Peter Plus Syndrome: A Neurosurgeon's Perspective.

Peter plus syndrome (PPS) is a rare, hereditary (autosomal recessive) disorder characterized by a mutation in the beta-1,3-galactosyltransferase-like gene (chromosome 13q12), which causes impaired glycosylation of several structural and functional proteins throughout the body. Clinical signs and symptoms of PPS are highly variable and include structural malformations affecting multiple organ systems including central nervous system. We aim to discuss a neurosurgeon's perspective to PPS in this report. A 2-year-old boy presented with congenital dysmorphic facies, bilateral central corneal opacities, delayed developmental milestones, short-stature (75cm), rhizomelia with brachydactyly, and history of surgery for anal atresia on the second day of life. Screening craniospinal magnetic resonance imaging revealed mild ventriculomegaly, cavum septum pellucidum, cavum velum interpositum, vermian hypoplasia, and normal spine. Cytogenetic analysis showed a mutation in the beta-1,3-galactosyltransferase-like gene on chromosome 13. Clinical picture in our patient suggested the diagnosis of PPS. Parents often seek ophthalmological consultation due to visual impairment predominantly, and this syndrome largely remains unknown among neurosurgeons. Nonetheless, babies with PPS may present with neurological symptoms such as seizures, spastic diplegia, tinnitus, or hearing loss as well as a life-threatening neurosurgical emergency arising due to raised intracranial pressure. Therefore, the role of neurosurgeon becomes crucial in managing these cases. Copyright:

Introduction

Peter plus syndrome (PPS) is a rare, hereditary (autosomal recessive) disorder, which is characterized by a mutation in the beta-1,3-galactosyltransferase-like gene. This genetic defect leads to impaired glycosylation of several structural and functional proteins throughout the body. Clinical presentation of PPS is highly variable and this syndrome affects multiple organ systems including the central nervous system (CNS). The aim of this report is to describe this rare syndrome from a neurosurgeon’s perspective as this syndrome may present with features of raised intracranial pressure requiring surgical intervention, apart from other neurological abnormalities.

Case Report

A 2-year-old boy, the first child of a consanguineous marriage, presented with congenital dysmorphic facies, bilateral central corneal opacities, and history of surgery for anal atresia on the second day of life. Examination revealed delayed developmental milestones, short-stature (75cm), rhizomelia with brachydactyly, tongue-tie, small cup-shaped ears, smooth long philtrum, and left-sided undescended testis [Figure 1]. Head circumference was normal (49cm) for age with closed anterior fontanelle. Ocular examination revealed bilateral leukoma with synechiae in the anterior chamber.

Figure 1

Clinical image of our patient (labeled) showing bilateral central corneal opacities, dysmorphic facies including small cup-shaped ears, smooth long philtrum, and limb anomalies

Screening craniospinal magnetic resonance imaging (MRI) revealed mild ventriculomegaly, cavum septum pellucidum, cavum velum interpositum, vermian hypoplasia, and normal spine [Figure 2]. Cytogenetic microarray performed was positive for mutation in the beta-1,3-galactosyltransferase-like gene (chromosome 13:31821992, B3GlCt gene).

Figure 2

Craniospinal MRI of our patient showing mild enlargement of lateral ventricles with cavum septum pellucidum (orange arrow) in T2-weighted image (WI) axial view (A) and coronal view (B). Hypoplasia with the vermis with normal cerebellar hemispheres was also noted (C–D). T2-WI midsagittal (E) and coronal view at level of body of lateral ventricles (F) showing cavum velum interpositum (red arrow) and a large interthalamic adhesion. Spinal screening in sagittal view (G) showing normal spine

Thus, clinical picture in our patient suggested the diagnosis of PPS. As the child was not having any features of raised intracranial pressure and the MRI head also showed mild-to-moderate ventriculomegaly with no periventricular lucency, no surgical intervention was performed and the child was advised regular follow-up. Parents of the child were counseled about the future possibility of cerebrospinal fluid diversion if the need arises. At 6-month follow-up, child had persistent delayed developmental milestones but there were no clinical features of raised intracranial pressure. There was no abnormal increase in the head circumference. Child was advised regular follow-up in the neurosurgery outpatient department.

Discussion

This rare hereditary (autosomal recessive) disorder, also called Krause–van Schooneveld–Kivlin syndrome, is marked by a mutation in the beta-1,3-galactosyltransferase-like gene (chromosome 13q12), which impairs glycosylation of several structural and functional proteins in the body. The exact incidence still remains unknown with nearly 75 cases reported worldwide as per the current literature.[12]

Clinical symptomatology of PPS is highly variable at presentation as well as in severity. Affected mothers have an increased risk for recurrent miscarriage and stillbirth.[345] Associated findings that may be identified on a prenatal high-resolution sonography include congenital heart defects, genitourinary abnormalities, and structural brain malformations.[3456] Even though, these findings are nonspecific, but are highly suggestive of the diagnosis, especially with a positive family history. Therefore, it should alert the obstetrician and help to counsel the parents accordingly. Nonetheless, a DNA analysis for the mutation should be carried out to confirm the diagnosis of PPS. Various structural malformations of CNS associated with PPS have been summarized in Table 1.

Table 1

A list of various structural malformations of CNS associated with Peter plus syndrome

Various structural malformations of the CNS associated with Peter plus syndrome
Cranial
Hydrocephalus
Enlarged/malformed lateral ventricles
Hypoplasia/agenesis of corpus callosum
Dandy-walker malformation
Encephalocele
Underdeveloped cerebellum
Microcephaly
Macrocephaly
Calcifications of thalamic arteries
Enlarged cisterna magna
Vermian hypoplasia
Optic atrophy
Spinal
Scoliosis
Hyper-kyphosis
Hemivertebrae
Vertebral segmentation defects
Sacral agenesis

Even though few patients with PPS may enjoy a normal lifespan, it is frequently marred by poor quality of life due to various morbidities—ocular, cardiac, or gastrointestinal. In addition, some babies may not even survive beyond their first birthday due to heart failure or other comorbidities.[3]

Parents often seek ophthalmological consultation due to visual impairment and this entity largely remains unknown among neurosurgeons. A review of previously reported case of PPS with various neurological presentations shows that most of these children were managed via a conservative approach and follow-up [Table 2]. Nonetheless, these babies may land up in neurosurgical clinics with symptoms such as seizures, spastic diplegia, tinnitus, hearing loss as well as a life-threatening neurosurgical emergency arising due to raised intracranial pressure (hydrocephalus) requiring urgent neurosurgical intervention. Motoyama et al.[12] have managed their case with surgical repair of the lumbar myelomeningocele and ventriculoperitoneal shunt for the hydrocephalus. A cochlear implant may be considered for hearing loss.[4]

Table 2

A summary of Peters plus syndrome cases who presented with CNS anomalies

Study	Age/sex	Clinical presentation	CT findings	Intervention	Family history	Outcome
Frydman et al.[7]	11 months/female	Rhizomelia, brachydactyly, dysmorphic facies with lenticular opacities, and increased intraocular pressure	Moderate communicating hydrocephalus with parietotemporal brain atrophy	Intraocular pressure was treated with oral acetazolamide and timolol acetate 0.5% eye drops twice daily	Negative	Slow growth rate at 8 months of follow-up
	37 weeks gestation/male	Brachydactyly, dysmorphic facies with lenticular opacities, ostium primum ASD, right cryptorchidism	Dilated ventricles and a residual right intraventricular hemorrhage. A hypodense extradural area in the left temporal lobe, probably reflected fluid accumulation	Corneal transplantation and ventriculoperitoneal shunting were advised, but the parents refused any further medical intervention	Positive	Last follow-up at 3.5 years of age. Mental retardation was present
Camera et al.[8]	1 month/male	Dysmorphic facial features, bilateral corneal leukoma, clinodactyly, bilateral cleft lip and palate, umbilical and inguinal hernia	Cranial CT showed agenesis of the corpus callosum	Not reported	Negative	Not reported
Ishikiriyama et al.[9]	35 weeks gestation/female	Dysmorphic facial features, bilateral corneal leukoma, clinodactyly	Cranial CT scan showed dilatation of the subarachnoid spaces, lateral and third ventricles without elevated intracranial pressure, i.e., cerebral atrophy	Not reported	Negative	Not reported
Kapoor et al.[10]	9 years/male	Microcephaly, scaphocephaly, dysmorphic facial features, pectus excavatum, clinodactyly	Spina bifida occulta at L5 S1 vertebral level	Not reported	Family history of early infantile death	He could perform most of the activities of daily living at 9 years age, though, he was unable to attend even primary school
Aliferis et al.[11]	20 months/male	Bilateral Peters anomaly with central corneal opacity, facial dysmorphy, short stature and intellectual delay, duplication of the left kidney, cryptorchidism, brachydactyly with clinodactyly, and cerebral malformations (ventricular dilatation and corpus callosum hypoplasia)	Ventricular dilatation and corpus callosum hypoplasia	Not reported	The mother was found to be a heterozygous carrier of mutation	Not reported
Motoyama et al.[12]	38 weeks gestation/female	Bilateral corneal opacities, dysmorphic facies, short stature, multicystic dysplastic kidneys with lumbar myelomeningocele and hydrocephalus	Not reported	Surgical repair of lumbar myelomeningocele on day 1. Ventriculoperitoneal shunt on day 6.	Negative	Shunt removed after 3 months due to infection without any recurrence of hydrocephalus
Faletra et al.[13]	4.5 years/female	Dysmorphic facies, growth delay, congenital bilateral cataracts, multicystic dysplastic kidneys, sacral dimple with vertebral defect	MRI suggestive of corpus callosal agenesis	Not reported	Parents had heterozygous mutation. Her elder brother died at the age of 9 months because of renal failure, showing Peters’ anomaly	Not reported
de Nie et al.[14]	34 weeks gestation/male	Bilateral cleft lip and palate, hypertelorism, a large anterior fontanel approaching the nasal bridge, bilateral clinodactyly of the fifth finger, rocker bottom feet, single umbilical artery, a sacral dimple, a hypertrophic bladder wall, dysplastic multicystic kidneys, and enlarged cerebral ventricles	Not reported	Penetrating keratoplasty in both eyes. No neurosurgical intervention performed	Carrier testing of the parents revealed both to carry one mutant allele	Patient required corneal transplantation of the left and right cornea at 4 and 9 weeks postpartum, respectively
Grande et al.[4]	40 weeks gestation/male	Dysmorphic facial features, bilateral corneal leukoma, cryptorchidism, recurrent bacterial meningitis, hearing loss, and typical absence seizures	USG suggestive of mild enlargement of lateral ventricles. MRI showed dysmorphic lateral ventricles with widening of 4th ventricle and enlarged cisterna magna.	Cochlear implantation for hearing loss. Antiepileptic drugs for seizures.	Negative	Seizure-free after 2 years of follow-up
Canda et al.[2]	21 weeks gestation/female	Fetal scan suggestive of dysmorphic facial features, short-for-age bones, and ventriculomegaly	Fetal MRI showed agenesis of the corpus callosum, ventriculomegaly, hypotelorism, and bilateral congenital cataracts	Conservative approach	Negative	Intrauterine fetal death occurred at the 23rd gestational week
Present case	2 years/male	Congenital dysmorphic facies, bilateral central corneal opacities, anal atresia	MRI revealed mild ventriculomegaly, cavum septum pellucidum, cavum velum interpositum, vermian hypoplasia and normal spine	Conservative approach	Negative	At 6-month follow-up, child had persistent delayed developmental milestones but there were no clinical features of raised intracranial pressure

ASD = atrial septal defect, USG = ultrasound

Individualized treatment depending on the severity of symptoms is recommended with utmost care to avoid corticosteroids, which may potentiate risk of glaucoma in these patients. Keeping the diagnosis and clinical presentation of our case in mind, the child was advised regular follow-up and no new-onset neurological deficits have developed during the follow-up period.

Conclusion

Children with PPS may present with neurological symptoms such as seizures, spastic diplegia, tinnitus, or hearing loss apart from life-threatening neurosurgical emergencies such as hydrocephalus, which may require surgery. Therefore, the neurosurgeon should have the requisite knowledge of such rare syndromes as sometimes, the role of neurosurgeon becomes crucial in managing these cases.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.