Thompson & Thompson Genetics in Medicine, 8th Edition

Case 23. Holoprosencephaly (Nonsyndromic Form) (Sonic Hedgehog (SHH) Mutation, MIM 236100)

Autosomal Dominant


• Developmental regulatory gene

• Genetic heterogeneity

• Position-effect mutations

• Incomplete penetrance and variable expressivity

Major Phenotypic Features

• Age at onset: Prenatal

• Ventral forebrain maldevelopment

• Facial dysmorphism

• Developmental delay

History and Physical Findings

Dr. D., a 37-year-old physicist, presented to the genetics clinic with his wife because their first child died at birth of holoprosencephaly. The pregnancy had been uncomplicated, and the child had a normal karyotype. Neither he nor his wife reported any major medical problems. Dr. D. had been adopted as a child and did not know the history of his biological family; his wife's family history was not suggestive of any genetic disorders. Careful examination of Dr. D. and his wife showed that he had an absent superior labial frenulum and slight hypotelorism but no other dysmorphic findings. His physician explained to him that the holoprosencephaly in his child and his absent superior labial frenulum and slight hypotelorism were suggestive of autosomal dominant holoprosencephaly. Subsequent molecular testing confirmed that Dr. D. had a mutation in the sonic hedgehog gene (SHH).


Disease Etiology and Incidence

Holoprosencephaly (HPE, MIM 236100) has a birth incidence of 1 in 10,000 to 1 in 12,000 and is the most common human congenital brain defect. It affects twice as many girls as boys.

HPE results from a variety of causes, including chromosomal and single-gene disorders, environmental factors such as maternal diabetes, and possibly maternal exposure to cholesterol-lowering agents (statins). The disorder occurs both in isolation and as a feature of various syndromes, such as Smith-Lemli-Opitz syndrome. Nonsyndromic familial HPE, when inherited, is predominantly autosomal dominant, although both autosomal recessive and X-linked inheritance have been reported. Approximately 25% to 50% of all HPE is associated with a chromosomal abnormality; the nonrandom distribution of chromosomal abnormalities predicts at least 12 different HPE loci, including 7q36, 13q32, 2p21, 18p11.3, and 21q22.3.

SHH, the first gene identified with mutations causing HPE, maps to 7q36. SHH mutations account for approximately 30% to 40% of familial nonsyndromic autosomal dominant HPE but for less than 5% of nonsyndromic HPE overall. Other genes implicated in autosomal dominant nonsyndromic HPE are ZIC2, accounting for 5%; SIX3 and TGIF, each accounting for 1.3%; PTCH1CDONGLI2, FOXH1, and NODALHPE6, and HPE8 are rare causes.


SHH is a secreted signaling protein required for developmental patterning in both mammals and insects (see Chapter 14).

Human SHH mutations are loss-of-function mutations. Some of the cytogenetic abnormalities affecting SHH expression are translocations that occur 15 to 256 kb 5′ to the coding region of SHH. These translocations are referred to as position-effect mutations because they do not mutate the coding sequence but disrupt distant regulatory elements, chromatin structure, or both, and thereby alter SHH expression.

Phenotype and Natural History

The prosencephalic malformations of HPE follow a continuum of severity but are usually subdivided into alobar HPE (no evidence of an interhemispheric fissure), semilobar HPE (posterior interhemispheric fissure only), and lobar HPE (ventricular separation and almost complete cortical separation) (Fig. C-23). Among HPE patients with a normal karyotype, 63% have alobar HPE, 28% have semilobar HPE, and 9% have lobar HPE. Other commonly associated central nervous system malformations include undivided thalami, dysgenesis of the corpus callosum, hypoplastic olfactory bulbs, hypoplastic optic bulbs and tracts, and pituitary dysgenesis.


FIGURE C-23 Holoprosencephaly (HPE) in patients with SHH mutations. A, Microcephaly, absence of nasal bones, midline cleft palate, and semilobar HPE. B, Semilobar HPE, premaxillary agenesis, and midline cleft lip. C and D, Mild facial findings with severe semilobar HPE on magnetic resonance imaging. E and F, Microcephaly, prominent optic globes, premaxillary agenesis, and cleft lip, with semilobar HPE on magnetic resonance imaging. G and H, Microcephaly, ocular hypotelorism, flat nose without palpable cartilage, midface and philtrum hypoplasia, normal intelligence, and normal brain on magnetic resonance imaging. All patients have SHH mutations. Patients A and B also have mutations of TGIF, and patient C also has a mutation in ZIC2. TGIF mutations indirectly decrease SHH expression. See Sources & Acknowledgments.

The spectrum of facial dysmorphism in HPE extends from cyclopia to normal and usually reflects the severity of the central nervous system malformations. Dysmorphic features associated with, but not diagnostic of, HPE include microcephaly or macrocephaly, anophthalmia or microphthalmia, hypotelorism or hypertelorism, dysmorphic nose, palatal anomalies, bifid uvula, a single central incisor, and absence of a superior labial frenulum.

Delayed development occurs in nearly all patients with HPE. The severity of delay correlates with the severity of central nervous system malformation; that is, patients with normal brain imaging usually have normal intelligence. In addition to delayed development, patients frequently have seizures, brainstem dysfunction, and sleep dysregulation.

Among HPE patients without chromosomal abnormalities, survival varies inversely with the severity of the facial phenotype. Patients with cyclopia or ethmocephaly usually do not survive a week; approximately 50% of patients with alobar HPE die before 4 to 5 months of age, and 80% before a year. Approximately 50% of patients with isolated semilobar or lobar HPE survive the first year.


Patients with HPE require an expeditious evaluation within the first few days of life. Treatment is symptomatic and supportive. Aside from the medical concerns of the patient, a major part of management includes counseling and supporting the parents, as well as defining the cause of HPE.

Inheritance Risk

Etiologically, HPE is extremely heterogeneous, and the recurrence risk in a family is dependent on identification of the underlying cause. Diabetic mothers have a 1% risk for having a child with HPE. For parents of a patient with a cytogenetic anomaly, the recurrence risk depends on whether one of them has a cytogenetic abnormality that gave rise to the abnormality in the patient. For parents of patients with syndromic HPE, the recurrence risk depends on the recurrence risk for that syndrome. In the absence of a family history of HPE or a cytogenetic or syndromic cause of HPE, parents and siblings must be examined closely for microforms, subtle features associated with HPE such as an absent frenulum or a single central upper incisor. For parents with a negative family history, no identifiable causes of HPE, and no microforms suggestive of autosomal dominant HPE, the empirical recurrence risk is approximately 4% to 5%. In some cases, digenic inheritance may explain the reduced penetrance of some SHH mutations.

Although autosomal recessive and X-linked HPE have been reported, most families with an established mode of inheritance exhibit autosomal dominant inheritance. The penetrance of autosomal dominant HPE is approximately 70%. Among obligate carriers of autosomal dominant HPE, the risk for having a child affected with severe HPE is 16% to 21% and with a microform, 13% to 14%. The phenotype of the carrier does not affect the risk for having an affected child, nor does it predict the severity if the child is affected.

Molecular testing for certain of the HPE mutations is currently available as a clinical service. Severe HPE can be detected by prenatal ultrasound examination at 16 to 18 weeks of gestation.

Questions for Small Group Discussion

1. What factors might explain the variable expressivity and penetrance of SHH mutations among siblings?

2. Discuss genetic disorders with a sex bias and the mechanisms underlying the sex bias. As examples, consider Rett syndrome to illustrate embryonic sex-biased lethality, pyloric stenosis to illustrate a sex bias in disease frequency, and coronary heart disease in familial hypercholesterolemia to illustrate a sex bias in disease severity.

3. Considering the many loci associated with HPE, discuss why mutations in different genes give rise to identical phenotypes.

4. Considering that GLI3 is in the signal transduction cascade of SHH, discuss why GLI3 loss-of-function mutations do not give rise to the same phenotype as SHH loss-of-function mutations.

5. Discuss the role of cholesterol in brain morphogenesis.


Kauvar EF, Muenke M. Holoprosencephaly: recommendations for diagnosis and management. Curr Opin Pediatr. 2010;22:687–695.

Solomon BD, Gropman A, Muenke M. Holoprosencephaly overview. [Available from]