7/29/2019 Plastic Surgery Considerations for Holoprosencephaly Patients

1/3

Plastic Surgery Considerations forHoloprosencephaly PatientsJennifer M. Hendi, MPH* Robert Nemerofsky, MD* Cynthia Stolman, PhD Mark S. Granick, MD*

Newark, New Jersey

Holoprosencephaly (HPE) is considered the lead-ing abnormality of the brain and face in humansand is frequently associated with a wide spectrumof specific craniofacial anomalies including mid-line facial clefts, cyclopia and nasal irregularities. Astandard course of treatment has not been devel-oped and management is symptomatic and sup-portive. In this work, the authors discuss the wide-ranging spectrum of HPE and propose surgicalguidelines to provide more uniform and appropri-ate care to patients suffering from holoprosenceph-aly. Assessment of the patients brain abnormalityis essential in determining the extent and benefit ofsurgical intervention. The authors discuss a medianstraight-line repair of the lip and repair of the an-terior palate in a one-year old female and reviewthe risks and benefits of surgery. Consistent withthe ethical approach of surgical beneficence, theauthors recommend intervention at the earliest pos-sible time.

Key Words: Holoprosencephaly, median oral facialcleft, surgical risks, beneficence, cleft lip repair

Holoprosencephaly was first described in1963 and is considered the foremost ab-normality of the brain and face in human

beings, with an estimated birth preva-lence of 5 to 12 per 100,000 live births.1 Most cases areassociated with severe brain malformations that areincompatible with life and often cause spontaneousintrauterine death. Less severely affected babiesdemonstrate a spectrum of defects and malforma-tions of the brain and face. Holoprosencephaly is fre-quently associated with specific craniofacial anoma-lies, including midline facial clefts, cyclopia, and

nasal irregularities.2

Less severe malformations in-clude facial defects that may affect the eyes, nose,

and upper lip, with normal or near-normal brain de-velopment. Some data indicate that patients with lesssevere manifestations of holoprosencephaly (i.e.,semilobar and lobar) have survived into adulthood.3

A standard course of treatment of holoprosenceph-aly has not been developed, and treatment is symp-tomatic and supportive.

Few guidelines have been described for surgicalcandidates, resulting in conflicting recommendationsas well as ethical and practical dilemmas for sur-geons. Given the prevalence and the wide-ranging

manifestations of this disease, surgical guidelinesshould be established to provide more uniform andappropriate care to patients suffering from holo-prosencephaly. Assessment of the patients brain ab-normality is essential in determining the extent and

benefit of surgical intervention.

CASE REPORT

A primary pediatrician referred a 1-year-old fe-male infant with semilobar holoprosencephalyto plastic surgery for cleft lip and palate repair (Fig1). The patient was born at 32 weeks with semilobarholoprosencephaly (Fig 2), an absent septum pellu-

cidum, a monoventricle, fused thalami, premaxillaryagenesis with a midline cleft lip, bilateral optic nervehypoplasia, and chromosome 8 deletion. The patientsuffered from bilateral hearing loss, bilateral visionloss, dysphagia, hypotelorism, cerebral palsy, andseizures. Developmentally, the patient exhibited noverbal output, an inability to sit up, and difficulty infeeding. The mother was anxious to proceed with cor-rective surgery to make the child look more normal.

The patient was missing the prolabium and theanterior prolabial segment of the primary palate. Thecolumella and nasal septum were also absent. It waselected to do a repair consisting of a median straight-

line repair of the lip and repair of the anterior palateby sealing off the nasal floor and upper palate (Fig 3).The procedure used a simple straight-line repair. Thecolumella and septal deficiencies were not ad-dressed. There were no surgical complications of thesurgery, and blood loss was minimal. The patientshospital course was prolonged to deal with feedingproblems, social issues, and seizure control. For 1

From the *Division of Plastic Surgery, Department of Surgery,and Division of Medical Ethics, Department of Pediatrics, New

Jersey Medical School-University of Medicine and Dentistry ofNew Jersey, Newark, New Jersey.

Address correspondence to Dr Granick, 90 Bergen Street, DOC7200, Newark, NJ 07103; e-mail: mgranickmd@umdnj.edu.

675

7/29/2019 Plastic Surgery Considerations for Holoprosencephaly Patients

2/3

year after surgery, the patient had a satisfactory es-thetic appearance and was independently feeding

but had made little additional functional gain. Themother was pleased with the outcome. The patientdied 13 months after surgery.

DISCUSSION

Holoprosencephaly has been described as themost common major malformation of the brainand face in human beings. Various gradations of fa-cial dysmorphism are commonly associated with ho-loprosencephaly, including cyclopia; ethmocephaly;

cebocephaly; median cleft lip; and less severe facialdysmorphism such as hypotelorism or hypertelor-ism, lateral cleft lip, and/or iris coloboma. Associ-ated anomalies include a single maxillary central in-cisor, absence of nasal septal cartilage, stenosis of thepyriform aperture, absence of the labial frenum, andabsence of the philtral ridges.4

Holoprosencephaly is caused by teratogens andgenetic factors. Maternal diabetes, alcohol, and reti-noic acid are teratogens associated with holopros-encephaly; however, their significance has not beendetermined.5 Evidence for genetic causes of holo-prosencephaly comes from nonrandom chromosom-al anomalies in regions that have been theorized tocontain genes essential for normal forebrain devel-

opment.5 As many as 12 chromosomal regions havebeen implicated in the pathogenesis of holoprosen-cephaly.5

Three classifications of the disease currently ex-ist. Alobar is considered the most severe manifesta-tion, with patients exhibiting premaxillary agenesisand unilateral or bilateral cleft lip. Approximatelyhalf of the infants born with this form of the diseasedie before the age of 4 to 5 months, and 20% to 30%live for at least 1 year.3 Semilobar holoprosencephalyresults from less development of the anterior brainstructures, with only partial separation into twohemispheres. In this form of the disease, the facial

anomalies are mild or absent. Patients with lobar ho-loprosencephaly, considered the least severe expres-sion of the disease, are less clinically abnormal thanpatients with alobar or semilobar holoprosenceph-aly. These patients may exhibit mild or moderatedevelopmental delay, hypothalamic-pituitary dys-function, or visual problems.6

Computed tomography findings of the brainFig 2 CT scan demonstrating semilobar holoprosencephaly.

Fig 1 A patient with semilobar holoprosencephaly andmedian oro-facial clefting.

Fig 3 The patient seen 12 months post-operatively.

THE JOURNAL OF CRANIOFACIAL SURGERY / VOLUME 15, NUMBER 4 July 2004

676

7/29/2019 Plastic Surgery Considerations for Holoprosencephaly Patients

3/3

coupled with a period of observation can help todistinguish patients who will benefit from surgicalintervention from those who are unlikely to thrive.The degree of treatment performed may be deter-mined by the extent of the malformation. For in-stance, patients suffering from mild retardation may

benefit most from repair of the false median cleft lipand palate, whereas a patient exhibiting normal ornear-normal mentality with hypotelorism and naso-maxillary hypoplasia can be treated with simulta-neous midface advancement, facial bipartition ex-pansion, and nasal reconstruction.7 A classificationsystem proposed by Elias et al. identifies patientanomalies, with greater emphasis on the wide spec-trum of midface hypoplasia and false median cleftsthat can exist in the absence of brain malformation.7

The differentiation of these cases from true medianclefts addresses the embryological origin of the defi-cit and, ultimately, more precise guidelines for thesurgical management of these patients.

Among the dilemmas faced by treating physi-cians are the decision to operate, the timing, and theextent of surgery. Given the patients limited likeli-hood of long-term survival, is it ethical to proceedwith surgery at all? Ethical considerations in supportof surgery are based on the principle of beneficence,the physicians primary obligation to provide medi-cal benefits.8

Beneficence places a positive duty on the part ofthe surgeon to intervene actively to further the pa-tients best interests. When parents indicate a desirefor surgical repair, even with limited life expectancyand anesthesia obstacles, the physician is obligated

to consider on balance the benefits of successfultreatment against the risks of anesthesia and patientcare without treatment. For a child with semilobarholoprosencephaly and limited survival beyond in-fancy, perhaps surgical intervention should be con-sidered as soon as is practical. Sadov et al. suggestthat single-stage repair of the median cleft lip is ap-propriate in cases where there is some developmen-tal progress shown, the patient is 1 year old, and/orthe procedure will contribute to the infants socialacceptance.9 Early surgical intervention offers an in-creased quality of life for a longer period, therebyenabling improved infant care (e.g., easier feeding,

less frequent suctioning, hydration of the oral cavity)and socialization (e.g., bonding with the mother orcaregiver, earlier discharge from the hospital, accep-tance into the family and society). Surgery should betailored to meet these limited objectives.

The child described lived for 25 months. If thesurgery had been performed earlier, she would haveenjoyed an improved appearance and enhanced fam-

ily interaction for a significant additional portion ofher life. The surgical procedure was basic and ad-dressed limited but important goals. Had the patientsurvived and the family requested repair of the col-umella, this could have been accomplished with localflaps.10 Holoprosencephaly patients have a greater

anesthesia risk because of their altered thermoregu-latory ability, depressed seizure threshold, and alter-ation of upper airway anatomy as a result of medianorofacial clefting.11 Nevertheless, in a stable patient,anesthesia can be performed safely.

In summary, a holoprosencephaly patient pre-sented with multiple congenital defects and physi-ological derangements. The decision to undertake re-constructive surgery requires an assessment of thepatients needs and specific anomalies. An assess-ment of altered respiratory, cardiac, and central ner-vous system function is required to ensure that pa-tient health is not compromised. Although fewguidelines have been established for selecting surgi-cal candidates, we believe that surgery is warrantedfor patients with semilobar and lobar holoprosen-cephaly as soon as is practical. The goals of surgeryare limited to improving function (i.e., feeding) andappearance to facilitate the integration of the patientinto the family and society. Because the life expec-tancy of these patients may be short, surgical inter-vention performed as early as possible will providethe patients with improved quality of life for a sig-nificantly longer portion of their lives.

REFERENCES

1. Kinsman SL, Plawner LL, Hahn JS. Holoprosencephaly: recent

advances and new insights. Curr Opin Neurol 2000;13:1271322. Golden JA. Holoprosencephaly: a defect in brain patterning. JNeuropathol Exp Neurol 1998;57:991997

3. Barr M, Jr, Cohen MM, Jr. Holoprosencephaly survival andperformance. Am J Med Genet (Semin Med Genet) 1999;89:116120

4. Muenke M, Cohen MM, Jr. Genetic approaches to understand-ing brain development: holoprosencephaly as a model. MentRetard Dev Disabil Res Rev 2000;6:1521

5. Roessler E, Muenke M, Holoprosencephaly: a paradigm forthe complex genetics of brain development. J Inherit MetabDis 1998;21:481497

6. Simon EM, Barkovich AJ. Holoprosencephaly: new concepts.Pediatr MR Neuroimaging 2001;9:149164

7. Elias DL, Kawamoto H, Jr, Wilson LF. Holoprosencephaly andmidline facial anomalies: redefining classification and man-agement. Plast Reconstr Surg 1992;90:951-958

8. Beauchamp TL, Childress JF. Principles of Biomedical Ethics.3rd ed. New York: Oxford University Press, 1989:195, 2109. Sadov AM, Eppley BL, DeMyer W. Single stage repair of the

median cleft lip deformity in holoprosencephaly. J Craniom-axillofac Surg 1989;17:363366

10. Taub PJ, Bradley JP, Markowitz BL. Single-stage lip and nasalreconstruction in holoprosencephaly. Plast Reconstr Surg2003;111:23242327

11. Katende RS, Herlich A. Anesthetic considerations in holo-prosencephaly. Anesth Analg 1987;66:908910

PLASTIC SURGERY CONSIDERATIONS FOR HOLOPROSENCEPHALY /Hendi et al

677