Warburg micro syndrome in siblings from India.

Warburg syndrome is a rare disorder characterized by microcephaly, microcornea, congenital cataract, developmental delay, and hypogonadism. Here, we report two siblings from India who presented with developmental delay, microcornea, microphthalmia, and bilateral congenital cataracts, born to the third-degree consanguineously married couple. Both children had hypoplasia of corpus callosum. In this report, we aim to highlight and compare clinical features of these two cases with previously reported cases.

Introduction

Warburg micro syndrome is a rare autosomal recessive genetic disorder characterized by microcephaly, microcornea, congenital cataract, developmental delay, and hypogonadism (OMIM #600118).[1] Till this date, 144 families have been reported so far with nil reports from India.[2] Here, we report two siblings with micro syndrome.

Case Reports

Case report 1

An 8-year-old male, 1st born child to third-degree consanguineously married 26-year-old mother and 32-year-old father, Muslim couple, was brought for delayed development. He was born after an uneventful antenatal period, term normal vaginal delivery with birth weight of 2.5 kg (at 25th centile). Mother noticed child having white reflex in eyes at 4 months of age for which he was evaluated. He had bilateral cataracts, for which lens aspiration was done, with no improvement in vision.

Child has not attained neck control, turns head to sound, and does not try to with development quotient of 3.6%. He has no history of seizures. Mother noticed stiffness in legs at 6 months of age, for which she is giving physiotherapy.

On examination, child is wasted and stunted. His weight is 8 kg (<3rd centile), length is 95 cm (<3rd centile), and occipitofrontal circumference (OFC) is 45.0 cm (<3rd centile).

He has microcephaly, with plagiocephaly, hypertrichosis of forehead, microphthalmia, microcornea, broad root of nose, long philtrum, long, low set and prominent ears, with poor dentition (16 teeth), high arched palate, retrognathia, and widely spaced nipples. He has bilateral undescended testis and micropenis. He had bilateral simian crease, long fingers, syndactyly of 2nd–3rd toe of left foot, equinus deformity of right foot, and scoliosis with concavity to left, present since birth. The child has hypotonia of upper limbs, hypertonia of lower limbs and all deep tendon reflexes were brisk. Pupil was atonic, not responsive to light, and mydriatics, so fundus examination was not possible. His brainstem evoked response audiometry and visual evoked potential (VEP) were abnormal. His magnetic resonance imaging (MRI) showed right frontal pachygyria, right ventriculomegaly, and hypoplasia of corpus callosum, with normal myelination for age [Figure 1].

Figure 1

A 7-year-old boy with microphthalmia, microcornea, prominent root of the nose (a), low set posteriorly placed ears (b), with micropenis, cryptorchidism (c), with syndactyly of the 2nd–3rd toe (d). Magnetic resonance imaging of brain shows hypoplasia of corpus callosum (e), right ventriculomegaly and frontal pachygyria (f)

Case report 2

The above child's younger sibling, 4-year-old male, was brought to the hospital for neurodevelopmental delay.

He is a third born child with uneventful antenatal period and full term normal vaginal delivery, with birth weight of 2.3 kg (<25th centile); birth OFC and length are not known. Mother noticed that child had poor vision at 4 months for which he was evaluated and found to have bilateral cataracts. Lens aspiration was done. He started having feeding difficulties and stiffness of both the lower limbs at 6 months of age. He has not attained head control, smiles occasionally, and makes cooing sounds, with developmental quotient of 4.16%. At 7 months, he had the 1st episode of generalized tonic-clonic convulsions, lasting for few minutes and antiepileptics were started. He had multiple episodes of seizures until 2 years, and then seizures were controlled with optimum doses of antiepileptic drugs.

On examination, child looked wasted and stunted, with weight of 6.4 kg (<3rd centile), length 86 cm (below 3rd centile), and OFC 44 cm (at 3rd centile). The child has microcephaly, plagiocephaly, low hairline, and narrow forehead. Deep-set eyes, microphthalmia, microcornea, and bilateral aphakia were seen. Nose appeared normal. Ears were low set and posteriorly placed. Oral cavity shows delayed dentition (presently only 12 teeth) with caries, high-arched palate, and spastic tongue. He has long fingers with bilateral simian crease and scoliosis with concavity to left. His nipples are widely spaced, bilateral undescended testes with micropenis. Left foot has equinus deformity and contractures were present bilaterally. Upper limbs are hypotonic and lower limbs hypertonic. Deep tendon reflexes are brisk. Pupil is atonic [Figure 2].

Figure 2

A 7-year-old boy with microphthalmia, microcornea (a), low set posteriorly placed ears, widely spaced nipples (b), with micropenis, cryptorchidism, lower limb hypertonia (c), with kyphoscoliosis (d). Magnetic resonance images showing corpus callosum agenesis and cerebral atrophy (e and f)

His MRI showed corpus callosum agenesis and cerebral atrophy. VEPs were abnormal.

Ultrasonography abdomen showed no abnormality. Torch profile was negative.

Discussion

Warburg first described Warburg micro syndrome (WMS) in 1993, in three affected children from an inbred family who had microcornea, microcephaly, congenital cataract, severe mental retardation, retinal dystrophy, hypothalamic hypogenitalism, and agenesis of the corpus callosum.[3] Most cases have been described in Muslim community, with male predominance and consanguineously married parents.

Micro syndrome is characterized by postnatal growth retardation rather than in utero growth restriction. Salam et al. in his case series on seven children with micro syndrome noticed 5/7 children with IUGR at birth, as we have observed in these two cases.[4] Developmental delay is characteristic, present in all reported cases, ranging from severe to profound, and head circumference is below 25th centile.[5]

Deep-set eyes, prominent nasal root, large dysmorphic ears, highly arched or narrowing palate, and micrognathia seem to be the most frequent dysmorphic facial features, present in all reported cases of micro syndrome. Hypertrichosis on the forehead is another common finding reported in eight cases. Cataract, microcornea, or microphthalmia and optic atrophy are the most frequent eye findings. Cataract is usually congenital and bilateral. Optic atrophy is also frequently seen. Children have profound mental retardation with lower limb hypertonia and upper limbs and trunk hypotonia.[5678] MRI findings of pathognomic of this condition are hypoplasia/agenesis of corpus callosum. Other MRI features seen are gyral abnormalities, subcortical atrophy, reduced myelination, plagiocephaly, hippocampic malformation, and pachygyria.[5] Older sibling had almost all the facial features and MRI findings of Warburg syndrome. On the other hand, younger one did not have forehead hypertrichosis, retrognathia, or philtrum changes. Both the children had single simian crease, bilaterally, which has been reported by Yüksel et al. and Graham et al.[57] Seizures are not commonly seen in this syndrome, but younger sibling has seizures. Mutations in RAB3GAP have been implicated in the pathogenesis of WMS.[89]

Differential diagnoses for this condition are Martsolf syndrome, cerebro-oculo-facial syndrome (COFS), and prenatal infections (e.g., toxoplasmosis, cytomegalovirus).

A closely resembling entity is Martsolf syndrome. The main characteristics of the syndrome are craniofacial anomalies including microcephaly, maxillary retrusion, pouting mouth, malaligned teeth, and mildly dysplastic pinnae. The metacarpal and phalangeal bones are short.[10] Martsolf syndrome is less severe disorder. These two syndromes represent a phenotypic continuity due to the severity of the mutations present in RAB3GAP1 and RAB3-GAP2.[8] In view of the severity of disease, Martsolf syndrome is unlikely.

COFS is characterized by blepharophimosis, camptodactyly, arthrogryposis, generalized osteoporosis, dysplastic acetabula, coxa valga, and vertical talus manifesting as rocker bottom feet.[11] As these children did not have arthrogryposis, this was unlikely.

Children with WMS have profound mental retardation and physical disability requiring multidisciplinary approach for optimizing their life. Feeding problems and malnutrition are present in most of the children due to their physical and mental disability. As the child grows, puberty is delayed due to hypogonadism which is a part of this syndrome. This report aims to generate awareness regarding this rare cause of bilateral congenital cataract with developmental delay. Seizures are uncommon in this disorder. It is imperative that parents are counseled regarding the poor outcome of vision despite surgery. Genetic counseling should be offered to parents wherever feasible.

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.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.