Lissencephaly Case File

Lissencephaly Case File

Eugene C. Toy, MD, Ericka Simpson, MD, Pedro Mancias, MD, Erin E. Furr-Stimming, MD

CASE 50

A 13-month-old baby boy is brought to the clinic by his pregnant mother after he experienced a seizure. He has had recurrent seizures since age 6 months and had generalized spasms as an infant. She expresses concern that he has not been able to sit up by himself yet and has always been a weak baby. He has not been feeding well and lately has had a wet cough with low-grade fevers. Developmentally, he has not said his first word, compared to his older sister who was able to say three words as well as “Mama” and “Dada” by the same age. His birth history is significant for intrauterine growth restriction and reduced fetal movements. After birth, he underwent surgery for cryptorchidism. On examination, his head circumference is small for his age. General examination reveals a high forehead with vertical wrinkling, bitemporal hollowing, widely spaced eyes with epicanthal folds, flattened ears, short nose with upturned nares, prominent nasal folds, a flat midface with a round philtrum and upper lip, and a small chin. He is tachycardic, and his chest sounds are diminished in the right lower lobe. A back examination reveals a sacral dimple. Neurologically, he has generalized hypotonia and is unable to support himself when sitting up.

▶ What is the most likely diagnosis?

▶ What is the next diagnostic step?

▶ What is the next step in therapy?

ANSWERS TO CASE 50:

Lissencephaly                                                       

Summary: A 13-month-old baby boy with history of developmental delay, dysmorphic facial features, and infantile spasms is brought for evaluation by his mother for recurrent seizures. He has severe mental retardation and motor developmental delays as well as poor feeding. His past history is significant for intrauterine growth restriction in pregnancy and cryptorchidism. On examination, he has microcephaly, craniofacial dysmorphisms including hypertelorism with epicanthal folds, short nose with upturned nares, and micrognathia, tachycardia, a sacral dimple, and generalized hypotonia.

• Most likely diagnosis: Miller-Dieker syndrome (MDS) or lissencephaly type 1
• Next diagnostic step: Magnetic resonance imaging (MRI) of the brain
• Next step in therapy: Symptomatic management of seizures and poor feeding/swallowing, genetic counseling

ANALYSIS

Objectives

1. Know the clinical features and epidemiology of MDS.
2. Understand the differential diagnosis of lissencephaly.
3. Understand the management of lissencephaly patients and their families.

Considerations

The 13-month-old child in the case is a typical case of MDS. Severe mental retardation, recurrent seizures, and infantile spasms are typical. Refractory epilepsy presents during the first 6 months of life in 75% of affected children, with infantile spasms beginning shortly after birth in 80%. Overall, more than 90% of these patients will develop seizures. Mental retardation and developmental delay are severe, with most affected children not capable of progressing beyond the 3- to 6-month level of milestones. Distinct craniofacial dysmorphic features as described for our patient, generalized hypotonia that progresses to opisthotonus, and spasticity with age, contractures, clinodactyly, cryptorchidism, omphaloceles (an abdominal wall defect), cardiac and renal abnormalities are all phenotypic. Feeding and swallowing problems often result in poor weight gain and aspiration pneumonia. Past history will often reveal a gestation complicated by polyhydramnios, intrauterine growth restriction, and decreased fetal movements.

APPROACH TO:

Lissencephaly                                                  

DEFINITIONS

LISSENCEPHALY: Genetic malformation of the cerebral cortex in which abnormal neuronal migration during early neural development results in smooth cerebral surfaces with absent (agyria) or decreased (pachygyria) convolutions.

MILLER-DIEKER SYNDROME (MDS): A severe lissencephaly phenotype secondary to deletion on chromosome 17p13.3 with agyria and characteristic dysmorphic features.

ISOLATED LISSENCEPHALY SEQUENCE: Milder phenotype compared to MDS, with pachygyria and mild or absent dysmorphic features because of autosomal dominant mutations in the LIS1 gene on chromosome 17p13.3 or X-linked mutations in the doublecortin (DCX) gene on chromosome Xq22.3. Pachygyria caused by LIS1 mutations is posterior predominant on neuroimaging, whereas anterior-predominant pachygyria is more typical of DCX mutations.

SUBCORTICAL BAND HETEROTROPIA: It refers to a band of heterotopic gray matter located just beneath the cortex and separated from it by a thin zone of normal white matter.

INFANTILE SPASMS: Dramatic repetitive bouts of rapid neck flexion, arm extension, hip and knee flexion, and abdominal flexion, often with arousal from sleep. The mother might describe them as unprovoked startle responses or colicky spells as a result of abdominal pain, although there is no crying typical of colic. Typical presentation occurs between 3 and 8 months of age.

HYPERTELORISM: Abnormally increased distance between the eyes.

EPICANTHAL FOLD: Skin fold of the upper eyelid (from the nose to the medial side of the eyebrow) covering the medial corner (medial canthus) of the eye.

CLINODACTYLY: Congenital condition where the little finger is curved toward the ring finger.

OPISTHOTONUS: Severe hyperextension of the back caused by spasm of the muscles along the spinal column.

CLINICAL APPROACH

Epidemiology and Differential Diagnosis

MDS is an inherited form of lissencephaly and has been reported to occur in 11.7 per million live births. This severe form is estimated to be the cause of almost one-third of patients with identified lissencephaly. It is caused by chromosome microdeletions in the chromosome 17p13.3 of the LIS1 gene. In approximately 80% of cases it is due to a de novo deletion, and in 20% of cases it is inherited from a parent who carries a balanced chromosome rearrangement. The main differential diagnosis is isolated lissencephaly sequence (ILS), which has a milder phenotype and is caused by a smaller mutation in the LIS1 gene, with an autosomal dominant pattern of inheritance, or a mutation in the DCX gene, with X-linked transmission. Microdeletions in the LIS1 gene will cause the “agyria-pachygyria-band” spectrum of cortical malformation. The phenotypes include MDS, ILS, and subcortical band heterotopia (SBH).

These microdeletions will cause central nervous system (CNS) abnormalities of the embryo, due to interruption or disruption of three development stages: cell proliferation, cell migration, and cortical organization. Lissencephaly refers to smooth brain and is due to disruption of abnormal cell migration. The word lissencephaly is derived from the Greek word lissos meaning smooth and encephalos meaning brain. With lissencephaly, the early brain development is normal until month 3 or 4 of development, when the brain fails to progress normally. The human brain normally has a convoluted surface, but in patients with lissencephaly these convolutions are completely or partially absent from the brain, or areas of it, giving the smooth appearance. The convolutions are also called gyri, and their absence is known as agyria (without gyri). In some cases, convolutions are present, but thicker and reduced in number, and the term pachygyria (broad gyri) is used. The neocortex of patients contains four layers instead of six. The diagnosis is usually made by MRI scan of the brain, which can show classical findings of the hourglass configuration, thick cortex, thin subcortical white matter interdigitation, and shallow sylvian fissure (Figure 50–1).

Figure 50–1. Features of classical lissencephaly showing the four severity grades. All images are T1- or T2-weighted MRI scans. The top row shows axial scans, and the bottom row shows coronal scans. Grade 1 is near complete agyria, grade 2 is posterior agyria and rudimentary shallow gyri anteriorly, grade 3 is posterior agyria and anterior pachygyria, and grade 4 is generalized pachygyria. (Leventer RJ, Guerrini R, Dobyns WB. Malformations of cortical development and epilepsy. Dialogues Clin Neurosci. 2008;10[1]:47-62.)

Both MDS and ILS are considered classical lissencephalies or lissencephaly type 1. The differential diagnosis also includes other migration defect syndromes that present with seizures, mental retardation, and lissencephaly, including lissencephaly with cerebellar hypoplasia (AR, RELN gene on 7q22) and lissencephaly with abnormal genitalia (X-linked, ARX on Xp22.13). Related syndromes that present with similar clinical presentations but different neuroimaging findings include SBH (LIS1 or DCX), polymicrogyria, bilateral periventricular nodular heterotopia, and schizencephaly.

DIAGNOSIS

An accurate diagnosis is important for two reasons. First, if the condition is genetic and has been inherited, it will allow parents to understand the risk for future pregnancies and also whether other children in the same family are also carriers for the faulty gene. Second, it is useful for parents of children with lissencephaly to meet other parents and children with the same condition so they can learn from each other’s experience.

A condition of lissencephaly or pachygyria is not a full diagnosis, and the cause cannot be determined without a more detailed evaluation from a neurologist, pediatrician, or geneticist. Neuroimaging is very important in the evaluation and diagnosis. An MRI scan is almost always superior for detailing the brain malformation, especially for conditions such as polymicrogyria where computed tomography (CT) scans do not provide the resolution required.

TREATMENT

The management for patients with lissencephaly is mainly supportive, centering around the three major complications: epilepsy, poor feeding, and spasticity. Improved symptomatic therapy has lengthened the life expectancy of these patients from a few years to the early teens. The use of steroids (prednisone) and adrenocorticotropic hormone (ACTH) is an accepted treatment for infantile spasms but may or may not be successful. Seizures will return following treatment with steroids and are often intractable. Multiple anticonvulsants are often required with vigilance for life-threatening status epilepticus. Poor feeding and swallowing predispose to malnutrition and aspiration pneumonia; a feeding tube and gastrostomy in the long term can help reduce these comorbidities. Hypotonia in the early years progresses to spasticity and contractures that, if untreated, can result in severe pain and discomfort, as well as immobility and complications such as falls, atelectasis, and decubitus ulcers. Frequent stretching physical therapies, braces, and muscle relaxants can slow the development of spasticity and contractures, and special wheelchairs and mattresses can reduce problems arising from immobility. Lissencephaly patients can also have congenital cardiac and renal abnormalities that must be closely monitored and managed.

As in the case of this patient’s family, genetic counseling plays an important role because of concern for a hereditary syndrome. The recurrence risk for MDS is very low because most cases are caused by a de novo chromosomal deletion. However, recurrence risk can be as high as 33% if a familial reciprocal translocation is determined. The workup can begin with a fluorescent in situ hybridization (FISH) analysis for the 17p13.3 deletion, and a genetics specialist can be consulted. Prenatal testing is possible through fetal chromosome analysis by karyotyping, FISH, chorionic villus sampling, or amniocentesis. Imaging for cerebral gyral malformations is more sensitive beyond 28 weeks of gestation.

COMPREHENSION QUESTIONS

50.1 A 14-month-old child is diagnosed as having MDS. Which of the following would be most likely noted on physical examination?

A. Macrocephaly

B. Motor delay

C. Ambiguous genitalia

E. Abnormal X-chromosome studies

50.2 Which of the following is one of most common sequela of MDS?

A. Epilepsy

B. Respiratory failure

C. Hypotonia

D. Rhabdomyolysis

50.3 A 2-month-old infant is noted to draw up his legs and tighten his abdomen after feeding with formula. There seems to be no abnormal seizure activity. The developmental milestones seem to be normal. Which of the following is the most likely diagnosis?

A. Infantile spasms

B. Intestinal colic

C. Lissencephaly, early onset

D. Noonan syndrome

ANSWERS

50.1 B. Motor delay, seizures, and microcephaly are the hallmarks of MDS. Ambiguous genitalia is typically not seen. Chromosome 17 (17p13.3 microdeletion) is typically affected and not the X chromosome.

50.2 A. The management of the Miller-Dieker lissencephaly patient is supportive, centering around the three major complications: epilepsy, poor feeding, and spasticity. The children are affected with profound psychomotor retardation, failure to thrive, and muscle spasms. Typically, rhabdomyolysis is not seen.

50.3 B. This infant is normal in every way except the drawing up of his legs and tightening of the abdomen after feeding, which is most likely intestinal colic. The keys include measurement of the head circumference, reaching developmental milestones, and absence of seizure activity.

    CLINICAL PEARLS    

▶ Lissencephaly should be considered in the differential diagnosis of a child presenting with mental retardation, motor delay, infantile spasms, and characteristic craniofacial dysmorphic features including microcephaly, short nose with upturned nares, and micrognathia. ▶ MRI of the brain and consultation with a pediatric neurologist are important steps in the workup of lissencephaly. ▶ Treatment of lissencephaly patients should focus on symptomatic therapy for complications including epilepsy, poor feeding, and spasticity. ▶ Genetic counseling is an important part of the care of lissencephaly patients and their families.

REFERENCES

Battal B, Ince S, Akgun V, Kocaoglu M, Ozcan E, Tasar M. Malformations of cortical development: 3T magnetic resonance imaging features. World J Radiol. 2015;7(10):329-335. 

Dobyns WB, Curry CJ, Hoyme HE, et al. Clinical and molecular diagnosis of Miller-Dieker syndrome. Am J Hum Genet. 1991;48(3):584-594. 

Dobyns WB, Das S. LIS1-associated lissencephaly/subcortical band heterotopia. In: Pagon RA, Adam MP, Ardinger HH, et al, eds. GeneReviews® (Internet). Seattle, WA: University of Washington; 1993-2017. 

Guerrini R, Marini C. Genetic malformations of cortical development. Exp Brain Res. 2006;173:322-333. 

Leventer RJ, Guerrini R, Dobyns WB. Malformations of cortical development and epilepsy. Diaglogues Clin Neurosci. 2008;10(1):47-62. 

Lissencephaly Contact Group. About lissencephaly. http://www.lissencephaly.org.uk/aboutliss/index.htm. Accessed Nov 1, 2016. 

Pilz D. Miller-Dieker syndrome. Orphanet encyclopedia. http://www.orpha.net/data/patho/GB/uk-MDS.pdf. Accessed September 2003. 

Radiology.com. CT scan files—lissencephaly type 1. http://www.radiologyworld.com/Ctscan-lissen.htm. 

Tulane University. Lissencephaly type 2. http://www.mcl.tulane.edu/classware/pathology/medical_pathology/neuropathology/congenitalq.htm. Accessed Nov 1, 2016.

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