Blake's pouch cyst and Werdnig-Hoffmann disease: Report of a new association and review of the literature.

BACKGROUND: We report a case of a neonate with proximal spinal muscular atrophy (SMA) type 1 (also known as Werdnig-Hoffmann disease or severe infantile acute SMA) associated with a Blake's pouch cyst; a malformation that is currently classified within the spectrum of Dandy-Walker complex. The association of the two conditions has not been previously reported in the English literature. A comprehensive review of the pertinent literature is presented. CASE DESCRIPTION: A male neonate was noted to have paucity of movement of the four limbs with difficulty of breathing and poor feeding soon after birth. Respiratory distress with tachypnea, necessitated endotracheal intubation and mechanical ventilation. Pregnancy was uneventful except for decreased fetal movements reported by the mother during the third trimester. Neurological examination revealed generalized hypotonia with decreased muscle power of all limbs, nonelicitable deep tendon jerks, and occasional tongue fasciculations. Molecular genetic evaluation revealed a homozygous deletion of both exons 7 and 8 of the survival motor neuron 1 (SMN1) gene, and exon 5 of the neuronal apoptosis inhibitory protein (NAIP) gene on the long arm of chromosome 5 consistent with Werdnig-Hoffmann disease (SMA type 1). At the age of 5 months, a full anterior fontanelle and abnormal increase of the occipito-frontal circumference were noted. Computed tomographic (CT) scan and magnetic resonance imaging (MRI) of the brain revealed a tetraventricular hydrocephalus and features of Blake's pouch cyst of the fourth ventricle.
CONCLUSIONS: This case represents a previously unreported association of Blake's pouch cyst and SMA type 1.

INTRODUCTION

The spinal muscular atrophies (SMAs) are a genetically and clinically heterogeneous group of disorders characterized by degeneration and loss of anterior horn cells of the spinal cord leading to muscle weakness and atrophy.[84] Proximal SMA (types I-IV) accounts for 80-90% of all SMA cases and is primarily caused by recessive mutations in the survival motor neuron 1 (SMN1) gene located in the chromosome region 5q11.2-5q13.3, with homozygous absence of exon 7 in more than 95% of cases.[4859] Blake's pouch cyst, in contrast, is defined as a failure of regression of Blake's pouch (the rudimentary fourth ventricular tela choroidea) secondary to nonperforation of the foramen of Magendi resulting in a posterior ballooning into the cisterna magna.[1675] Failure of perforation of the foramen of Magendi results in enlargement of the fourth ventricle and the supratentorial ventricular system until the foramina of Luschka open and establish equilibrium of cerebrospinal fluid (CSF) outflow from the ventricles into the cisterns.[16] Blake pouch cyst is one of the anomalies within the Dandy-Walker complex (DWC), which is a continuum of congenital anomalies comprising Dandy-Walker malformation (DWM), Dandy-Walker variant (DWV), mega cisterna magna (MCM) in addition to Blake's pouch cyst.[2078] To the best of our knowledge, the coexistence of SMA type 1 and Blake's pouch cyst (BPC) has not been previously reported in English literature.

CASE REPORT

A male neonate who is the first product of a nonconsanguineous marriage born at term with a body weight of 3.6 kg to a healthy young mother. Pregnancy was uneventful except for decreased fetal movements reported by the mother during the third trimester. Family history was negative for both parents.

Soon after birth, he was noticed to have paucity of movement of the four limbs with difficulty of breathing and poor feeding. He then developed respiratory distress with tachypnea, increased work of breathing, and oxygen desaturation that necessitated endotracheal intubation and mechanical ventilation. Clinically, his body weight, height and occipito-frontal circumference were all above 25th percentile; neurological examination revealed generalized hypotonia with decreased muscle power of all limbs, nonelicitable deep tendon jerks and occasional tongue fasciculations. No other clinical abnormalities were detected. Extensive metabolic workup and a TORCH (Toxoplasmosis, Rubella, Cytomegalovirus, Herpes simplex, HIV) screen revealed no abnormalities. Cranial and abdominal ultrasound examinations as well as cardiac echocardiogram were normal. Molecular genetic evaluation revealed a homozygous deletion of both exons 7 and 8 of the SMN1 gene, and exon 5 of the neuronal apoptosis inhibitory protein (NAIP) gene on the long arm of chromosome 5 consistent with Werdnig-Hoffmann disease (SMA type 1).

At the age of 5 months, a full anterior fontanelle and abnormal increase of the occipito-frontal circumference were noted. Computed tomographic (CT) scan and magnetic resonance imaging (MRI) of the brain revealed a tetraventricular hydrocephalus and features of BPC of the fourth ventricle. Endoscopic third ventriculostomy or ventriculoperitoneal shunt insertion were both refused by the parents after detailed counseling. A follow up MRI done 3 months later showed progressive hydrocephalus [Figure 1].

Figure 1

(a) Sagittal T2-weighted MR image demonstrating severe hydrocephalus with bulging third ventricular floor, open aqueduct and dilated fourth ventricle. Cerebellar vermis is compressed, relatively well-developed and is nonrotated. A thin line between dilated fourth ventricle and cisterna magna (Black arrow) indicates a Blake's pouch cyst. A high torcular Herophili with upward displacement of the tentorium is seen (b) Axial T2-weighted MR image with cystic dilatation of the fourth ventricle and compressed medial cerebellar hemispheres (Black arrows) (c) Coronal and (d) Sagittal T2-weighted MR images further demonstrate features of severe hydrocephalus

The parents refused any surgical maneuver for CSF diversion including ventriculoperitoneal shunting or endoscopic third ventriculostomy. Now, for 11 months since admission to neonatal intensive care unit (NICU), many trials of extubation failed and he had to be re-intubated every time, due to increased work of breathing and desaturation. Over his NICU course, he developed frequent respiratory tract infections that were timely treated. Currently, the patient is kept on mechanical ventilation and is receiving only supportive care.

DISCUSSION

We report a case of proximal SMA type 1 (Werdnig–Hoffmann disease or severe infantile acute SMA) associated with a Blake's pouch cyst; a malformation that is currently classified within the spectrum of DWC. An exhaustive search of the Medline failed to retrieve any previously reported association of the two conditions in the English literature. The patient had a homozygous deletion of both exons 7 and 8 of the SMN1 gene, and exon 5 of the NAIP gene on the long arm of chromosome 5. In addition to the posterior fossa anomaly and hydrocephalus in our patient, both clinical and genetic findings are consistent with the diagnosis of proximal SMA type 1. In a seemingly similar case, Panas et al. reported a combination of distal SMA with DWC and anterior polar cataracts in two brothers aged 23 and 25 years.[57] However, distal SMA and proximal SMAs represent completely different entities, making this case the first reported in the literature.

The spinal muscular atrophies

The SMAs are a genetically and clinically heterogeneous group of disorders characterized by degeneration and loss of anterior horn cells of the spinal cord leading to muscle weakness and atrophy.[84] Proximal SMA (types I-IV) accounts for 80-90% of all SMA cases and is primarily caused by recessive mutations in the SMN1 gene located in the chromosome region 5q11.2- 5q13.3, with homozygous absence of exon 7 in more than 95% of cases.[4859] Alias et al. found homozygous absence of SMN1 exons 7 and 8 in 671 (90%) of 745 SMA patients. SMN gene is present in two highly homologous copies, SMN1 and SMN2, but only deletions of the SMN1 gene (exons 7 and 8 or exon 7) are responsible for clinical manifestations of SMA.[5] Extended deletions that include the NAIP gene may correlate with the severtity of SMA.[48]

Depending on the age of onset, the maximum muscular activity achieved, and survivorship, proximal SMA types are classified as type I (Phenotype MIM number 253300), severe infantile acute SMA, or Werdnig–Hoffman disease; type II (Phenotype MIM number 253550), or infantile chronic SMA; type III (Phenotype MIM number 253400), juvenile SMA, or Wohlfart–Kugelberg–Welander disease; and type IV (Phenotype MIM number 271150), or adult-onset SMA.[54]

Non-SMN1 SMAs include nonproximal SMA, bulbar palsy, spinobulbar muscular atrophy (SBMA), and infantile SMA variants also known as “SMA plus”.[5784] These variants are characterized by SMA with additional or atypical features. They include SMA with respiratory distress, which can be caused by recessive mutations in Immunoglobulin μ-binding protein 2 (IGHMBP2); infantile lethal X-linked SMA with arthrogryposis and congenital fractures (SMAX2), caused by mutations in ubiquitin-activating enzyme E1 (UBE1); SMA1 with arthrogryposis and bone fractures, and SMA with pontocerebellar hypoplasia (SMA-PCH), also known as PCH type 1.[59]

Dandy-Walker complex and Blake's pouch cyst

The posterior fossa anomaly and the associated hydrocephalus in the patient of this report represent a BPC that is currently classified within the spectrum of DWC. DWC is a continuum of congenital anomalies comprising DWM, DWV, Blake's pouch cyst, and MCM.[2078] These anomalies are characterized by varying degrees of malformation of the medullary vela, the cerebellar vermis and hemispheres, the fourth ventricle choroid plexus, the posterior fossa subarachnoid cisterns, and the enveloping meningeal structures.[16] Persistent Blake's pouch and MCM are thought to represent less severe abnormalities within the Dandy–Walker continuum.[60]

The original description of DWM dates back to the year 1914 when Dandy and Blackfan described a huge cystic dilatation of the fourth ventricle with anterior displacement of the cerebellar vermis that was attributed to primary atresia of the foramina of the fourth ventricle.[22] Over the following years many cases were reported, expanding the limits of the malformation to include findings of one particular case or another, and in the meanwhile creating a great deal of confusion about the definition and limits of the syndrome.[42] Taggart and Walker in 1942 further defined the condition.[70] Subsequently, Benda in 1954 introduced the now widely accepted name of DWM and was the first to introduce the currently held opinion that atresia of the cerebellar foramina is not an essential feature of the malformation.[12]

Tortori-Donati et al. added persistent BPC as an independent entity within the DWC.[75] BPC is thought to result from failure of regression of Blake's pouch (the rudimentary fourth ventricular tela choroidea) secondary to nonperforation of the foramen of Magendi.[75] Failure of perforation of the foramen of Magendi results in enlargement of the fourth ventricle and the supratentorial ventricular system until the foramina of Luschka open and establish equilibrium of CSF outflow from the ventricles into the cisterns.[16] However, as the larger foramen of Magendi is permanently missing, the ventricles will stay enlarged.[20] The cerebellar hemispheres and vermis would rather be compressed (to a certain degree) than underdeveloped and would therefore re-expand in case of ventricular shunting.[9]

Typical radiological features of BPC are (i) tetraventricular hydrocephalus, (ii) infra- or retrocerebellar localization of the cyst, (iii) a relatively well-developed, nonrotated cerebellar vermis (as opposed to a DW), (iv) a cystic dilation of the fourth ventricle without cisternal communication, and (v) some degree of compression on the medial cerebellar hemispheres. Ideally, one may see the fourth ventricular choroid plexus continuing in the roof of the cyst on sagittal MR images.[20] These features were all noted in our patient's MR images [Figure 1]. Classically, the choroid plexus of the fourth ventricle is displaced into the superior cyst wall in Blake's pouch, absent in DWM, and normal in arachnoid cyst.[52] As it is evident in our patient [Figure 1], BPC may push the developing tentorium into an abnormal, relatively high position.[25] BPC is capable of producing a broad spectrum of findings ranging from being asymptomatic to a full-blown hydrocephalus.[20]

DWC has been associated with a long list of chromosomal and phenotypic abnormalities of both neural and mesenchymal elements [Table 1]. Heterozygous deletion of ZIC1 and ZIC4 on chromosome 3q24 was the first molecularly defined cause of classic DWM.[31] A second DWM-linked locus on 6p25.3 was associated with deletions or duplications encompassing FOXC1 causing cerebellar and posterior fossa malformations including cerebellar vermis hypoplasia (CVH), MCM and DWM. Foxc1-null mice have embryonic abnormalities of the rhombic lip due to loss of mesenchyme-secreted signaling molecules with subsequent loss of Atoh1 expression in vermis. Specific loss of FOXC1 and general defects in mesenchymal signaling may result in cerebellar malformations.[3]

Table 1

Clinical and chromosomal abnormalities associated with Dandy-Walker complex

Spinal muscular atrophy with pontocerebellar hypoplasia

SMA-PCH (PCH-1) is an important differential diagnosis of the case reported herein, and can be excluded based on both genetic and radiological grounds; SMA-PCH is a non-SMN1 condition on contrary to our patient with homozygous deletion of both exons 7 and 8 of the SMN1 gene on chromosome 5. MRI of our patient reveals a normal appearance of the brainstem and ventral pons in addition to other findings consistent with BPC [Figure 1]. PCH-1 is an autosomal-recessive disease of prenatal or infantile onset characterized by PCH and ventral horn cell degeneration. Clinically, polyhydramnios is usually present during pregnancy, and affected individuals present with bulbar dysfunction that leads to neonatal respiratory insufficiency, feeding difficulty, and congenital contractures; death often occurs before 1 year of age.[46] An extended clinical spectrum of PCH 1 with later onset of hypotonia, varying degrees of cerebellar or pontine hypoplasia and atrophy, peripheral nerve involvement, and longer survival has been reported.[61] All PCH syndromes [types 1-6] include a small cerebellum and brainstem with progressive microcephaly being a common finding.[59]

It is of relevance to this discussion to review the molecular genetic abnormality underlying PCH-1; namely the Vaccinia-related kinase 1 (VRK1) gene abnormality owing to its role in the pathogenesis of SMA and its probable contribution to the evolution of some cerebellar and posterior fossa congenital anomalies [Figure 2]. Renbaum et al. discovered a premature stop codon in the VRK1 gene that encodes a serine-threonine kinase and is located on chromosome 14q32 in affected siblings with PCH-1 in one family. VRK1 may be specifically important for spinal motor neuron survival or that it may also play a role in tRNA processing. In either case, identification of a VRK1 mutation as a cause of SMA-PCH points to new roles for this protein and suggests VRK2 [chromosome 2p16] and VRK3 [chromosome 19q13] as candidate genes for related phenotypes, including other PCHs and other SMAs.[59]

Figure 2

Schematic representation of the genetic events and interactions between VRK-1, SMA, and PCH-1

The existence of an autoregulatory loop between VRK1 and p53 may be of relevance to both development and maintenance of the nervous system. p53 regulates cell division and death during nervous system development and in response to neuronal insult or injury during life. Recessive mutations in Ataxia telangiectasia mutated (ATM), which phosphorylate p53 in response to DNA damage cause ataxia telangiectasia, in which loss of cerebellar neurons and ataxia are prominent features.[59] Moreover, p53 interacts directly with SMN1, an association disrupted by SMN1 mutations associated with SMA,[81] and might be of relevance to SMA pathogenesis.[76] In addition, VRK1 may be involved in cell cycle regulation, organization of chromatin, and organization of the nuclear envelope.[46] The role of VRK1 in cyclic AMP (cAMP) response element-binding (CREB) activation suggests that VRK1 mutations may lead to impaired CREB signaling, which can result in both developmental and degenerative neurological disease; Coffin–Lowry syndrome is caused by mutations in RSK2, another CREB kinase, Rubinstein–Taybi syndrome can be caused by mutations in CREBBP (a CREB binding protein). Interference with CREB-dependent transcription is a feature of polyglutamine stretches, common in spinocerebellar ataxias. CREB also binds to the SMN promoter and increases SMN expression, so its deficiency could promote an SMA phenotype.[59]

As it is well known that mutations in multiple genes can cause various central nervous system malformations,[46] we think that future reports and studies may reveal important molecular genetic links between DWC (specifically BPC) and Werdnig-Hoffmann disease.

CONCLUSION

This case represents a previously unreported association of BPC and SMA type 1 that further expands the current literature, and potentially directs future investigation of probable molecular genetic links between these conditions.