# Handbook of Genetic Counseling/Holoprosencephaly

Holoprosencephaly

## Contracting

* Introduce myself
* Elicit concerns of the family- what questions do they have?

## Interim Medical History

* Who are the doctors that Lil' Jane is currently seeing? Dr. Doktour- pediatrician?
* Has she had any illnesses since we saw her last? Does it take her longer to recover from colds than you would expect?
* Surgeries/hospitalizations?
* Recent test/procedures?
* Hearing (ABER) and vision test results? Did Lil' Jane see endocrinology? Results? Any pituitary involvement? Recommendation for hormone replacement therapy?
* When is she seeing cardiology again?
* Is she taking any medications?
* Is Lil' Jane still receiving EI services? PT and OT? How often?
* Address Dr. H's concern about hypertonia of the hip. Did increased PT help?
* Has she had any seizures?
* Trouble breathing? Turning blue?
* Diarrhea or constipation?
* What is she eating? How often?
* Developmental assessment- minimal: tell me what kinds of things Lil' Jane is doing? Is she babbling at all? Rolling over, smiling etc…

## Interim Family History

* Have there been any new births, deaths, or diagnoses on either side of the family?

## Psychosocial Issues

* Who is living in your home?
* How is the family coping?
* Support network?
* Who is helping with Lil' Jane's needs?
** Does a home health care nurse still help out during the week? How often?
* Do mom and dad work outside of the home? Occupation?
* Any plans of becoming pregnant?
* Are you happy with the care that Lil' Jane is receiving?
* How does the family feel? Anxious? Worried?
* Insurance? Any financial concerns?

## Recurrence Risks

* The risk for recurrence in this family is very low, 1-2 %, given that both parents have normal karyotypes.

## Definition

* Holoprosencephaly (HPE) is a structural anomaly of the brain (occurs during the 3rd week of gestation) in which the developing forebrain fails to divide into two separate hemispheres and ventricles. There is incomplete cleavage of the forebrain (prosencephalon) into right and left hemispheres, into the telecephalon and diencephalon, and into the olfactory and optic bulbs and tracts.

## Genetic Etiology

* An extremely variable phenotypic expression occurs both in sporadic HPE and among members of the same family with an inherited form of HPE
* Environmental
** Teratogen: Maternal diabetes; 1% risk of fetus having HPE
** Alcohol
** TORCH
* Genetic mechanism
** Chromosomal: 25-50% of HPE cases are caused by a chromosome abnormality
*** Numerical: Trisomies 13, 18 and Triploidy
*** Structural: Reported in virtually all chromosomes
**** Most common include duplications or deletions at (13q), del (18p), del (7)(q36),
**** Can occur due to a de novo rearrangement or from an inherited from a normal parent with a balanced rearrangement.
** Monogenic (gene penetrance ~ 30%): syndromic
*** Autosomal dominant, autosomal recessive, and multifactorial inheritance can be seen.
*** At least 25 different conditions have been described in which HPE is an occasional finding; the majority of these disorders are rare.
** Monogenic: nonsyndromic
*** The nonsyndromic forms of HPE that are best understood at a molecular genetic level are inherited in an autosomal dominant manner.
*** Genes associated:
**** SHH (7q36), ZIC2 (13q32), SIX3 (2p21), TGIF (18p11.3)

## Prevalence

* HPE is the most common forebrain defect in humans, with a prevalence of 1:250 in embryos and 1:10,000-1:12,000 at birth.

## Categories

* HPE encompasses a variety of brain malformations, with different degrees of severity.
** Alobar HPE, the most severe, in which there is a single ventricle and no separation of the cerebral hemispheres.
** Semilobar HPE, the left and right frontal parietal lobes are fused and the interhemispheric fissure is only present posteriorly.
** Lobar HPE, the mildest form, in which the left and right central hemispheres and the lateral ventricles are separated, but the most rostral aspect of the telencephalon, frontal lobes, are fused ventrally.
** Middle interhemispheric fusion variant (MIHF or syntelencephaly), in which there is failure of separation of the posterior frontal and parietal lobes, with varying lack of cleavage of the basal ganglia and thalami, and absence of the body of the corpus callosum but presence of the genu and splenium of the corpus callosum. It is debated whether MIHF is part of the HPE spectrum or a separate entity.

## Clinical Features

* HPE is accompanied by a spectrum of characteristic craniofacial anomalies in about 80% of patients.
* In the majority of patients with HPE, a correlation exists between the facial anomalies and the subtype of HPE. (Of note, patients with all subtypes can have a relatively normal facial appearance).
* The spectrum of facial anomalies begins with cyclopia and extends in an unbroken sequence to the normal face as seen in nonpenetrant carriers of autosomal dominant HPE.
* Malformations of the nose:
** complete absence
** agenesis of the nasal cartridge, and
** proboscis (flat nose with a single central nostril without nasal bones)
* Palatal anomalies:
** midline and lateral clefts
** midline palatal ridge,
** bifid uvula
** absence of the superior labial frenulum
** A single central incisor may be present. Although a single central incisor is a non-specific finding, it is a distinctive microform in autosomal dominant HPE.
Subtypes of HPE and the Range of Possible Craniofacial Findings :
| Subtype of HPE | Facial Findings |
| Alobar HPE | Cyclopia: single eye or partially divided eye in single orbit with a proboscis above the eye Cyclopia without proboscis Ethmocephaly: extreme ocular hypotelorism but separate orbits with proboscis between the eyes Cebocephaly: ocular hypotelorism with single-nostril nose Premaxillary agenesis with median cleft lip, ocular hypotelorism, flat nose Bilateral cleft lip Ocular hypotelorism only Anophthalmia or microophthalmia Relatively normal facial appearance |
| Semilobar HPE | Bilateral cleft lip with median process representing the philtrum-premaxilla anlage Flat nasal bridge Absent nasal septum Flat nasal tip Midline cleft (lip and/or palate) Ocular hypotelorism Flat nose Anophthalmia/microophthalmia Relatively normal facial appearance |
| Lobar HPE | Bilateral cleft lip with median process Ocular hypotelorism Flat nose Relatively normal facial appearance |
| MIHF | Relatively normal facial appearance |
* Developmental delay is present in virtually all individuals with the HPE spectrum of CNS anomalies. The degree of delay is variable, correlating with the severity of the brain malformation.
* Seizures are common.
* Hydrocephalus can occur.
* Hypothalamic and brainstem dysfunction may lead to instability of temperature, heart rate, respiration, and swallowing difficulties.
* Pituitary dysgenesis is manifested by partial or complete panhypopituitarism with abnormal function of any or all of the anterior and/or posterior pituitary hormones.
* Feeding problems sometimes require gastrostomy tube. Excessive intestinal gas/colic, irritability, and constipation frequently occur.
* Aspiration pneumonia can be a complication of poor coordination of swallowing.
* Erratic sleep patterns can occur.

## Natural History

* Age of onset: newborn period, when facial features warrant further investigation
* A significant proportion of more mildly affected children survive past 12 months.
* Among patients with a normal karyotype, an inverse relationship exists between the severity of the facial phenotype and survival length.
* Individuals with cyclopia generally do not survive beyond one week of age
* Approximately one half of children with alobar HPE die before the age of 4-5 months and 20% live past the first year of life.
* Among individuals with isolated semilobar or lobar HPE, without significant malformations of other organs, more than 50% are alive at the age of 12 months.
* Almost all survivors have apparently normal vision and hearing; they smile and demonstrate memory.

## Testing

* Imaging of the brain by CT scan or MRI confirms the diagnosis of HPE, defines the subtype, and identifies associated CNS anomalies such as hydrocephalus and pituitary involvement.
* Chromosome analysis of blood
* Molecular genetic testing of the genes known to cause HPE is currently available on a research only basis.

## Management

* Most children benefit from a multidisciplinary team approach.
* A major aspect of treatment is support and counseling of the parents.
* Hormone replacement therapy has been successful in some children with pituitary dysfunction.
* Anticonvulsive therapies can help decrease the frequency and intensity of seizures.
* Feeding difficulties and failure to thrive may be managed with gastrostomy tube placement.
* Placement of a shunt may be necessary in children with HPE and hydrocephalus.
* In older children, surgical repair of cleft of the lip and /or palate may be indicated

## Risk of Recurrence

* Dependent upon the mode of inheritance
* AD nonsyndromic HPE = 50% recurrence risk
* Numerical Chromosomal HPE = 1% or less (depends on the abnormality and the maternal age)
* Structural chromosomal HPE = depend on the type of structural rearrangement
* Sporadic: low - 50% (if gonadal mosaicism)

## References

* www.geneclinics.org

## Notes

The information in this outline was last updated in 2002.