A Case Report on Peters’ Plus Syndrome

Aaron Lemuel Y. Ong, Barbra Charina V. Cavan, M.D., Adele Marie M. Roa,

M.D., Viraliza June Bolok M.D.

Department of Pediatrics, Chong Hua Hospital, Cebu City

ABSTRACT:

Peters’ plus syndrome (PPS) is a rare disorder, clinically characterized by

anterior segment dysgenesis (ASD), such as Peter’s anomaly, short stature,

facial dysmorphism and varying degrees of developmental delay. This study

reports on an unusual form of PPS, presenting with bilateral sclerocornea

(another form of ASD). We report on a 15-month old female infant presenting

with bilateral corneal opacities since birth with characteristic facial features

including prominent forehead, short palpebral fissures, prominent ears, global

developmental delay, short stature with a patent ductus arteriosus (PDA). This

led to a diagnosis of PPS. Patient was managed by ligation of PDA and topical

application of mydriatics to improve visual stimulation and prevent complications

such as glaucoma. Regular follow-up was also done to monitor growth and

development. To the author’s knowledge, this is the first case of PPS presenting

with bilateral sclerocornea in the local setting. With emphasis on a thorough

history, physical exam and multi-disciplinary approach, a diagnosis of PPS can

be made which will result to better care for these patients.

KEY WORDS:

Peters’ plus, sclerocornea, anterior segment dysgenesis, short stature

INTRODUCTION:

Peters’ plus syndrome, is a rare autosomal recessive congenital disorder

manifesting with anterior segment dysgenesis, typically Peters’ anomaly, short

stature, facial dysmorphism, and varying degree of developmental delay/

intellectual disability first described by Van Schooeveld et. al.[1]. A cleft lip occurs

in 40% and rhizomelic limb shortening and/or short stature is invariably present in

all cases. Congenital heart defects, genitourinary and central nervous system

abnormalities also occur in around 10-30% of cases. Exact incidence is unknown

but thought to be <1/1,000,000 with only about 100 cases believed to be known

worldwide[1] [2]. Around 80% of PPS present with Peters’ anomaly but fewer

present instead with other anterior chamber defects such as cataracts or

sclerocornea [3]. Sclerocornea can be seen in PPS in around 25% of all reported

cases [4]. The authors were not able to find local data on the incidence of PPS or

sclerocornea but a retrospective study in Japan revealed sclerocornea seen in

6.4% of all corneal opacities, with 25% of all corneal opacities having systemic

abnormalities [5]. All patients with features of PPS, were shown to have mutations

in the B3GALTL gene, which codes for the instruction for producing the enzyme

beta 3-glucosyltransferase, involved in glycosylation [6]. Diagnosis is clinical and

can be confirmed by single gene testing. However, because the disorder is rare

with a variable phenotype, recognition of remains challenging. Further

observations are needed to improve diagnostic accuracy. Here is a case of a 15

month old presenting with distinct facial features, bilateral corneal opacities, a

congenital heart defect, short stature and global developmental delay.

CLINICAL CASE:

We report the case of a 15-month-old female presenting with bilateral

corneal opacities since birth. The mother was a 28 year old G3P1(1011) with

prenatal history revealing non-consanguineous parents (Figure 1). The

ultrasound showed intrauterine growth restriction with a negative congenital

anomaly scan. Pregnancy was otherwise unremarkable with no maternal

illnesses. Patient was born term via spontaneous delivery unrecalled APGAR,

Ballard score 37 weeks, birth weight of 2000g which was small for gestational

age. Other anthropometric measurements were not recalled. There were no

perinatal complications reported. The newborn screening was also negative.

Hearing screen was normal. Upon physical examination, the patient was

observed to have hazy eyes thus seen by a pediatric ophthalmologist at 2 weeks

of age and diagnosed with bilateral sclerocornea. She was initially maintained

with Tropicamide + Phenylephrine (Sanmyd) drops to prevent glaucoma as well

as to increase amount of light entering the pupil for better visual stimulation.

Penetrating keratoplasty (PKP) wasn’t advised due to age of the patient and

cornea was deemed to be too small. She was also noted to have a grade IV

holosystolic murmur which 2D echo revealed a patent ductus arteriosus (PDA).

She was maintained on Furosemide for ductus patency and advised for PDA
ligation at around 5-6 months of life. The medical history also revealed recurrent

pneumonia and septicemia. Developmental history showed delays in language

and fine motor development but parents attributed it to the ophthalmologic and

cardiac condition. At around 5 months of life, she underwent PDA ligation, which

was uneventful. During this period, she was still noted to have weight and height

less than 3rd percentile with global delay in developmental milestones. Thus,

regular follow up as outpatient for monitoring of growth and for further work-up

was advised. There is no history of congenital heart disorders, ocular defects or

familial short stature on both sides of the family. Older sibling is apparently well

and anthropometric measurements were within normal limits.

Figure 1: Pedigree of patient X showing the different heights of relatives.

Patient was seen with no subjective complaints from the parents, no

problems with feeding. She is currently on mixed feeding and eats solids with no
particular preference. Anthropometric measurements were all below 3rd

percentile for a 15-month-old (Figure 2).

Figure 2: Serial measurements of head circumference (A). Serial measurements

of length and weight-for-age (B). Note the relative macrocephaly (slightly below

3rd percentile) versus the length and weight (1% percentile).

Pertinent physical examination findings showed a prominent forehead, short

palpebral fissures (<3rd percentile) and prominent ears (Figure 3.). There is noted

relative macrocephaly due to the prominent forehead. Ophthalmologic findings

include good fixation to light with vertical nystagmus and occasional esotropia on

both eyes. Slit lamp examination revealed that the entire limbus is obscured by

the opacities with partial central clearing. Tonometry wasn’t performed due to the

nystagmus. The extremities were complete with no defects/malformation. The

rest of the physical exam was unremarkable. Neurologic exam did not reveal any

cranial nerve defects, motor or sensory deficits. Developmental profile using the

Ages and Stages Questionnaire (ASQ-3) revealed delays in language and fine

motor skills, which were only at par for a 9-month old.

A B C

Figure 3: Characteristic facial features with prominent forehead and ears (A & B).

Bilateral sclerocornea (C). Note the obscured limbus with central corneal

clearing.
The patient was referred to a geneticist for evaluation. The presence of bilateral

sclerocornea, along with short stature, congenital heart defect (PDA), global

developmental delay and characteristic facial features led to a working diagnosis

of PPS. Transcranial ultrasound and Ultrasound of the kidneys, ureters and

bladder were performed to exclude structural abnormalities that may accompany

PPS. These were all unremarkable. Chromosome karyotyping was offered but

was not performed at the time due to financial constraints. Genetic analysis,

however, was not available in the local setting. Patient was then referred to an

endocrinologist to rule out possible secondary causes of short stature. There

was concordance that the short stature was most likely primary in nature, given

its prenatal onset. It was also pathologic, since full adult height potential would

not be reached even at 20-year point based on the current growth trend. Familial

short stature was also ruled out based on mid-parental height.

Management of the patient involved a multi-disciplinary approach.

Ophthalmologic intervention included continuation of Tropicamide +

Phenylephrine (Sanmyd) drops to promote visual stimulation and to prevent

complications such as glaucoma. Bi-annual visits with the ophthalmologist were

advised. Visual stimulation training exercises were emphasized such as sensory

pairing (e.g., using a toy that emits a sound to stimulate a child’s interest in a

distant object). This also included spending most of the patient’s waking hours in

environments where illumination is greatest (e.g, watching television, playing

outdoors). It was also recommended for the patient to enroll in Braille at 5 years

old. For the genetic aspect, risk assessment was done, and counseling regarding
the 25% recurrence for PPS due to its autosomal recessive nature. The parents

were advised to have karyotyping and genetic analysis in the future once with

adequate funds. For the endocrine aspect, monitoring of the diet and growth

were planned.

DISCUSSION AND CONCLUSION:

Peters’ Plus syndrome is a rare disorder with autosomal-recessive

inheritance involving an ocular defect (anterior segment dysgenesis) and other

systemic congenital anomalies. The most common ocular finding is Peter’s

anomaly (73% of patients), a developmental defect characterized by the triad of

central corneal opacity, defects in the posterior layers of the cornea, and

lenticulo-corneal and/or irido-corneal adhesions. Around 25% will present with a

different anterior chamber defect (such as sclerocornea, posterior embryotoxon,

or Axenfeld-Rieger anomaly) and the remainder will have other congenital eye

malformations [4] [7].

The approach to a patient with congenital corneal opacities first lies in

determination of the type of corneal opacity. The American Academy of

Ophthalmology lists the following differentials in the form of a mnemonic

STUMPED [8]. These include sclerocornea, tears in Descemet membrane

(usually due to forceps trauma or congenital glaucoma), ulcers (infection),

metabolic (eg, mucopolysaccharidosis), Peters anomaly, edema (e.g., congenital

hereditary endothelial dystrophy [CHED], posterior polymorphous dystrophy,

congenital hereditary stromal dystrophy [CHSD], glaucoma), and dermoid.

Sclerocornea usually occurs sporadically or may be inherited as an autosomal-

dominant/recessive manner. It may occur in isolation or with other systemic

abnormalities as seen in our patient [8]. The patient’s sclerocornea posed a

unique challenge since the vast majority of PPS present with Peter’s anomaly.

Peter’s anomaly presents with a clear cornea in the periphery, whereas

sclerocornea has scleral tissue extension and vascularization in the periphery of

the cornea [9]. Although morphologically different, both anterior chamber defects

are initiated by several genes, one of which is B3GALTL, the gene involved in

PPS. This gene encodes β1,3-glucosyltransferase, which is involved in synthesis

of the disaccharide Glc- β1,3-Fuc-O- that occurs on thrombospondin type 1

repeats (TSRs) of many biologically important molecules The B3GALTL

transcripts are present in various sites such as the brain, heart and kidney [10].

In a mutational analysis done by Reis et. al, B3GALTL mutations

appeared to be strongly associated with classic cases of PPS presenting with

ASD, short stature and brachydactyly with variable other defects [11]. A review of

other reports also concurred that the presence of ASD (Peter’s anomaly or

sclerocornea) and short stature is 100% predictive of B3GALTL mutations while

no mutations in B3GALTL were seen in atypical PPS (some but not all of these

typical features) [6] [11]. Furthermore, developmental delay was seen in 85% of

mutation-positive cases. The study done by Oberstein, et. al however did not

report on the incidence of brachydactyly in their report of mutation-positive PPS

[6]. These studies indicate that the patient is a good candidate for gene analysis

given the ASD, short stature, characteristic facial features and developmental
delay despite not having rhizomelic limb shortening, cleft lip or brachydactyly as

some other cases have. It must be taken into consideration however, based on

the author’s review of literature, that there are currently no studies on the

genotypic-phenotypic correlation of this disorder which is defined as an above-

chance probability of a distinct mutation being associated with a particular

physical feature or abnormality. Another limitation is single gene testing is not

available in the local setting and cost is a factor.

The sclerocornea would have ideally been managed by penetrating

keratoplasty (PKP) at 3-6 months of life to prevent amblyopia, preserve vision

and prevent glaucoma, which is the most common complication. However, due to

the age and small cornea, PKP wasn’t advised. Patient currently shows signs of

deep amblyopia such as the vertical nystagmus and esotropia, indicating

impaired vision. These, along with the opacity at the limbus are considered poor

prognostic factors for a successful corneal grafting with graft survival only at 25%

versus 60-85% in classic Peters’ anomaly [9] [12]. Thus, the current management is

aimed at preserving the limited vision of the patient, with mydriatics and visual

stimulation training exercises as mentioned.

The patient’s growth and development is also in keeping with PPS. The

growth charts show a prenatal onset short stature and despite undergoing PDA

ligation, growth is still below the 3rd percentile. It was also apparent that the

growth was less than 5cm of the mid-parental height, which is the allowable limit

for growth variation/potential. Thus, this would show a pathologic variant of short

stature. These are usually seen in conditions such as Turner’s syndrome and
another chromosomal abnormalities. The delays in language and fine motor

domains may also be compounded by the impaired vision. It is recommended to

provide compensatory learning experiences that permit the child to learn through

other modalities such as auditory strategies, group learning, dual media, and

symbols [13]. From preschool on, teaching of skills to gain independence that will

eventually lead to vocational training. The goal is to enable them to be as

independent as possible and to integrate smoothly into the family and community

leading to satisfying lives.

Beyond the science, the family has expressed much gratitude for the care

provided to them. It has given them insight regarding the diagnosis and

decreased the anxiety of not knowing about their child’s condition. The close

physician-patient relationship has led to better health-seeking behavior and

allowed them to be more vigilant of the unique needs of the patient.

In conclusion, we report of a case of bilateral sclerocornea along with a

PDA, short stature and developmental delay fitting the criteria of PPS [14] The

management of such cases is multidisciplinary, allowing recognition of several

features that may be syndromic which will afford better care for the patient.

INFORMED CONSENT:

Informed consent was obtained from the parents with permission to

photograph the patient.

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