1 AL Shifa Hospital, Department of Radiodiagnosis and Imaging, India
2 Banas x-ray and sonography Clinic, India.

Synonyms [1]: Holoprosencephaly
Midline cleft syndrome
DeMyer sequence
Isolated holoprosencephaly (not syndromic, not chromosomal)
Familial holoprosencephaly
Arhinencephaly
Cyclopia

Definition: Holoprosencephaly (OMIM 236100) is a complex human brain malformation resulting from incomplete cleavage of the prosencephalon into right and left hemispheres, occuring between the 18th and the 28th day of gestation [1].

Three levels of increasing severity are described [2]: lobar holoprosencephaly, where the right and left ventricles are separated, but with some continuity across the frontal cortex; semilobar holoprosencephaly with a partial separation, and the most severe form, alobar holoprosencephaly, with a single brain ventricle and no interhemispheric fissure.

The forebrain malformations are generally associated with facial anomalies ranging from anophthalmia, cyclopia or proboscis in the most severe cases, to midline cleft lip, a simple hypotelorism or even no anomalies in the less severe holoprosencephaly forms [3,4].

Etymology:  [5]  Holos means whole, entire (Greek, from holos)
Prosencephalon comes from New Latin, from Greek.
Proso means forward.
Enkephalos means brain, meaning forebrain ie, the part of the brain that develops from the anterior part of the neural tube.

Prevalence: It is estimated to occur in 1 / 16000 live births and 1 / 250 conceptuses [1]

Etiology: The etiology of holoprosencephaly is very heterogeneous[1]. First, this pathology can be caused by environmental or metabolic factors[1]. The only formally recognized environmental factors are insulin dependent diabetes mellitus (1 % risk of holoprosencephaly) [7] and maternal alcoholism with a risk that cumulates with smoking [8].

Holoprosencephaly  in humans has also been noted in association with prenatal exposure to drugs ( retinoic acid, cholesterol biosythesis inhibitors[9] or to infections (Cytomegalo virus[10],[11], Toxoplasma[12],[13], Rubella,[13],[14] ). The OMIMS classification shows that holoprosencephaly can also be associated in about 25% of cases with several defined multiple malformation syndromes with a normal karyotype like Smith–Lemli–Optiz[15], Pallister Hall [16] or velocardio– facial syndrome [17]. Holoprosencephaly can be due to chromosomal abnormalities with a higher prevalence observed in trisomy 13 (70%), trisomy 18 and triploidy[1]. Finally holoprosencephaly may be a solitary manifestation (neither chromosomal nor syndromic) and several genes are implicated in this isolated form of holoprosencephaly[1].

Pathogenesis:[18] Holoprosencephaly results when the forebrain (prosencephalon) fails to undergo diverticulation. The anterior telencephalon fails to divide into cerebral hemispheres and a monoventricle results. The diencephalon fails to diverticulate into separate thalami and the olfactory bulbs fail to develop. The development of the face is intimately related to development of the brain, so a spectrum of facial defects occurs ranging from mild hypotelorism to large midline clefts and cyclopia.

Sonographic findings: Sonographic findings are described under case report.

Implications for targeted examination: Fetal cranium and face should be carefully scanned to look for interhemispheric fissure, falx cerebri, thalami and ventricles, position and number of eyes, presence of any abnormal linear structure in the midline, cleft lip & cleft plate.

Differential diagnosis:

1-Hydranencephaly
2-Massive hydrocephalus: In massive hydrocephalus unlike alobar holoprosencephaly, the falx and interhemispheric fissure are present and in hydranencephaly, the thalmi are not fused[18].

Associated anomalies:  Reported extracranial abnormalities include polydactyly, renal dysplasia, omphalocele, and hydrops [19].

Prognosis: Alobar holoprosencephaly is uniformly lethal while the prognosis of lobar is variable. Infants with the lobar type  may have mild, moderate or severe mental retardation. Semilobar holoprosencephaly has an intermediate but generally quite poor, prognosis [20],[21].

Recurrence and risk: With absence of chromosomal abnormalities, it has been estimated to be 6% (but this includes both truly sporadic events and hereditary conditions with 25 – 50% risk); with abnormal karyotype such as trisomy it is associated with about 1% recurrence [22]. Identification of mutations responsible for holoprosencephaly can confer significant recurrence risks in a clinically normal family [23]  in future pregnancies, woman should be offered a detailed ultrasound scan in the first trimester to diagnose a severe recurrence early and a further ultrasound scan in the second trimester to look for more subtle abnormalities [23].

Management: Fetal karyotype is mandatory when holoprosencephaly is discovered by ultrasound. Termination of pregnancy should be offered to parents of previable fetuses [22] the care of the child with holoprosencephaly requires a multidisciplinary management [1]. Neurological complications’ management of a child with holoprosencephaly is not specific and requires anticonvulsive, physical and occupational therapies, as for children with other brain malformations [1]. It is important to consider endocrine disorders testing blood and urine samples and look after dysautonomic dysfunction [1]. Surgery is needed to repair cleft lip and / or palate [1].

Case report:

Case 1: Johny Poulose Brahmakulam, MD,MBBS, MD(AM), DMRD A 20-year-old patient was referred for antenatal ultrasound scanning to exclude congenital anomalies at a gestational age of 23 weeks 6 days.
She is gravida 2 with one abortion at about 20 weeks in the year 2010. It was a spontaneous abortion (Details not available).
She has no history of diabetes mellitus or hypertension or teratogenic drug intake during pregnancy. No recent history of infectious disease noted. Prenatal ultrasound findings:

• Biometric parameters were within normal range.
• Abnormal cranium: Cranium showed enlarged central cavity with compressed parenchyma in the periphery (Fig.1). Interhemispheric fissure and falx cerebri could not be observed. 
• Thalami were fused in the midline towards the base of the brain (Fig.2).
• Eyes and nose could not be visualised. A midline echogenic linear structure with round end was seen in the mid face suggestive of proboscis (Fig.3).
• Amniotic fluid index was within normal range. Fetus showed adequate movements. An ultrasonological age of 21 weeks 5 days was noted against a menstrual age of 23 weeks 6 days.

Figure 1, 2:

Figure 3: A midline echogenic linear structure with round end was seen in the mid face suggestive of proboscis.

Findings on post morterm fetus:
Single nostril noted as a cleft in a soft tissue mass. Close to this, small eyes were seen slightly laterally, lower than in the usual site. Hypotelorism was evident. Above the single nostril in the midline, proboscis was seen (See Figures 4, 5, 6, 7)
Both ears and mouth appeared normal.
No evidence of polydactyly or limb abnormalities were noted.

Figure 5,6,7: Postmorterm baby; Hypotelorism, single nostril, proboscis were noted.

Case 2: Suresh K.Patel Gujarat., MD 26 years old, Gravida 2 , 28 weeks, unremarkable history. Ultrasound findings:

• Semilobar holoprosencephaly, midline face defects, brachycephaly.
• Dandy-Walker cyst.
• Bilateral club foot
• Spine, heart, urinary system, gastrointestinal tract were normal. 
• 4 limbs were observed.

Figure 1, 2: Semilobar holoprosenencephaly and Dandywalker cyst.

Figure 3, 4:Two normal eyes with lens. Median cleft-lip defect.

Figure 5: Normal heart

Figure 6, 7: Normal transverse plane of abdomen.

Figure 8-11: Cleft lip

Figure 12, 13: Club feet

References:

1. Christele Dubourg, Claude Bendavid, Laurent Pasquier, Catherine Henry, Sylvie Odent, and Veronique David. Orphanet J Rare Dis. 2007; 2:8.Published online 2007 Feb 2. doi : 10. 1186 / 1750 – 1172 – 2 – 8.

2. DeMyer W, Zeman W. Alobar Holoprosencephaly ( Arhinencephaly) with median cleft lip and palate : Clinical, electroencephalographic and nosologic considerations. Confin Neurol. 1963; 23 : 1- 36.

3. DeMyer W, Zeman W, Palmer CG. The Face predicts the Brain : Diagnositc significance of median Facial Anomalies for holoprosencephaly (Arhinencephaly) Pediatrics. 1964; 34 : 256 - 263.

4. Delezoide AL, Narcy F, Larroche JC. Cerebral midline developmental anomalies : Spectrum and associated features. Genet Couns 1990; 1: 97 – 210.

5. Thesaurus and Encyclopedia

6. Joseph R Siebert PhD, author ( University of Washington). Harvey B Sarnat MD, editor ( University of Calgary in Alberta, Canada). Publication dates: Originally relased october 21, 1994; last updated August 11, 2011 (Neurology, MedLink)

7. Barr M. Jr, Hanson JW, Currey K, Sharp S, Toriello H, Schmickel RD, Wilson GN. Holoprosencephaly in infants of diabetic mothers. J Pediatr. 1983; 102 : 565 – 568. doi:10. 1016 / S0022 – 3476 (83) 80185 - 1

8. Croen LA, Shaw GM, Lammer EJ. Risk factors for Cytogenetically normal holoprosencephaly in California: a population based case – control study. Am J Med Genet. 2000; 90: 320 – 325. doi: 10. 1002 / (SICI) 1096 – 8628 (20000214) 90: 4<320:: AID – AJMG 11> 3.0. CO; 2 – 8

9. Repetto M, Maziere JC, Citadelle D, Dupuis R, Meier M, Biade S, Quiec D, Rouxe. Teratogenic effect of the cholesterol synthesis inhibitor AY 9944 on rat embryos in vitro. Teratology. 1990; 42 : 611 – 618. doi : 10. 1002 / tera. 1420420605.

10. Frenkel LD, Gaur S, Tsolia M, Scudder R, Howell R, Kesarwala H. Cytomegalovirus infection in children with AIDS. Rev infect Dis. 1990; 12 Suppl 7:S820 – 6.

11. Byrne PJ, Silver MM, Gilbert JM, Cadera W, Tanswell AK. Cyclopia and congenital cytomegalovirus infection. Am J Med Genet. 1987; 28; 61 – 65 doi : 10. 1002 / ajmg. 1320280110.

12. Lison MP, Armbrust – Figueiredo J, Mega D. [Arhinencephalia : Considerations apropos of a case diagnosed during life] Acta Neurol Psyschiatr Belg. 1967 ; 67 : 25 – 36.

13. Castel Y, Riviere D, Toudic L, Nouaille Y, L’ Henoret J, Duparcmeur H, Leroy JP, Balouet G [ Two cases of cyclopia ] Ann Pediatr ( Paris) 1976; 23 : 647 – 651.

14. Probst C. Cerebral edema : neurosurgical aspects of pathological, diagnostic and therapeutic problems ( author’s transl) Schweiz Rundsch Med Prax. 1976; 65 : 948 – 956.

15. Kelley RL, Roessler E, Hennekam RC, Feldman GL, Kosaki K, Jones MC, Palumbos JC, Muenke M. Holoprosencephaly in RSH / Smith – Lemli – Optiz syndrome : does abnormal cholesterol metabolism affect the function of Sonic Hedgehog. Am J Med Genet. 1996; 66: 478 – 484. doi: 10. 1002 / (SICI) 1096 – 8628 ( 19961230) 66 : 4 < 478 : : AID – AJMG 22> 3.0. CO; 2 – Q.

16.  Hall JG, Pallister PD, Clarren SK, Beckwith JB, Wiglesworth FW, Fraser FC, Cho S, Benke PJ, Reed SD. Congenital hypothalmic hamartoblastoma, hypopituitrism, imperforate anus and postaxial polydactyly –a  new syndrome. Part I : Clinical causal and pathogenetic considerations. Am J Med Genet. 1980 ; 7 ; 47 – 74. doi : 10 . 1002 / ajmg. 1320070110.

17.  Wraith JE, Super M, Watson GH, Phillips M, Velo –cardio – facial syndrome presenting as holoprosencephaly . Clin Genet 1985 ; 27: 408 - 410.

18.  Poe LB, Coleman LL, Mahmud F. Congenital Central Nervous system anomalies. Radiographics. Sep 1989; 9 (5) : 801 – 26.

19.   Nyberg DA, Mack LA, Bronster A et al: Holoprosencephaly : Prenatal sonographic diagnosis, AJNR 8: 871 – 878, 1987

20. Manelfe C, Sevely A. Neuroradiological study of Holoprosencephalies. J Neuroradiol. 1982 ; 9 : 15 – 45.

21. Gorlin RJ, Cohen MM , Levin LS. Syndromes of the head and neck, third edition. The holoprosencephalic disorders. New york : Oxford university press, 1990 , 573 - 582.

22. 1994 – 04 – 11 – 14 Holoprosencephaly : alobar © Achiron www. the fetus. Net. Reuwen Achiron, MD, Anat Achiron, MD, PhD, Shlomo Lipitz, MD, Shiomo Mashiach, MD, Bolek Goldman,MD.

23. The risk of recurrence of holoprosencephaly in euploid fetuses. David Anna L. PhD, MRCOG; Gowda, Vatsala MD; Turnbull, Clare BMBch, MRCP; Chitty, Lyn S. PhD, MRCOG