A 2-year-old female came to clinic with her mother for her health supervision visit. She had semilobar holoprosencephaly with developmental delay, abnormal facial features, intermittent seizures that were well controlled with medication, nasogastric tube for supplemental feedings, constipation, various endocrinology issues, and was wheelchair bound. The mother vocalized that she felt she was getting more stressed as the children got older and their needs increased. Her Patient Health Quotient score was 2. The social history showed that the parents were married and had a 4 year old son as well who was playing in the room. Her father had an office job and provided care and was supportive at home. Her mother primarily cared for the children. They had some intermittent respite care from family members who would travel from 2 hours away.
The pertinent physical exam showed a non-communicative patient with weight in the 15%, length in the 25% and head in the 25%. The physical examination showed narrowed forehead and eyes with a more prominent nose. Her dentitia was okay but she already had some capped teeth. Her heart, lung and abdomen were normal. She was generally hypotonic. Her skin examination was normal.
The diagnosis of a child with holoprosencephaly and a mother who was probably depressed was made. The pediatrician discussed some potential options for the family including looking for consistent skilled nursing and respite care, potential preschool for her brother and referral for the mother’s depression. “I know that in the past you have wanted to care for the kids by yourself and you have done a great job, but you also need to take care of yourself,” the pediatrician began. “I know. But we thought that she would only be with us for a short time, and I love her, and I wanted to spend that with her and her brother. We really didn’t expect her to be with us and have so many problems,” the mother confided. “I can understand that, but she is still with us, and everyone in the family needs a healthy mom, especially you. Would it be okay if I try to work with one of the social workers to get you some home health care while you think about preschool for your son. The front office staff can also help scheduling you to see your own doctor soon about your possible depression. Can I do these things for you?” she asked. “I’m not sure about the preschool, but having some respite care so my son and husband can do some things together would be good. I think I might like to talk with my doctor too but I want to think some more before I do that,” she replied. “Okay, but I’m going to call you in a few days to check in and see what you have decided about preschool and your doctor after you have talked with your husband,” the pediatrician said.
Holoprosencephaly (HPE) is a clefting problem of the brain. “[HPE] the result of incomplete or absent midline division of the embryonic forebrain into distinct cerebral hemispheres (prosencephalon) between the 18th and 28th day after conception.”
There are four distinct subtypes:
- Alobar – both hemispheres are completely fused and are not separated into the left and right hemispheres. There is agenesis of the corpus callosum, arrhinencephaly and a single ventricle with fused thalami. Facial features are almost always affected.
- Semilobar – the cerebral hemispheres are fused anteriorly but are separated posteriorly. There is agenesis or hypoplasia of the corpus callosum and the olfactory bulbs and tracts are usually absent. Facial features are often affected.
- Lobar – the cerebral hemispheres are almost completely separated however the corpus callosum and olfactory lobes may be incompletely developed. Facial features may not be affected or are affected to a lesser degree.
- Middle interhemispheric – occurs when the posterior frontal and parietal lobes are incompletely separated. This is the least severely affected form.
The prevalence of HPE is one in 10,000 to 100,000 live births depending on the study. In certain subtypes there is a female preponderance.
“Cyclopia a congenital malformation characterized by the presence of a single eye,…located in the middle of the face in the place normally occupied by the roof of the nose.” This is one of the severest malformations that can be seen in alobar HPE. Cyclopia is often seen in HPE but it can be seen with other congenital defects in about 1/3 of the cases.
Problems associated with HPE include:
- Development delays including intellectual disability
- Motor problems – hypotonia, dystonia or spasticity
- Oral motor problems – problems with swallowing, dysphagia
- Pulmonary problems – particularly aspiration
- Gastrointestinal problems – gastroesophageal reflux, slow gastric emptying, constipation
- Hypothalamic problems – abnormal sleep wake cycles, temperature dysregulation, diabetes insipidus, hypothyroidism, hypoadenocorticoism, growth hormone deficiency
In general and not surprisingly, more severe forms of HPE are correlated with higher morbidity and mortality. However within the subtypes there is a wide range of morbidity and mortality.
One study found that “…33% died within the first 24hr and 58% died within the first month, yet 29% survived the first year.” Another study found 57% with syndromic HPE died within 2 days of life, but 54% with isolated HPE lived longer than 1 year. A consortium group who manages and follows patients with HPE reports that the mean age of their patients was 4 years with 15% being between 10-19 years. Patients with alobar HPE have the highest mortality.
The consortium authors conclude “[b]ecause most deaths occur within the first few days to weeks of life, even children with alobar HPE who survive the first month are likely to survive beyond infancy.” Therefore appropriate primary and speciality care with support of the family is important for the patients and families.
Questions for Further Discussion
1. What are the genetics of cleft lip and palate? A review can be found here
2. How are malformations of brain cortical development grouped? A review can be found here
3. What are NORD and OMIM and how can they help learn more about rare diseases?
4. What is the role of a primary care pediatrician for families with a rare disease? A review can be found here
- Age: Toddler
To Learn More
To view pediatric review articles on this topic from the past year check PubMed.
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Sedano HO, Gorlin RJ. The oral manifestations of cyclopia. Review of the literature and report of two cases. Oral Surg Oral Med Oral Pathol. 1963;16:823-838. doi:10.1016/0030-4220(63)90321-9
Orioli IM, Amar E, Bakker MK, et al. Cyclopia: An epidemiologic study in a large dataset from the International Clearinghouse of Birth Defects Surveillance and Research. Am J Med Genet C Semin Med Genet. 2011;157C(4):344-357. doi:10.1002/ajmg.c.30323
Levey EB, Stashinko E, Clegg NJ, Delgado MR. Management of children with holoprosencephaly. Am J Med Genet C Semin Med Genet. 2010;154C(1):183-190. doi:10.1002/ajmg.c.30254
Kaliaperumal C, Ndoro S, Mandiwanza T, et al. Holoprosencephaly: Antenatal and postnatal diagnosis and outcome. Childs Nerv Syst ChNS Off J Int Soc Pediatr Neurosurg. 2016;32(5):801-809. doi:10.1007/s00381-016-3015-4
Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa