Management of Children with Holoprosencephaly

American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 154C:183–190 (2010) ARTICLE

Management of Children With Holoprosencephaly

ERIC B. LEVEY,* ELAINE STASHINKO, NANCY J. CLEGG, AND MAURICIO R. DELGADO

Holoprosencephaly (HPE) is the most common malformation of the embryonic forebrain in humans. Although HPE occurs along a continuous spectrum, it has been categorized into four types from most severe to least severe: alobar, semilobar, lobar, and middle interhemispheric (MIH) variant. Facial malformations are often associated with HPE and usually correlate with the severity of brain malformation. With the most severely affected newborns, there is a high mortality rate in the ﬁrst month of life, however, with milder forms of HPE, the majority survive beyond infancy. The Carter Centers for Brain Research in Holoprosencephaly and Related Malformations have enrolled 182 living children in a prospective research study. Based on previously published reports using this database, reports from other investigators, as well as our experience and personal observations, the range of developmental, neurological, and medical problems found in children with HPE is described in this article. Virtually all children with HPE have some developmental disability and the severity correlates with the severity of the brain malformation on neuroimaging. Common medical problems include hydrocephalus, seizures, motor impairment, oromotor dysfunction with risk of poor nutrition and aspiration, chronic lung disease, gastroesophageal reﬂux, constipation, hypothalamic dysfunction with disturbed sleep–wake cycles and temperature dysregulation, as well as endocrine dysfunction. Diabetes insipidus in particular is found in about 70% of children with classic HPE. Recommendations for management of these problems are given based on experiences of the authors and familiarity with the literature. ß 2010 Wiley-Liss, Inc.

KEY WORDS: holoprosencephaly (HPE) How to cite this article: Levey EB, Stashinko E, Clegg NJ, Delgado MR. 2010. Management of children with holoprosencephaly. Am J Med Genet Part C Semin Med Genet 154C:183–190.

INTRODUCTION into two separate hemispheres between a brain malformation with a continuous the 18th and 28th day after conception spectrum of anomalies ranging from the Holoprosencephaly (HPE) is the most [Golden, 1999]. Both genetic and envi- most severe (alobar) form to the milder common malformation of the embry- ronmental factors play a role in the forms of lobar and middle interhemi- onic forebrain (prosencephalon) seen in process of abnormal midline division, spheric variant types of HPE. humans, occurring in approximately 1 which is described elsewhere in this HPE is associated with a spectrum in 250 embryos [Matsunaga and Shiota, issue. HPE has traditionally been cate- of midline facial anomalies whose 1977], and about 1 in 10,000 births gorized into three classic types, as severity typically corresponds with the [Croen et al., 1996; Rasmussen et al., originally described by DeMyer, rang- severity of the brain malformation, 1996; Ong et al., 2007; Orioli and ing from most severe to least severe: which gave rise to the aphorism ‘‘the Castilla, 2010]. HPE results from a alobar, semilobar, and lobar [DeMyer face predicts the brain’’ [DeMyer et al., primary defect of induction and pattern- and Zeman, 1963]. With alobar HPE, 1964], although this does not hold true ing that leads to partial or complete there is a monoventricle and no inter- in a substantial minority of cases [Cohen, failure of division of the prosencephalon hemispheric ﬁssure. With semilobar 1989; Olsen et al., 1997; Plawner et al., HPE, there is partial separation of the 2002]. The most severe facial malforma- hemispheres posteriorly, and with lobar tions such as cyclopia (ranging from a Grant sponsor: Carter Centers for Brain HPE there are almost fully developed single midline eye to the fusion of two Research in Holoprosencephaly and Related Malformations; Grant sponsor: Don and cerebral hemispheres, but with some eyes in a single midline orbit), ethmo- Linda Carter Foundation; Grant sponsor: continuity across the frontal cortex. The cephaly (close-set eyes with a tube-like Crowley-Carter Foundation. middle interhemispheric variant of HPE nose), and cebocephaly (close-set eyes *Correspondence to: Eric B. Levey, Department of Neurology and Developmen- (MIH), which has been more recently and a nose with a single nostril, but no tal Medicine, Kennedy Krieger Institute, 801 described, involves failure of separation lip cleft) are only seen with alobar North Broadway, Baltimore, MD 21205. of the posterior frontal and parietal lobes HPE [Cohen, 1989]. Milder facial E-mail: [email protected] DOI 10.1002/ajmg.c.30254 and is the least severe form [Lewis et al., malformations can be seen with all types Published online 26 January 2010 in Wiley 2002; Simon et al., 2002; Hahn and of HPE and include ﬁndings such as InterScience (www.interscience.wiley.com) Barnes, 2010]. HPE should be viewed as median cleft lip and palate (premaxillary

ß 2010 Wiley-Liss, Inc. 184 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE agenesis), midface hypoplasia and hypo- purpose of this article is to give an died within the first month, telorism, congenital nasal pyriform updated review of outcomes and com- aperture stenosis, and single maxillary mon medical problems found in children yet 29% survived the central incisor [Ming and Muenke, with HPE, with recommendations for first year. 1998]. Even children with alobar management. We present data and find- HPE can have minimal or no facial ings from previous studies, but also malformation [Solomon et al., 2010]. include some more recent data and The authors of this article are observations from the Carter Center mortality correlates with several factors, clinicians and researchers in the Carter database where appropriate, as well as including the severity of brain malfor- Centers for Brain Research in Holopro- recommendations based on the authors’ mation, the severity of facial malforma- sencephaly and Related Malforma- personal experience in treating children tion, the presence of chromosomal tions (www.stanford.edu/group/hpe), with HPE. abnormalities, and the presence of a a national consortium of five institutions multiple congenital anomaly syndrome that have been studying living children or other organ involvement [Whiteford with HPE over the past 11 years. Three We present data and findings and Tolmie, 1996; Olsen et al., 1997; of the Carter Centers (Kennedy Krieger Bullen et al., 2001]. Mason and Barr Institute in Baltimore, Maryland; Texas from previous studies, but also found in their study of 62 children with Scottish Rite Hospital in Dallas, Texas; include some more recent data alobar HPE, that those with more severe and Lucille Packard Children’s Hospital facial malformations such as cyclopia, of Stanford University) have collabo- and observations from the ethmocephaly, and cebocephaly have rated on an IRB-approved International Carter Center database where very limited survival, rarely surviving Database study to evaluate clinical out- appropriate, as well as beyond the first week of life. Of children comes in children with HPE. Each child with alobar HPE and mild or no facial has a brain scan evaluated by our neuro- recommendations based on malformations, about 50% died by 4– radiology group with confirmation of the authors’ personal 5 months of age, but 20–30% lived HPE diagnosis, determination of HPE beyond 1 year of age [Mason and Barr, type, and grading of various structures experience in treating 1999]. Children with isolated HPE involved. Each child is also clinically children with HPE. (nonchromosomal and nonsyndromic) evaluated at one of the Carter Centers, at tend to have the best survival. In a study which time the database questionnaire is of 82 infants with HPE born in New completed. A number of studies of YorkState between 1984 and 1989, 57% children of HPE using the Carter Center of newborns with syndromal HPE died database have been published. A more within the first 2 days after birth, while complete description of the database OUTCOMES 54% of children with isolated HPE study is available in the article by survived beyond the first year of life Plawner et al. [2002]. Of the 182 Survival [Olsen et al., 1997]. children (107 female, 75 male) with In one of our previous studies, we Overall, mortality is high for newborns HPE enrolled in our database study to reported that the mean age of partic- with HPE, however, some patients will date, 15% have alobar, 54% semilobar, ipants was 4 years and that 15% of survive beyond the neonatal period, 18% lobar, and 15% MIH type HPE. In a children with HPE were between 10 with smaller numbers surviving for review of evaluation and management of and 19 years of age. The mean age of many years. Of 24 liveborn infants with HPE, Hahn and Plawner [2004] from children with alobar HPE was 2 years HPE in the North of England between the Carter Centers previously summar- [Stashinko et al., 2004]. Children with 1985 and 1998, 33% died within the ized many of our findings, describing the alobar HPE as a group have the highest first 24 hr and 58% died within the variety of medical problems seen in mortality, while children with milder first month, yet 29% survived the children with HPE, including craniofa- forms of HPE, that is, lobar HPE and first year [Bullen et al., 2001]. Higher cial malformations, hydrocephalus, MIH type HPE, should be expected to seizures and epilepsy, motor and devel- live for many years. Although survival is opmental dysfunction, oromotor dys- associated with the severity of brain function, and hypothalamic and Of 24 liveborn infants with malformation, there is still significant endocrine dysfunction. A group at the variability in survival within each type of Rennes University Hospital Center in HPE in the North of HPE. Some children with isolated alobar France has also studied a large number of England between 1985 and HPE will survive into adolescence and children with HPE, and their findings even into adulthood. Survival of chil- have been similar to ours [Lazaro et al., 1998, 33% died within dren with semilobar HPE is intermedi- 2004; Dubourg et al., 2007]. The the first 24 hr and 58% ate between alobar and lobar HPE, with ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 185 some early mortality in the first significant development focus on the child’s ability and desire to few months of life, though the majority engage socially with others [Roesler live into childhood. For children with of cognitive and language skills, et al., 2006]. semilobar HPE who survive beyond the especially receptive language. first year, there is an ongoing small but COMMON MEDICAL not insignificant risk of mortality that is PROBLEMS AND Because children with semilobar HPE affected by the multiple problems asso- MANAGEMENT ciated with HPE, including impaired tend to have severe motor impairment, speech is significantly impaired and mobility, risk of aspiration, epilepsy, Hydrocephalus temperature instability, and endocrine typically does not develop beyond a few dysfunction. consonant-vowel vocalizations or single About one-sixth of children with HPE word approximations, even among the in our database have had a cerebrospinal older children [Roesler et al., 2006]. fluid (CSF) shunt placed for treatment of Developmental Outcomes Many children with semilobar HPE can hydrocephalus. Children with alobar Developmental disabilities are present in learn to communicate through eye gaze, HPE are more likely to need a shunt virtually all children with HPE. The gestures, picture-based communication than children with other types of HPE. degree of developmental disability gen- systems or augmentative communication The presence of a dorsal cyst is strongly erally correlates with the severity of the devices. Of 30 patients with semilobar correlated with lack of separation of the brain malformation on neuroimaging. HPE in our study, 4 had mildly impaired thalami and development of hydroce- Children with alobar HPE make mini- to normal hand function and 2 could phalus. It is hypothesized that thalamic mal developmental progress and gener- speak in multiword sentences [Plawner nonseparation blocks CSF egress from ally have profound global impairments. et al., 2002]. the third ventricle [Simon et al., 2001]. They can develop some skills, although Children with lobar HPE have The challenge in evaluating chil- never achieve milestones beyond those much better development of motor skills. dren with HPE for hydrocephalus is of an early infant. In our previous study, About one-half have mildly impaired to trying to distinguish large CSF spaces none of the children with alobar HPE normal hand function, are able to walk from hydrocephalus with increased were able to sit independently, reach and independently or with assistance, and intracranial pressure. Children with attain objects, or utter words [Plawner speak single words or multiword senten- HPE and a dorsal cyst should be followed et al., 2002]. Some could bat at objects. ces [Plawner et al., 2002]. Compared closely for hydrocephalus. Virtually all Most children with alobar HPE can hear with lobar HPE, children with MIH type children with HPE who do not have and some will react to sounds, for HPE have somewhat better hand/arm hydrocephalus will have microcephaly. example, by turning their head. Most function and speech and similar mobility A child with HPE and normal head children with alobar HPE who do not [Lewis et al., 2002]. circumference or macrocephaly suggests have ocular malformations have some Because of the severe motor and the presence of increased intracranial vision and can focus on faces or nearby expressive language impairment seen in pressure. If hydrocephalus is suspected, objects, and some of these children will many children with HPE, their cogni- clinicians can follow serial head circum- develop the ability to track objects and tive development cannot be assessed by ferences and head ultrasounds. If a respond to facial expressions [Barr and traditional tests. The Carter Neuro- child has macrocephaly or their head Cohen, 1999]. cognitive Assessment (CNA) was devel- circumference increases in percentiles The range of developmental out- oped in order to minimize the impact of over time, then consideration should be comes for children with semilobar HPE motor and expressive language impair- given to placing a CSF shunt. We have is very wide. Some children with semi- ment on performance and can be used to also had a few cases in which a child with lobar HPE make little developmental quantify a range of skills reflecting a semilobar HPE who was making devel- progress, while others show significant cognitive level up to 18–24 months opmental progress began losing mile- development of cognitive and language [Leevers et al., 2005]. The CNA has stones and demonstrated increased skills, especially receptive language. been useful for evaluating abilities in oropharyngeal dysphagia. These patients children with HPE, although children responded to CSF shunting with im- with milder forms of HPE often have provement in development and swal- The range of developmental skills beyond its ceiling level. It was lowing. Besides the potential for a better outcomes for children with found that social awareness is an area of developmental and functional outcome, strength for children with HPE and that placing a shunt for treatment of hydro- semilobar HPE is very wide. most are very socially engaging and cephalus will help in avoiding a propor- Some children with semilobar respond positively to faces and voices. tionally large head that makes the child Educational and therapeutic activities difficult to position and care for. Treat- HPE make little developmental should utilize eye gaze as a primary ing hydrocephalus can also reduce progress, while others show communicative response and should irritability. When placing a shunt, the 186 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE neurosurgeon also needs to consider the precipitant of seizures in some children glaucoma and should not be used in possibility of overdrainage with develop- who have never had seizures before. patients at risk. Some patients with HPE ment of subdural fluid collections. Use It is important to remember that have stopped the medication because of of an adjustable valve can allow for the some antiepileptic medications can increased hyperkinetic movements or a gradual reduction of intracranial pres- have effects on blood sodium level. significant change in behavior. sure without additional surgery and Carbamazepine and oxcarbazepine allow the pressure to be individualized augment release of antidiuretic hor- Oromotor Dysfunction, Feeding for each child, minimizing the risks of mone and tend to cause hyponatremia and Nutrition overdrainage. in normal children. These affects can be used to the advantage of the child Children with more severe motor Seizures and Epilepsy with HPE who also has diabetes insip- impairment tend to have more severe About one-half of children with HPE idus and elevated sodium levels at impairment of swallowing function, so have had at least one seizure, and epilepsy baseline. some swallowing problems are seen in requiring treatment with antiepileptic almost all children with alobar and medication occurs in only about 40% semilobar HPE. About two-thirds of Motor Impairment (73/182) of children with HPE enrolled these children have required placement in the Carter Center database. Onset of Abnormal muscle tone and impaired of a gastrostomy tube because of risk of seizures is usually during infancy. While coordination are seen to some extent in aspiration or inadequate oral intake. a variety of seizure types affect these virtually all children with HPE, Common symptoms of oropharyngeal children, complex partial seizures are the although some children with MIH and dysphagia include choking, coughing, most common type (43%). Although lobar HPE seem to have minimal motor or gagging with feeds or increased children with alobar HPE have signifi- impairment. Most children with HPE respiratory symptoms following feeds, cant disabilities, it may surprise some can be said to have cerebral palsy. Mixed such as wheezing, coughing, and that only 56% of these children require patterns are common, with many chil- increased secretions. Problems in coor- treatment for epilepsy. Intractable seiz- dren showing truncal hypotonia, dysto- dinating suck and swallow can lead to ures are seen in about one-third of nia of the upper extremities and more aspiration of food and secretions into the patients with HPE who have epilepsy, spasticity of the lower extremities. airway. Penetration and aspiration of and seem to occur more often in patients Hypotonia in infancy can progress to food below the vocal cords can be with more significant cortical malfor- spasticity and/or dystonia as the child documented by videoflouroscopic swal- mation. grows and develops. low study. Children with impaired Most children with HPE do not As with other children with cerebral swallowing are at risk for acute aspiration have epilepsy. Of the ones who do have palsy, children with HPE may benefit pneumonitis as well as development of epilepsy, most can be treated with a from physical and occupational therapy, chronic lung disease. Recurrent micro- single antiepileptic medication such as bracing, and in some cases, orthopedic aspiration can lead to chronic lung carbamazepine or levetiracetam. A surgery. A number of patients with disease without a history of acute smaller group may require the addition severe spasticity and/or dystonia have aspiration events. Children with oro- of second line agents such as topiramate, benefited tremendously from placement motor dysfunction have a more zonisamide, or lamotrigine for treat- of intrathecal baclofen pumps. For treat- difficult time managing their secretions ment of refractory epilepsy. Some chil- ment of dystonia, we have used oral when they have increased secretions and dren with refractory epilepsy respond trihexyphenidyl with some success, nasal congestion due to aviral respiratory well to high dose phenobarbital. We including improved oromotor and infection, making them more suscepti- have treated a few patients successfully upper extremity function. Trihexyphe- ble to severe illness with common viral by pushing phenobarbital levels to nidyl, an anticholinergic drug which infections, such as influenza. Children the high 50 mcg/ml without apparent crosses the blood–brain barrier, is avail- without frank aspiration may have adverse effects. The detrimental cogni- able as a 2 mg/5 ml elixir and most older oromotor difficulties that make feeding tive effects of phenobarbital may be infants can be started at 1 ml (0.4 mg) slow and laborious, leading to poor oral more acceptable in children with alobar three times daily. The dose can be intake and failure to thrive. HPE who have minimal function at escalated, monitoring for adverse effects Besides oromotor dysfunction, baseline. with each increase in dose, up to a facial anomalies such as cleft lip and As with other children, seizures can maximum of about 2 mg/kg/day. Com- palate and congenital nasal pyriform be triggered by hypoglycemia or fluid mon adverse effects of trihexyphenidyl aperture stenosis contribute to feeding and electrolyte disturbances, especially include those typical of anticholinergic problems as well. Nurses experienced in rapid fluctuations in sodium level or medications such as dry mouth, dry eyes, feeding infants with cleft lips and palates significant dehydration. Hyponatremia constipation, decreased sweating, and may be able to offer some guidance. as an iatrogenic consequence of treat- potential for overheating. Trihexyphe- Special nipples designed for children ment of diabetes insidipus has been the nidyl can exacerbate acute narrow-angle with cleft palates may also help. Some of ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 187 these children may need a gastrostomy influenza vaccination starting at Hypothalamic Dysfunction tube. 6 months of age and administration of The hypothalamic nuclei play an Children with HPE tend to be small the 23-valent pneumococcal vaccine important role in homeostasis and in for a number of reasons, including (Pneumovax) should be considered after regulating important bodily functions nutritional and hormonal causes, so their 2 years of age. such as sleep, temperature, appetite, weight may be low for age, but may be and thirst. Hypothalamic nonsepara- appropriate for their height. When tion by imaging correlates with hypo- evaluating nutritional status, it is impor- Gastrointestinal Problems thalamic dysfunction in children tant to look at weight for height centile or with HPE [Plawner et al., 2002]. body-mass index centile for age. For tube As with children with cerebral palsy and Abnormal sleep–wake cycles, temper- fed patients, it is the primary author’s other neurodevelopmental disabilities, ature instability, and impaired thirst practice to set a goal to keep the weight- gastrointestinal problems are common in mechanisms are common in children for-height of patients with HPE between children with HPE. In general, the GI with HPE. the 10th and 25th centiles. tract is normal, however, patients have functional GI disorders including poor gastric emptying, gastroesophageal Pulmonary Issues reflux, and constipation, presumably Abnormal sleep–wake cycles, As mentioned above, children with HPE due to abnormal regulation by the and oromotor dysfunction are at risk for nervous system. Use of H2 blockers or temperature instability, and aspiration and development of recurrent proton-pump inhibitors to suppress acid impaired thirst mechanisms respiratory problems and/or chronic production is appropriate. Use of a lung disease. Children with HPE can prokinetic to improve gastric emptying are common in children also have upper airway obstruction due can also be helpful, however, clinicians with HPE. to facial anomalies. Some children with need to use caution in prescribing HPE and facial anomalies have had a metoclopramide (Reglan) as it can be tracheostomy tube placed during the associated with significant adverse neonatal period for treatment of upper effects, including exacerbating dystonia, Altered and erratic sleep–wake airway obstruction. Central apnea can be seizures, and irritability. Low-dose cycles are common in children with present in those more severely affected erythromycin can be used as a prokinetic HPE, with various patterns observed, and, in children with alobar HPE, likely and may improve gastric emptying and including day–night reversal, frag- contributes significantly to the high reflux. With children who are tube fed, mented sleep patterns with children mortality during the first few months adjusting the rate, volume and schedule only sleeping for a few hours at a time, of life. of tube feedings can help with feeding reduced need for sleep, and increased Symptoms of chronic lung disease tolerance, as can selection of formula. need for sleep. As these problems can be can include chronic cough, recurrent Some children do not tolerate feeds very frustrating for parents and care- wheezing, and eventually low oxygen when asleep, while others do. Slowing givers and contribute to caregiver bur- saturations at baseline. Children with the rate down can improve comfort and den, they should not be taken lightly. chronic lung disease have less pulmonary GERD. If reflux continues to be a Parents are instructed in good sleep reserve and are more susceptible to problem despite medical management, hygiene including setting a regular bed- severe pneumonia when they do an anti-reflux procedure such as Nissen time for their child, and minimizing become ill. Children with HPE can be fundoplication or gastrojejunostomy light and loud noises. Melatonin is a treated similarly to children with cere- tube placement can be considered. naturally occurring hormone that is bral palsy in regards to pulmonary Frequent venting of air through the important for regulation of the sleep– management. Inhaled beta-agonists such gastrostomy tube can help reduce dis- wake cycle. It is available as an over-the- as albuterol and inhaled steroids can be tension and irritability due to excessive counter nutritional supplement in the used to treat bronchospasm and chronic air swallowing. Simethicone drops U.S. We often trial patients on a 1- inflammation. Because of motor impair- may be helpful and are a relatively month course of melatonin before trying ment, clearance of airway secretions is benign intervention. Constipation can other medications, typically recom- often poor. Suctioning and chest phys- be exacerbated by poor fluid intake or mending a 1–5 mg dose 30–60 min iotherapy can be helpful. Some children relative dehydration due to diabetes before bedtime. Some children have a have benefited greatly from physiother- insipidus. More aggressive treatment of dramatic response to melatonin, while apy vests that utilize high frequency constipation can also decrease reflux, others do not seem to respond at all. chest wall oscillation (e.g., The Vest distension, and irritability. Often a Antiepileptic medications, tone medi- Airway Clearance System) for improved combination of polyethylene glycol cations, and other sedating medications mobilization and clearance of secretions. 3350 (Miralax) and rectal suppositories can be adjusted to give a larger dose at Children with HPE should have yearly is effective. bedtime, using their sedative effects to 188 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE aid with sleep. While chloral hydrate Endocrine Dysfunction and apnea. ACTH deficiency can be and diazepam may help, these medica- life-threatening, especially in the setting In one of our previous studies of 117 tions may become habit forming and of acute illness. Hormone replacement patients with HPE, central diabetes after prolonged use often lose their therapy should be initiated depending insipidus (DI) occurred in approxi- effectiveness. Clonidine and gabapentin on severity and clinical context. Diabe- mately 70% of patients with classic have been used effectively in some tes insipidus can be detected by mon- HPE. Anterior pituitary hormone defi- patients. itoring plasma sodium levels for ciencies such as hypothyroidism (11%), Hypothalamic control of body hypernatremia. We have observed that hypoadrenocorticism (7%), and growth temperature control is often impaired a number of children with HPE have hormone (GH) deficiency (5%) were [Barr and Cohen, 1999]. In our study, stable hypernatremia at baseline, in the much less common [Hahn et al., 2005]. 32% of children had abnormal temper- range of about 148–153 meq/L, and ature regulation and the degree of remain asymptomatic without signs of dysfunction correlated with the In one of our previous studies dehydration. Some have interpreted degree of hypothalamic nonseparation similar children as having neurogenic [Plawner et al., 2002]. Some children of 117 patients with HPE, hypernatremia, which they differentiate with HPE have lower than normal body central diabetes insipidus from true diabetes insipidus [Lazaro temperatures at baseline, while some et al., 2004]. These children may in have elevated temperatures in the (DI) occurred in approximately effect have an altered osmostat or set- absence of infection, and some go to 70% of patients with classic point for plasma sodium due to hypo- both extremes. Knowing the usual thalamic dysplasia, rather than more temperature range for each child is HPE. Anterior pituitary typical central DI due to an abnormal important in identifying illness and hormone deficiencies such as pituitary gland. In our study, about 73% abnormal fluctuations that should be hypothyroidism (11%), of patients with HPE diagnosed with DI further evaluated and treated. Relative were treated with DDAVP and the hypothermia can manifest as lethargy, hypoadrenocorticism (7%), remainder was treated with fluid man- low heart rate and blood pressure, and and growth hormone (GH) agement alone [Hahn et al., 2005]. Some decreased respirations. Relative hyper- children with HPE and DI will decom- thermia is often accompanied by deficiency (5%) were much pensate with illness, so it is reasonable to increased seizures and irritability and less common. check serum electrolytes in the acute can be exacerbated by dehydration. setting. End-organ dysfunction is possible, especially when body temperature goes None of the children with MIH HPE below 338C. Fluctuations in body tem- had DI although a few had anterior APPROACH TO perature can be attributed to the effects pituitary hormone deficiency. The MANAGEMENT of ambient temperature, state of arousal, degree of DI correlated with the degree The parents of children with HPE need endocrine dysfunction, medications, of hypothalamic separation but did not to be given a balanced and realistic and sometimes infectious illness. Man- correlate with the degree of pituitary prognosis for their child in order to agement of temperature instability in abnormality by neuroimaging. In a study make decisions about ongoing medical that included 29 patients with HPE children with neurologic disabilities has care. Some newborns with HPE will not been studied or well-described. referred to a pediatric endocrinology need interventions such as tracheostomy, Most children can be managed by center, 54% were found to have DI, 42% mechanical ventilation, and tube feeding modifying their environment. An indi- had GH deficiency, and 21% had in order to survive. The decision- vidualized protocol, including steps for deficiency of multiple pituitary hor- making process works best when the monitoring and responding to temper- mones [Traggiai and Stanhope, 2002]. parents are fully informed, but do not atures out of their usual range, can be The higher rate of GH deficiency in this feel pressured by the medical team. developed for children with HPE and study could be because of referral bias Parents should be offered support and and their use of stimulation tests for significant temperature instability. guidance and should feel that they will Guidelines to families should be written diagnosis. be supported by the medical team no with a goal of avoiding moderate to Children with HPE should be matter what they decide. No matter how severe hypothermia (<33–348C) or evaluated for endocrine dysfunction grim the prognosis, some parents will hyperthermia (>40–418C) while not during the neonatal period with a low want to do everything possible for their requiring excessive vigilance and inter- threshold for repeat evaluations, as vention. In some cases, a water-filled deficiencies can evolve over time. Pos- medical heating/cooling pad has been sible symptoms of anterior hormone used for temperature modulation with deficiencies include hypoglycemia, poor Parents should be offered some success. feeding, poor linear growth, lethargy, support and guidance and ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 189

should feel that they will be other children their age. At the time of providers as well as other family mem- newborn discharge, the parents may bers and friends. Many parents of supported by the medical team decide that if their child were to have children with HPE also find great no matter what they decide. an acute life-threatening event, that they benefit in sharing their experiences with would not want their child resuscitated. each other. Families for HoPE (www.fa- No matter how grim the Other than decisions about resuscita- miliesforhope.org) is an online com- prognosis, some parents will tion, decisions can usually be made as munity that connects parents of children want to do everything possible situations arise. At some point, they may with HPE with each other and has a need to consider a feeding tube or forum for discussion of various issues. for their child. whether to provide life-sustaining care in the event of serious illness. It is reasonable to discuss these scenarios in child [Redlinger-Grosse et al., 2002]. advance, but parent and provider per- SUMMARY AND Parents need to feel that their beliefs and spectives are likely to change as time goes CONCLUSIONS opinions are respected, especially when by.Some children with HPE are resilient Although there is high early mortality medical team members may have views and have few illnesses while others are with severe cases of HPE, some children that are contrary. extremely fragile. with alobar HPE and most children with There is a common misperception At the time of discharge, newborns milder forms will survive beyond that most children with HPE have with HPE should have at least one infancy. Virtually all children with limited survival, without consideration medical provider who has agreed to HPE will have some developmental of type of HPE, presence of chromoso- follow them closely for several months disability, the severity correlating with mal abnormalities, severity of facial and help coordinate their care. The the severity of the brain malformation. malformations, or other organ system provider could be a Geneticist, Neo- Children with HPE typically have involvement. It has been our experience natalogist, Pediatric Neurologist, Devel- multiple medical problems, many that that many newborns with HPE are opmental Pediatrician or Primary Care are typical of other children with discharged to home with their parents Pediatrician. Parents need to have some- cerebral palsy. Because HPE is a midline with the expectation that they will not one they trust who they can call to ask defect commonly involving the hypo- live beyond a few months of age [Barr questions or to discuss ongoing medical thalamus, it is associated with temper- and Cohen, 1999; Stashinko et al., care. Depending on medical issues that ature instability, disturbed sleep–wake 2004]. Patients are sometimes inap- arise, the child can be referred to cycles, and endocrine dysfunction in a propriately referred to hospice care. In Endocrinology, Neurology, Pulmonol- high percentage of patients. Because some cases, parents have been told not to ogy, and Gastroenterology as appropri- survival of newborns with HPE is often do anything for their child, and not to ate. If death seems imminent, hospice uncertain after discharge, parents are seek any routine or specialty medical care can be arranged. The first often desperate for the support and care. Unfortunately, The Carter Centers several months after birth are the most guidance of medical providers, yet often are often contacted after a period critical for the child with HPE and the feel abandoned. Not only do parents of time by parents who have an infant parents, whether the child lives or dies. need clinicians who are familiar with the with HPE who has survived, and Families need support and guidance natural history and common medical they feel abandoned by their medical along with respect for their beliefs and problems associated with HPE, they providers and no longer trust them. wishes. They should not feel abandoned need a clinician who can serve as a point These parents often turn to The Carter by the medical system. person after discharge. Medical care of Centers in order to ask us what to Because HPE is a rare condition the child with HPE often requires do next and are actively looking for among living children, most parents of coordination of multiple medical and direction. children with HPE do not know anyone rehabilitative specialists and a plan of care Because most deaths occur within else with a child with HPE, and feel that that changes as the outlook, treatment the first few days to weeks of life their medical and other providers lack goals, and parents’ priorities evolve. [Whiteford and Tolmie, 1996], even familiarity with the condition. HPE is a children with alobar HPE who survive cause of cerebral palsy, which is a much the first month are likely to survive more common condition, and one with ACKNOWLEDGMENTS beyond infancy. Once newborns with which most medical and other service HPE are discharged to home, unless providers are familiar. Empowering The database study was supported by the death is imminent, clinicians should parents with the concept that their child Carter Centers for Brain Research in provide them with all routine childcare has cerebral palsy due to HPE can help Holoprosencephaly and Related Mal- including immunizations and pediatric them in finding appropriate medical formations, the Don and Linda Carter visits. These patients should be evaluated providers, services, and resources, and Foundation, and the Crowley-Carter and treated for acute illnesses as would help them in communicating with Foundation. 190 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE

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