth Darji, Pratik Khokhani
Department of Radiology, Smt. S.C.L. Municipal General Hospital, Smt. N.H.L. Municipal Medical College, Ahmedabad, Gujarat, India
Correspondence to Dr Hemang D Chaudhari, drhdc1@yahoo.com
Summary
Holoprosencephaly is a rare spectrum of cerebral and facial malformations resulting from incomplete division of the embryonic forebrain
(prosencephalon) into distinct lateral cerebral hemisphere. Holoprosencephaly spectrum in the fetus is often associated with other
anomalies, particularly of the face and extremities. Here we present three different cases of patients with holoprosencephaly who failed to
attain routine sonography during 11–20 weeks owing to some unavoidable circumstances. Two of them were diagnosed during the third
trimester and one in the late second trimester. Ultrasound findings of associated anomalies were confirmed after a clinical examination of
the delivered fetuses.
BACKGROUND
Holoprosencephaly is estimated to occur in 1 of 10 000–
20 000 live births. It is divided into alobar, semilobar and
lobar forms, although there are no clear-cut defining fea-
tures. A series of facial anomalies are frequently asso-
ciated, owing to the common origin of the embryonic
forebrain and mid-face from the prechordal mesoderm,
along with some other anomalies. We report the three
selected cases for their rarity and different anomalies
associated with them, in addition to holoprosencephaly.
This case report evaluates the importance of early ultra-
sound in prenatal diagnosis of holoprosencephaly and
associated anomalies in a fetus and the dreaded outcome
if diagnosed late.
CASE PRESENTATION
Case 1
A 27-year-old primigravida with natural conception was
referred in the third trimester for fetal well-being. A previ-
ous ultrasonography was done at 6 weeks for confirm-
ation of pregnancy and showed a single intrauterine
gestational sac with fetal pole with cardiac activity.
Crown rump length was 4.2 mm, consistent with a
6-week 2-day maturity. After that, she came for an ultra-
sonography examination directly in the third trimester.
Case 2
A 36-year-old woman, gravida 5, para 3, abortion 1, live
issues 3, was admitted with labour pains and referred for
sonography for the first time at 35 weeks of gestation for
fetal well-being and advanced maternal age in her fifth
pregnancy. She did not have any previous sonography
available with her. She had three normal children and one
abortion at 9 weeks in her second pregnancy, because of
some unknown cause.
Case 3
A 22-year-old Indian woman, gravida 1 para 0, came for
the first time in the second trimester of her pregnancy for
sonographic confirmation of gestational age.
In all the above-mentioned cases, rest of the medial and
family histories were unremarkable.
Physical examinations and all other laboratory investi-
gations were within normal limits.
INVESTIGATIONS
Case 1
Ultrasonography revealed a single monoventricular cavity
with partial agenesis of the corpus callosum and fused
thalami suggestive of semilobar-type holoprosencephaly.
A mild degree of hypotelorism was noted. In addition, the
Figure 1 Two different sections of fetal skull showing a large monovetricular cavity.
BMJ Case Reports 2012; doi:10.1136/bcr-03-2012-6129 1of6
fetus had a cleft lip. The fetal spine did not reveal
any abnormality. Fetal parameters were consistent with a
32–33-week maturity of the fetus (figures 1–4).
Case 2
Ultrasonography revealed a single intrauterine live fetus.
Biparietal diameter, abdominal circumference and femur
length were consistent with the clinically estimated gesta-
tional age of 34–35 weeks. Axial sonograms of the fetal
head showed a dilated, large monoventricle with a periph-
eral rim of the cortex and fused thalami. Falx cerebri
was present. The fetal spine showed meningomyelocoele
in the lower lumbar region. Extrarenal pelvis was noted
in the right kidney, an incidental finding. No facial or
extremity anomalies were noted (figures 5–8).
Case 3
Case 3 Sonographic examination of the uterus revealed a
single living fetus. Axial sonograms of the fetal head
showed dilated cerebral ventricles and fused thalami. The
spine showed meningomyelocoele in the lumbar region.
Fetal biparietal diameter, abdominal circumference and
femur length were consistent with the clinically estimated
gestational age of 26–27 weeks. Mild polyhydramnios was
noted (figures 9–11).
OUTCOME AND FOLLOW-UP
Case 1
A male child was born by vaginal delivery after induction.
A clinical examination revealed the presence of a cleft lip
and a mild degree of hypotelorism. The neonate also had
limb abnormalities that were not documented on sonog-
raphy because of the abnormal position and slightly less
amount of liquor (9–10 amniotic fluid index). (However,
we had informed the gynaecologist about this possibility.)
The neonate died several hours after birth.
Case 2
A male child was born by vaginal delivery. A clinical exam-
ination revealed the presence of meningomyelocoele in the
lower lumbar region. The neonate was admitted to the
neonatal intensive care unit and died 2 days after birth.
Case 3
Subsequent sonographies at 30 and 34 weeks were done.
The sonogram at 34 weeks confirmed the suspected fetal
Figure 2 Semilobar type of holoprosencephaly showing fused
thalami.
Figure 3 Profile view of face showing cleft lip.
Figure 4 Postnatal image of neonate showing cleft lip and limb abnormalities.
2of6 BMJ Case Reports 2012; doi:10.1136/bcr-03-2012-6129
demise. The female child showed meningocoele in the
lumbar region on postnatal examination.
DISCUSSION
Holoprosencephaly arises from disruption of the normal
induction and patterning of the rostral neural tube during
early embryogenesis.
1–6
The primary brain vesicles, the prosencephalon, mesen-
cephalon and rhombencephalon, are formed by the third
embryonic week. Separate lateral telencephalic and
diencephalic structures develop from a single prosencepha-
lic vesicle, normally beginning by the fifth embryonic
week of gestation.
6
Holoprosencephaly results from incomplete cleavage
of the prosencephalon, occurring between the 18th and
the 28th day of gestation and affecting the forebrain
and the face. Deficiencies in embryonic forebrain cleav-
age range from the most severe or alobar forms to the
Figure 7 Meningomyelocoele in the lower lumbar spine.
Figure 6 Fetal skull showing fused thalami and falx crebri.
Figure 5 Axial section of fetal skull showing a large monoventricular cavity and a peripheral thin rim of brain parenchyma.
BMJ Case Reports 2012; doi:10.1136/bcr-03-2012-6129 3of6
least severe or lobar forms and middle interhemispheric
variant.
13
Distinctive midline facial malformations occur in most
cases. These malformations are correlated with the degree
of holoprosencephaly and have prognostic importance.
78
This includes:
▸Cyclopia, in which a single, midline, fused eye exists in
a single orbit below a proboscis.
▸Ethmocephaly, in which ocular hypotelorism is present
with an interorbital proboscis.
Figure 8 Axial section of the abdomen showing extrarenal pelvis in the right kidney, an incidental finding.
Figure 9 Semilobar type of holoprosencephaly showing a large monoventricular cavity and fused thalami.
Figure 10 Meningomyelocoele in the lumbar spine.
4of6 BMJ Case Reports 2012; doi:10.1136/bcr-03-2012-6129
▸Cebocephaly, in which ocular hypotelorism is present
with a single-nostril nose.
▸Ocular hypotelorism and midline clefting.
▸Ocular hypotelorism and bilateral clefting.
13
Other malformations include arhinencephaly (absent
olfactory bulbs and tracts), absent thalami, hydrocephalus
and neural migration abnormalities. In case 1, ocular
hypotelorism and midline clefting were present.
The frequency of holoprosencephaly is 1 in 10 000–
20 000 live newborn. During the early embryonic period,
the frequency is 1 in 250 but progressively declines
because of high fetal death rates.
4910
Researches into the aetiology of holoprosencephaly
have revealed multiple teratogenic and genetic causes
(chromosomal and single gene). The involvement of mul-
tiple genes has been implicated in ventral forebrain induc-
tion; their products include the Sonic Hedgehog (Shh)
protein and the Hedgehog signal transduction proteins
patched (Ptc),
11
as well as proteins in the Gli family and
cholesterol biosynthesis pathways.
12
Prenatal diagnosis of holoprosencephaly is based on
transabdominal or transvaginal ultrasonography and
MRI to identify most cases of alobar or semilobar
holoprosencephaly.
In our cases, diagnosis was based on transabdominal
ultrasonography and clinical examination.
Treatment in severe forms of holoprosencephaly is
symptomatic and supportive, and requires a multidiscip-
linary management. The outcome of the child depends on
the severity of holoprosencephaly and the associated
medical and neurological complications.
Learning points
▸Holoprosencephaly can be diagnosed even in the first
trimester after 11–12 weeks. So, routine prenatal
ultrasound should be carried out in all patients during
this period.
▸Ultrasound is a good modality for prenatal diagnosis of
holoprosencephaly that is frequently associated with
midline face deformity such as cleft lip and palate, as
mentioned earlier in case 1.
▸In addition to facial anomalies, anomalies of the spine
and extremities are frequently associated with it and
one must look for them, such as meningomyelocoele in
case 2 and case 3 and limb abnormalities in case 1.
▸The radiologist should remain vigilant in suspected
patients who have a history of a child with
holoprosencephaly, or in high-risk patients such as
elderly gravida.
Competing interests None.
Patient consent Obtained.
REFERENCES
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pediatric ultrasound: a casebook approach. New York: McGraw-Hill, 2001:12–16.
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3. Tegay DH, Cohen HL, Rosovsky M. Holoprosencephaly imaging, Medscape
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Figure 11 Postnatal image of neonate showing
meningomyelocoele.
BMJ Case Reports 2012; doi:10.1136/bcr-03-2012-6129 5of6
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  • Feb 2007
  • ORPHANET J RARE DIS
Holoprosencephaly (HPE) is a complex brain malformation resulting from incomplete cleavage of the prosencephalon, occurring between the 18th and the 28th day of gestation and affecting both the forebrain and the face. It is estimated to occur in 1/16,000 live births and 1/250 conceptuses. Three ranges of increasing severity are described: lobar, semi-lobar and alobar HPE. Another milder subtype of HPE called middle interhemispheric variant (MIHF) or syntelencephaly is also reported. In most of the cases, facial anomalies are observed in HPE, like cyclopia, proboscis, median or bilateral cleft lip/palate in severe forms, ocular hypotelorism or solitary median maxillary central incisor in minor forms. These latter midline defects can occur without the cerebral malformations and then are called microforms. Children with HPE have many medical problems: developmental delay and feeding difficulties, epilepsy, instability of temperature, heart rate and respiration. Endocrine disorders like diabetes insipidus, adrenal hypoplasia, hypogonadism, thyroid hypoplasia and growth hormone deficiency are frequent. To date, seven genes have been positively implicated in HPE: Sonic hedgehog (SHH), ZIC2, SIX3, TGIF, PTCH, GLI2 and TDGF1. A molecular diagnosis can be performed by gene sequencing and allele quantification for the four main genes SHH, ZIC2, SIX3 and TGIF. Major rearrangements of the subtelomeres can also be identified by multiplex ligation-dependent probe amplification (MLPA). Nevertheless, in about 70% of cases, the molecular basis of the disease remains unknown, suggesting the existence of several other candidate genes or environmental factors. Consequently, a "multiple-hit hypothesis" of genetic and/or environmental factors (like maternal diabetes) has been proposed to account for the extreme clinical variability. In a practical approach, prenatal diagnosis is based on ultrasound and magnetic resonance imaging (MRI) rather than on molecular diagnosis. Treatment is symptomatic and supportive, and requires a multidisciplinary management. Child outcome depends on the HPE severity and the medical and neurological complications associated. Severely affected children have a very poor prognosis. Mildly affected children may exhibit few symptoms and may live a normal life.
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Loss-of-function mutations in the human GLI2 gene cause pan-hypopituitarism and holoprosencephaly-like features
Article
Full-text available
  • Dec 2003
Diminished Sonic Hedgehog (Shh) signaling is associated with the most common forebrain defect in humans, holoprosencephaly (HPE), which includes cyclopia, a phenotype also seen in mice and other vertebrates with defective Shh signaling. The secreted protein Shh acts as a crucial factor that patterns the ventral forebrain and is required for the division of the primordial eye field and brain into two discrete halves. Gli2 is one of three vertebrate transcription factors implicated as obligatory mediators of Shh signal transduction. Here, we show that loss-of-function mutations in the human GLI2 gene are associated with a distinctive phenotype (within the HPE spectrum) whose primary features include defective anterior pituitary formation and pan-hypopituitarism, with or without overt forebrain cleavage abnormalities, and HPE-like midfacial hypoplasia. We also demonstrate that these mutations lack GLI2 activity. We report on a functional association between GLI2 and human disease and highlight the role of GLI2 in human head development.
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Genetics of ventral forebrain development and holoprosencephaly
Article
  • Jul 2000
  • CURR OPIN GENET DEV
The disease holoprosencephaly is the basis of the most common structural anomaly of the developing forebrain in humans. Numerous teratogens when administered during early gastrulation, have been associated with this condition. Recent studies have characterized molecules expressed in the prechordal plate which are critical for normal brain formation. Perturbation of signaling pathways involving these molecules have been shown to cause holoprosencephaly in humans and other organisms.
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Neuroanatomy of holoprosencephaly as predictor of function Beyond the face predicting the brain
Article
  • Oct 2002
Despite advances in neuroimaging and molecular genetics of holoprosencephaly (HPE), the clinical spectrum of HPE has remained inadequately described. To better characterize the clinical features of HPE and identify specific neuroanatomic abnormalities that may be useful predictors of neurodevelopmental function. The authors evaluated 68 children with HPE in a multicenter, prospective study. Neuroimaging studies were assessed for the grade of HPE (lobar, semilobar, and alobar), the degree of nonseparation of the deep gray nuclei, and presence of dorsal cyst or cortical malformation. In general, the severity of clinical problems and neurologic dysfunctions correlated with the degree of hemispheric nonseparation (grade of HPE). Nearly three-quarters of the patients had endocrinopathies, with all having at least diabetes insipidus. The severity of endocrine abnormalities correlated with the degree of hypothalamic nonseparation (p = 0.029). Seizures occurred in approximately half of the children with HPE. The presence of cortical malformations was associated with difficult-to-control seizures. The presence and degree of dystonia correlated with the degree of nonseparation of the caudate and lentiform nuclei and the grade of HPE (p < 0.05). Hypotonia correlated with the grade of HPE (p < 0.05). Mobility, upper extremity function, and language correlated with the degree of nonseparation of the caudate, lentiform and thalamic nuclei, and grade of HPE (p < 0.01). Patients with HPE manifest a wide spectrum of clinical problems and neurologic dysfunction. The nature and severity of many of these problems can be predicted by specific neuroanatomic abnormalities found in HPE.
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Middle interhemispheric variant of holoprosencephaly: A distinct cliniconeuroradiologic subtype
Article
  • Dec 2002
The middle interhemispheric variant (MIH) is a subtype of holoprosencephaly (HPE) in which the posterior frontal and parietal areas lack midline separation, whereas more polar areas of the cerebrum are fully cleaved. While the neuroradiologic features of this subtype have been recently detailed, the clinical features are largely unknown. To present the clinical manifestations of MIH and to compare them with classic subtypes (alobar, semilobar, and lobar) of HPE. The authors evaluated 15 patients with MIH in a multicenter study. Neuroimaging and clinical data were collected and correlated. They compared the data with those of 68 patients who had classic HPE. The frequency of endocrinopathy in MIH (0%) was lower compared with the classic subtypes (72%) (p < 0.0001). This correlated with the lack of hypothalamic abnormalities. The percentage of patients with seizures (40%) did not significantly differ from classic HPE. Spasticity was the most common motor abnormality, seen in 86% of MIH patients, similar to other subtypes. The frequency of choreoathetosis in MIH (0%) was lower than that for semilobar HPE (41%) (p < 0.0039). This correlated with the lack of caudate and lentiform nuclei abnormalities. Developmental functions, including mobility, upper-extremity function, and language, of the MIH group were similar to the least severe classic type, lobar HPE. MIH is a recognizable variant of HPE with differing clinical prognosis. Similar to the lobar subtype by functional measures, MIH differs from classic HPE by the absence of endocrine dysfunction and choreoathetosis.
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The Face Predicts The Brain: Diagnostic Significance Of Median Facial Anomalies For Holoprosencephaly (Arhinencephaly)
Article
  • Sep 1964
Two patients with orbital hypotelorism, flat nose, and bilateral lateral cleft of lip and palate with a hypoplastic philtrumpremaxilla Anlage are described. Both patients had holoprosencephaly (arhinencephaly), a brain defect characterized by an arrest in prosencephalic cleavage with no or incomplete proplasia of frontal poles and olfactory bulbs. The two patients are an intermediate stage in a graded series of median facio-cerebral malformations which begins with cyclopia, and then, as face and brain transform toward normality, extends through ethmocephaly, cebocephaly, median cleft lip, and the two patients presented here. The facies of these patients are diagnostic of the type of brain malformation. Careful attention to face-brain relationships will significantly extend the number oif diagnostic facies which currently can be recognized. Physiological defects include poikilothermia, apnea, seizures, rigidity, and lack of psychomotor development. Useful diagnostic studies include skull roentgenograms to show orbital hypotelorism and absent crista galli, electroencephalography, dermatoglyphics, chromosome studies, and sometimes pneumoencephalography. Some holoprosencephalic patients, such as our first patient, who have few or no extracephalic malformations, have a 46 chromosome karyotype. Others, such as Patient 2, have many extracephalic anomalies. The literature suggests that the latter patients are apt to have 13-15 trisomy. The face predicts the holoprosencephalic brain irrespective of extracephalic anomalies or karyotype.
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Frequency of holoprosencephaly in the International Clearinghouse Birth Defects Surveillance Systems: Searching for population variations
Article
  • Aug 2008
  • BIRTH DEFECTS RES A
Holoprosencephaly (HPE) is a developmental field defect of the brain that results in incomplete separation of the cerebral hemispheres that includes less severe phenotypes, such as arhinencephaly and single median maxillary central incisor. Information on the epidemiology of HPE is limited, both because few population-based studies have been reported, and because small studies must observe a greater number of years in order to accumulate sufficient numbers of births for a reliable estimate. We collected data from 2000 through 2004 from 24 of the 46 Birth Defects Registry Members of the International Clearinghouse for Birth Defects Surveillance and Research. This study is based on more than 7 million births in various areas from North and South America, Europe, and Australia. A total of 963 HPE cases were registered, yielding an overall prevalence of 1.31 per 10,000 births. Because the estimate was heterogeneous, possible causes of variations among populations were analyzed: random variation, under-reporting and over-reporting bias, variation in proportion of termination of pregnancies among all registered cases and real differences among populations. The data do not suggest large differences in total prevalence of HPE among the studied populations that would be useful to generate etiological hypotheses.
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