Holoprosencephaly with Endocrine Dysfunction--A Case Report  

Said Azzoug , Mohamed Bendali , Farida Chentli
Endocrinological Department Bab El Oued Hospital Algiers, Algeria
Author    Correspondence author
International Journal of Clinical Case Reports, 2014, Vol. 4, No. 4   doi: 10.5376/ijccr.2014.04.0004
Received: 12 Mar., 2014    Accepted: 28 Mar., 2014    Published: 24 Jul., 2014
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Preferred citation for this article:

Azzoug et al., 2014, Holoprosencephaly with Endocrine Dysfunction--A Case Report, International Journal of Clinical Case Reports, Vol.4, No.4, 1-3 (doi: 10.5376/ijccr.2014.04.0004)

Abstract

Holoprosencephaly is a brain malformation resulting from incomplete cleavage of the prosencephalon, occurring between the 18th and the 28th days of gestation, four subtypes are described, sometimes it may be familial. Facial anomalies, developmental delay and neurological disorders are the main manifestations but endocrine dysfunction is also frequently reported. We reported the observation of a male patient who presented at 18 years for growth retardation and pubertal delay; hormonal assessment showed growth hormone and gonadotrophins deficiencies, other pituitary functions were normal. MRI imaging found holoprosencephaly and triventricular hydrocephaly but without radiological anomalies of pituitary or pituitary stalk. The patient was treated with growth hormone with a good growth catching and after that he was treated with androgens; hydrocephaly which was only monitored was stable over time. Holoprosencephaly requires a multidisciplinary management; its prognosis depends on the severity of the disease and associated complications.

Keywords
Holoprosencephaly; Endocrine dysfunction; Prognosis; Case report

1 Introduction
Holoprosencephaly (HPE) is a congenital brain malformation resulting in a lack of cleavage of the forebrain. It occurs between the 18th and 28th day of gestation, resulting in non separation of brain hemispheres (BH) (Manus and Benjamin, 2012).

It is an heterogeneous disease. It is often associated with craniofacial defects and endocrine damages that can even reveal the disease as was the case in our patient (Manus and Benjamin, 2012).

2 Case report
Mr. SA 28 years old, presented first at 17 years for growth retardation. Clinical examination revealed a height of 146 cm (-4DS) a BMI of 16.3 kg/m2 an impuberism, a discrete dysmorphic syndrome with a high forehead, a broad flat nose, spaced teeth and genu valgum. Bone age was estimated at 12 years.

Hormonal evaluation found growth hormone and gonadotrophins deficiency normal basal cortisol with inadequate reserves (Table 1).

 

 

Table 1 Hormonal assesment

 
CT scan found a slight triventricular passive hydrocephalus. MRI showed an aspect of holoprosencephaly with dilatation of the lateral ventricles, absence of the septum pellucidum and a septo-optic dysplasia (Figure 1).

 

 

Figure 1 MRI showing an holoprosencephaly aspect

 
The patient received growth hormone treatment reaching a height of 169 cm after 5 years of treatment.

Hypogonadism was treated with androgens with a good development of secondary sexual characters.

3 Discussion
There are 4 forms of HPE with variable severity according to the degree of non separation of the cerebral hemispheres: alobar (complete fusion of CH), semilobar (fusion of frontal lobes), lobar (fusion of the basal part of the frontal lobes), Interhemispheric or syntélencéphalie (fusion of the posterior part of the frontal lobes and the parietal lobes) (Hahn and Barnes, 2010).

The Septo-optic dysplasia as described in our patient is now recognized as a form of lobar HPE, with aplasia of the septum pellicidum, moderate dilatation of the lateral ventricles with rectangular appearance of frontal horns, a hail aspect of the optic chiasma with presence of a ventral inter-hemispheric fissure of the frontal lobes (unlike the classic lobar form).

HPE is associated with craniofacial abnormalities related to the degree of non separation of CH (DeMyer et al., 1964). Signs that may be encountered ranging from cyclopia to normal facies or almost (Xin and Guillermo, 2009), as in our patient who just has a wide flat nose.

HPE can be caused by (Muenke et al ., 2001):

-Structural or numerical chromosomal abnormality

-Exposure to environmental factors and teratogens in utero as maternal diabetes, alcoholism, smoking, drugs and maternal infections

-Be part of a syndrome (Smith-Lemli-Opitz syndrome, Pallister Hall, Rubinstein-Taybi, Meckel etc.)

In our patient we only noted maternal diabetes, that occurred few years after birth, this does not exclude the possibility of a gestational diabetes participating in the genesis of HPE.

Finally there is the isolated forms or non-chromosomal, non syndromic, due to a mutation in one of the 12 known genes. Genetic forms are inherited as an autosomal dominant forms with highly incomplete penetrance and variable expressivity (Benjamin, 2010).

The clinical picture varies according to CNS structures involved. Functions controlled by the hypothalamus such as thermal regulation, thirst, appetite, sleep and blood pressure may be affected, all functions seem preserved in our patient, but close attention should be paid during the follow-up to detect any disturbance. The pituitary gland is not spared (Hahn et al., 2005), abnormalities can be structural or functional as in our case. Diabetes insipidus is more frequent than anterior pituitary deficits in HPE due to the hypothalamic origin of the cores regulating hydric balance.

Neurological signs include motor dysfunction (hypotonia, dystonia, spasticity), epilepsy (50% of patients) and hydrocephalus. Delayed psychomotor development and mental retardation are also observed in our patient and classically described in HPE.

The prognosis is closely related to the degree of brain malformation:

The alobar and semi lobar forms have a dire prognosis (death within few weeks or few months of life). Other forms like our patient, have a better prognosis and can expect an almost normal life provided an adequate monitoring and management of their medical problems involving a multidisciplinary team with an endocrinologist, a neurologist, an ophthalmologist a and a neurosurgeon (Barr and Cohen, 1999).

References
Barr Jr. M., and Cohen Jr. M.M., 1999, Holoprosencephaly survival and performance. Am J Med Genet. 89: 116-120
http://dx.doi.org/10.1002/(SICI)1096-8628(19990625)89:2<116::AID-AJMG10>3.0.CO;2-4

Benjamin D., 2010, Analysis of Genotype-Phenotype Correlations in Human Holoprosencephaly. Am J Med Genet C Semin Med Genet., 154C: 133-141
http://dx.doi.org/10.1002/ajmg.c.30240

DeMyer W., Zeman W., and Palmer C.G., 1964, The face predicts the brain: diagnostic significance of median facial anomalies for Holoprosencephaly (arhinencephaly). Pediatrics, 34: 256-263

Hahn J.S., Hahn S.M., Kammann H., Barkovich A.J., Clegg N.J., Delgado M.R., 2005, Endocrine disorders associated with holoprosencephaly. J Pediatr Endocr Met. 18: 935-941
http://dx.doi.org/10.1515/JPEM.2005.18.10.935

Hahn J.S., and Barnes P.D., 2010, Neuroimaging advances in holoprosencephaly: refining the spectrum of the midline malformation, Am J Med Genet C Semin Med Genet., 154C: 120-132
http://dx.doi.org/10.1002/ajmg.c.30238

Manu S., and Benjamin D., 2012, Holoprosencephaly: A Guide to Diagnosis and Clinical Management, Indian Pediatrics, 48: 457-466

Muenke M., and Beachy P.A., 2001, Holoprosencephaly. In: Scriver C.R., Beaudet A.L., Sly W.S., Valle D., editors. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. NewYork: McGraw-Hill; pp.6203-6230

Xin G, and Guillermo O., 2009, Pathogenesis of holoprosencephaly, JCI., 119: 1403-1413
http://dx.doi.org/10.1172/JCI38937

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