Nigerian Journal of Paediatrics

Holoprosencephaly sequence with a constellation of anomalies in Yenagoa a Niger Delta Region Report of two cases

Niger J Paediatr 2018; 45 (1): 19 - 24

CASE REPORT

Tunde-Oremodu II

CC – BY Holoprosencephaly sequence with

Enefia KK

Idholo U,

a constellation of anomalies in

Ofure AO

Yenagoa, a Niger Delta Region:

Kunle-Olowu OE

report of two cases

Oyedeji A

DOI:http://dx.doi.org/10.4314/njp.v45i1.5

Accepted: 5th March 2018

Abstract : This report is on holo-

features suggested the diagnoses of

prosencephaly (HPE) sequence

HPE

Sequence.

Holoprosen-

Tunde-Oremodu II (

)

with other clinical and radio-

cephaly (HPE) occurs due to a

Idholo U, Ofure AO

graphic anomalies of other or-

primary defect in prechordal meso-

Department of Paediatrics,

gans. This condition which has

derm, resulting in fusion anomaly

Federal Medical Centre,

never been reported in Yenagoa,

of the forebrain with also varying

Yenagoa, Nigeria

an oil rich Niger Delta Region

degrees of midline facial develop-

Email: imatunde@gmail.com;

was observed simultaneously in

ment anomalies. Although, HPE

two neonates within a period of

could be isolated, in certain condi-

Enefia KK

two months at different hospitals

tions, it may occur in combination

Department of Radiology,

in this area. The inhabitants who

with other anomalies of the central

include pregnant mothers with

nervous system and other organs.

Kunle-Olowu OE

their fetuses are predisposed to

The causes of HPE are generally

Oyedeji A

health challenges associated with

unknown but genetic and environ-

Department of Paediatrics,

the exposure to toxic chemicals

mental factors have been impli-

Niger Delta University Teaching

derived from environmental deg-

cated. Recognizing the prognosis

Hospital, Okolobiri, Bayelsa State

radation and pollution due to oil

in management, considerations

Nigeria

spillage/processing. This report is

vary from being conservative to

therefore aimed at providing a

reconstructive surgeries. The first

neonate died on the 13

description of HPE associated

day of

with varying multi-systemic con-

life, while the second neonate is

ditions in order to motivate re-

still alive on supportive manage-

searches on prevalence of con-

ment of anticonvulsants and nutri-

tional support on the 11 week of

genital anomalies and induce sup-

port in ensuring appropriate health

life at the time of writing this re-

care services. The approach to

port.

clinical evaluation and experience

on diagnostic evidence is dis-

Key words: Congenital malforma-

cussed. The importance of karyo-

tions, Craniofacial malformations,

typing which could not be carried

Dysmorphism, Holoprosencephaly

out cannot be overlooked. How-

sequence, Niger Delta region

ever, the clinical and radiological

Introduction

challenging issues associated with its management in the

area.

Holoprosencephaly (HPE) sequence is a rare series of

The WHO estimated that neonatal deaths from congeni-

cerebral and facial structural malformations due to fail-

tal anomalies worldwide increased from 260,000 (7% of

ure in the division of the embryonic forebrain

all neonatal deaths) in 2004 to 303 000 (11.6% of all

neonatal deaths) in 2016. This may be on account of

7,8

(prosencephalon) into lateral cerebral hemispheres from

the fourth to eighth week of gestation.

1-3

Holoprosen-

improved diagnostic facilities. However, in Nigeria a

cephaly poses important health challenges because of

collaborative study using verbal/social autopsy (VASA)

the high mortality rate, chronic disability issues, psycho-

interviews reported in 2017 that out of 723 neonatal

social disruptions as well as the financial burden on the

deaths, congenital malformations were responsible for

only 0.9-1.1%. Studies emanating from Nigeria had

family and the society.

1-4

There are also reported adverse

effects of this exposure on fetal development and out-

reported varying prevalence of congenital anomalies to

comes of pregnancy from paternal and maternal associ-

be 4.15, 5.51 and 15.84 in the South East, North East

and South West regions of Nigeria respectively

.10-12

ated factors.

5,6

Since Yenagoa is a city in an oil produc-

ing area, there is a need to report for the first time HPE

higher prevalence of 20.73 per 1,000 live births was

in order to encourage more researches and highlight

reported in Port Harcourt a Niger Delta/South South

region in 2017. This higher prevalence could be due to

This baby was found to be in respiratory distress with

cyanosis and hyperpyrexia (40 C). He had dysmorphic

the peculiarities of an oil producing environment. HPE

accounts for the most common malformation of the em-

features (Fig 1a) consisting of facial anomalies: flattened

bryonic forebrain.

1,3,4

The HPE prevalence rate reported

nasal bridge; absent nasal philtrum and nasal septum;

by Orioli and Castilla in their review of 21 epidemi-

microphalmia; micrognathia; midline cleft lip and palate

ologic studies and data obtained from the West Mid-

(keilognatopalatoskysis). His weight (2800g) was within

the 10 percentile while his length (45cm) and occipi-

lands Congenital Anomaly Register (WMCAR) was 1

to 1.7 per 10,000 of live and stillbirths.

13,14

However,

tofrontal circumference (30cm) were less than10% per-

this increased to about 50 per10,000 in aborted em-

centile. The baby had talipes calcaneo varus deformity;

bryos. There is apparently no Nigerian National birth

chest hypertelorism, pectus carinatum and low set ears.

defects surveillance network and data on congenital

There were neurologic abnormalities which included:

anomalies with special emphasis on HPE is sparse.

hypotonia, absent primitive reflexes and recurrent sei-

However, there have been Case Reports from Port Har-

zures. The blood chemistry and complete blood count

court and Ibadan (South-south and South-west regions

results were within normal range. The chest radiography

of Nigeria respectively) describing the condition.

15,16

revealed cardiomegaly (Fig 2) while the echocardiogra-

The females to males ratio at birth is reported as 2:1 and

phy: showed mitral and tricuspid valve incompetence;

increases with worsening severity of HPE.

The cause

absent shunts (Fig 3). The transfontanelle ultrasound

of this gender disparity is said to be on account of a

scan through the coronal section and midline sagittal

greater male death.

section showed absent midline structures; poorly devel-

oped forebrain; well developed posterior fossa and thal-

There are different types of HPE consisting of alobar,

ami consistent with semilobar HPE (Fig 4). The baby

semilobar, lobar and middle inter-hemispheric variant

was managed conservatively with antibiotics, anticon-

(in order of reducing severity).

1,3,4,17

The etiologies of

vulsants, fluid, calories, electrolytes, oxygen administra-

HPE vary ranging from the unknown to multifactorial

tion and subsequent commencement of gavage feeding.

factors with MRI preferably used to confirm the diagno-

Financial support for care by parents was limited due to

sis, while Chromosomal microarray (CMA) identifies

poverty and perceived feeling of stigma, rejection and

those with genetic involvement. The treatment is sup-

[3]

shame despite the intervention of the Social Welfare

portive, and requires a multidisciplinary management

Unit whose assistance was sought. Logistic reasons pe-

depending on the degree of forebrain defect.

2-4

The mid-

culiar to the facility and financial constraints hindered

line facial anomalies are pointers to severe brain malfor-

further diagnostic tests such as karyotype and chromoso-

mations and functions with significantly reduced sur-

mal analysis. The fever persisted with subsequent devel-

vival beyond neonatal period in babies with severely

opment of apnea which continued until his death on the

13 day of life.

malformed forebrain.

1-3

We hereby report two cases of

HPE in order to highlight the health challenges in an oil

producing area and to draw attention to the financial and

socio-cultural issues associated with the management of

Fig 1a: Photograph of case 1

congenital malformations.

showing facial anomalies: flat-

tened nasal bridge; absent nasal

Case description/presentation

philtrum and nasal septum;

midline cleft lip and palate.

Case 1

A 12 hour old male neonate presented in the Tertiary

Federal Government Health facility in Yenagoa due to

cleft lip and palate, respiratory distress from birth and a

high grade fever on the 17 of February, 2017. This was

Fig 1b: Photograph of case 2

the first offspring of a 36 year old bricklayer father and a

showing cranio-facial anoma-

27 year old mother who registered late for antennal care

lies: flattened nasal bridge,

at six months of gestation at a Primary Health Care Cen-

absent nasal philtrum and nasal

tre. The drugs that the mother received were routine

septum; midline cleft lip and

antenatal drugs and over the counter medications (names

palate; chest hypertelorism

unknown). The mother’s only illness during pregnancy

was fever in the first trimester which resolved with in-

take of antimalarial (Artesunate/Lumefantrine). Native

body massage was carried out but there was neither use

of traditional medications during pregnancy nor expo-

sure to radiation. There was prolonged obstructed labor

Fig 2: Chest Xray of case 1

at 42 weeks gestation and delivery at home assisted by a

showing cardiomegaly

nurse which resulted in baby not crying at birth. A posi-

tive history of a living third degree relative with cleft lip

abnormality was obtained. There was no history of con-

sanguinity.

Case 2

Fig 3:

Echocardiography of case 1 showing mitral and

tricuspid valve incompetence; absent shunts

A female baby was delivered by emergency caesarean

section in a private facility in Yenagoa, on account of

previous caesarean section in a diabetic mother at 37

weeks gestation. She was the second surviving child

among 3 children of a 29 years old mother and 35 years

old father. The mother registered late for antenatal care

at gestational age of 4 months, received insulin and rou-

tine antenatal drugs. She often ingested and drank the

juice of fresh bitter-leaf (vernonia). The APGAR scores

were 1 in 5 minutes; 8 in 5 minutes; 10 in 10 minutes.

There is a previous history of sibling death in the first

Fig 4: Transfontanelle ultrasound scan of case 1through cor-

week of life from macrosomia, severe birth asphyxia and

onal section and midline sagittal section showing absent mid-

birth injury. There is also a family history of profound

line structures, poorly developed forebrain, well developed

mental retardation, developmental delay and micro-

posterior fossa and thalami

cephaly in a second degree relative. There was no his-

tory of consanguinity. The baby was admitted into the

neonatal intensive care unit (NICU) of the private facil-

ity on account of respiratory distress and the multiple

congenital abnormalities.

On examination she had dysmorphic features (Fig 1b)

consisting of: cranio-facial anomalies: flattened nasal

bridge; absent nasal philtrum and nasal septum; midline

cleft lip and palate (keilognatopalatoskysis); low set ears

and orbital hypotelorism with inner canthal distance of

1.5cm (Normal of 1.6 – 2.5cm).

She weighed 3800g

Fig 5: Cranial CT scan of case 2 showing absent midline struc-

(>90% centile); length 45cm (10 centile). There was

tures; fusion of both lateral ventricle; poorly developed occipi-

microcephaly with occipitofrontal circumference of

tal, frontal and parietal lobes.

30cm (<10% percentile) and her anterior fontanel size

was 2.75 cm (diameters of 2.5 by 3cm). She had talipes

calcaneo varus deformity and a dimple at the lumbo-

sacral region. Chest hypertelorism was present with inter

-nipple distance of 11cm (normal: 8.6 ±0.5)18.

The

baby had neurologic abnormalities consisting of recur-

rent seizures and the presence of only sucking and grasp

primitive reflexes. The blood chemistry was within nor-

mal range except for a low calcium result. The complete

blood count was normal. The cranial CT scan revealed

an absent midline structures; fusion of both lateral ven-

tricle; poorly developed occipital, frontal and parietal

lobes; well developed posterior fossa, normal brain

stem, fourth ventricle, cerebellum and temporal lobes.

Discussion

This was consistent with semilobar HPE. (Fig 5) The

skeletal X-ray, Chest X-ray and abdominal X-ray re-

The prosencephalon, mesencephalon, and rhomben-

vealed no abnormalities. The echocardiography that was

cephalon, develop by the third embryonic week. At the

requested for was not done as the parents authorized the

fifth embryonic week of gestation, the primary brain

Doctors to stop further investigations and medications.

(prosencephalic) vesicle separate into lateral telen-

cephalic and diencephalic structures.

1,2

The management comprised of antibiotics, anticonvul-

HPE occurs as a

sants, oxygen administration, intravenous fluids contain-

result of incomplete separation of the prosencephalon,

ing calories and electrolytes then subsequent gavage

by the 18th to the 28th day of gestation thereby affecting

the forebrain and midfacial development.

2.20,21

feeding with infant formula. There was refusal by par-

The ab-

ents to accept responsibility for the baby and carry out

normalities of forebrain vary from the most severe alo-

their financial obligations despite intensive counseling.

bar form to the semilobar, lobar and middle interhemi-

spheric variant.

3,4

At the time of this report, the baby is 2 months old re-

Two babies with semilobar HPE have

ceiving anticonvulsants, occasional antipyretics and

been described whose mothers registered for prenatal

feeding but has been abandoned in the hospital.

care after the first trimester when the forebrain and mid-

facial development would have taken place.

The two cases reported were of different gender how-

ever, previous reports have shown gender disparity with

female preponderance in a ratio of 2:1.

3,4,22

The etiology

of HPE are heterogenous consisting of genetic or envi-

lies could not be identified. This is a pointer to the chal-

ronmental causes.

1,3,4

Some of the genetic causes that

lenges that exist in the diagnosis and management of

were considered include aneuploidy syndromes such as

congenital abnormalities which could have been miti-

Trisomy 13 (Patau syndrome) and Trisomy 18(Edward

gated with the availability of improved technological

syndrome).

1,2

Single-gene disorders, mutations in genes

diagnostic facilities and access to a special congenital

and structural chromosomal aberrations including Pallis-

anomaly group tailor-made health insurance policy. The

ter – Hall, Rubinstein – Taybi, Kallmann, Smith – Lemli –

diagnoses of the two cases reported were made from

Opitz, and Meckel- Gruber Syndrome have also been

cranial CT scan, transfontanelle ultrasonography and the

associated with HPE.

1-4

Genetic predisposition was iden-

clinical manifestations.

tified in both babies through the family history which

Previously, it was reported that majority of children with

revealed similar problems in their second and third de-

the severe form of HPE rarely survive beyond early

gree relatives respectively. Infants of diabetic mothers

infancy hence the treatment for this was symptomatic

and supportive.

2,4,17,20

have also been reported to have HPE in addition to other

Considering ethical issues regard-

congenital anomalies.

3,4,22

The large for gestational age

ing surgical beneficence, intervention when carried out

should be done at the earliest possible time. However,

infant of a diabetic mother with poor glycaemic control

who delayed assessing prenatal care suggested the het-

where the prognosis is very poor, limiting extraordinary

erogenous aetiology of HPE.

medical assistance aimed towards survival is recom-

mended.

2,4,17,29

In the milder forms, since a large number

The HPE craniofacial abnormalities consisting of mid

of the children survive past the first year; a multidisci-

facial anomalies: flattened nasal bridge; absent nasal

plinary approach to management consist of interventions

philtrum and nasal septum; midline cleft lip and palate;

by plastic surgeons, neurologists, maxillofacial surgeons

and psychologists.

2,4,17,24

and microcephaly are classical presentations. ("the face

Unfortunately, the cultural ta-

predicts the brain").

3,23,24

Other associated features: limb

boos associated with having a child with dysmorphic

abnormalities, chest hypertelorism, congenital heart de-

features influenced the parents to limit care and in one

fects occur in genetic conditions and in offsprings of

instance, abandon the baby in the hospital.

mothers with some medical conditions.

1,4

Medical prob-

lems that could be associated include seizures, motor

impairment, motor dysfunction, risk of poor nutrition,

gastroesophageal reflux, aspiration and constipation.

25,26

Conclusion

Hydrocephalus, chronic lung disease, hypothalamic dys-

function, disturbed sleep – wake cycles and temperature

Holoprosencephaly sequence is a complex spectrum of

dysregulation, as well as endocrine dysfunction are also

congenital structural anomaly of the forebrain largely

some of the associated medical challenges.

21,22

associated with characteristic mid-facial craniofacial

anomalies. Considering the heterogenous etiology and

The diagnosis of the different types of HPE can be done

challenges associated with stigmatization, it is vital that

prenatally through trans-abdominal, trans-vaginal ultra-

a diagnosis of HPE is made during the fetal life through

sonography and magnetic resonance imaging (MRI).

3,22

ensuring compulsory/routine antenatal congenital anom-

However a study reported the need for routine foetal

aly ultrasound scan. This will provide for a well in-

MRI in suspected cases of HPE, and reduction in reli-

formed medicolegal counseling of families, prognosti-

ance on ultrasound alone.

22,23,27

In neonates, radiological

cating and planning of the HPE management. This re-

diagnosis of HPE is best obtained through cranial

port has also created awareness regarding the huge fi-

(MRI).

21.27

However, MRI was not done for any of our

nancial burden of management of children with HPE

patients due to financial constraints. Instead financial

hence the need for subsidized services from the Govern-

support was provided for the cheaper cranial CT scan

ment and private businesses that have oil-derived wealth

and transfontanelle ultrasonography which have also

from the Niger Delta region.

been reported to assist in defining the anatomic subtype,

and identifying associated CNS anomalies. Determin-

ing

the

karyotype

and

chromosomal

analysis

(chromosomal microarray) are important investigations

Limitations

for babies and their parents when genetic causes are

considered.

This could not be done for the patients,

These babies would have benefitted from genetic stud-

due to non-availability of such laboratory procedures in

ies, radiological and other specific investigations but

the State and financial constraints in accessing it outside

were hindered by socio-cultural drawbacks, financial

the state hence abnormal karyotypes or genomic anoma-

constraints and logistic challenges.

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