Craniosynostosis in a child with I-cell disease: The need for genetic analysis before contemplating surgery in craniosynostosis.

We are reporting a rare case of I-cell disease presenting with craniosynostosis. An 11-month-old child presented with abnormal head shape, developmental delay and bent bones. We planned for corrective surgery for craniosynostosis, but on genetic analysis I-cell disease was confirmed. After explaining the prognosis of I-cell disease, parents denied surgery. This case report emphasizes the fact that syndromic evaluation of craniosynostosis is very much essential before proceeding for corrective surgery.

Introduction

Craniosynostosis refers to premature fusion of the cranial vault. The cranial bones form during early few weeks of fetal life. At birth, the cranial bones are separated by sutures and fontanelle which will accommodate the growing brain. Premature closure of one or more of these sutures results in cessation of skull bone growth perpendicular to the suture with compensatory expansion of the skull parallel to the closed suture. This will result in deformity of the skull vault along with raised intra cranial pressure and the resulting neurocognitive and ophthalmological complications. The severity depends on the timing of sutural closure.[1]

Case Report

The present case report is about an 11-month-old male child born as the third offspring of 3rd degree consanguineous parents was brought for evaluation and management of abnormal skull shape noted since birth. The mother had also had a spontaneous first trimester abortion before this child. He was delivered by cesarean section at full term and had normal cry at birth. He was noted to have global developmental delay since early infancy. He could not recognize his mother, had not attained stable head control and was unable to sit even with support at 11 months of age. On examination, there was microcephaly with a head circumference of 40.5 cm (4 SDs below mean for age and sex). The other features noted on examination included coarse facial features with bilateral proptosis, upturned tip of nose with depressed nasal bridge, micrognathia, gum hypertrophy, low set ears, narrow chest, joint contractures and bent forearms, thighs and legs with folds of the overlying skin [Figure 1]. Hepatomegaly was noted on palpation of the abdomen. The diagnosis of craniosynostosis was quite evident clinically. Computed tomography (CT) of the head showed fusion of the anterior sagittal suture, bicoronal sutures, bilateral lambdoid sutures and temporo-parietal sutures. There was bilateral temporo-parietal bossing with diffuse thickening of all skull bones. Mild ventriculomegaly was also noted. We explained to the parents regarding the progressive nature of disease, risk of increased intra cranial pressure and cosmetic deformity. Before contemplating corrective surgery, the child was evaluated for associated syndromes in the Department of Medical Genetics. Skeletal survey [Figure 2] showed significant dysostosis with broad oak shaped ribs, inferior beaking of vertebrae and diaphyseal and epiphyseal dysplasia with periosteal cloaking. As these clinical features and skeletal features were suggestive of I-cell disease, fluorometric assays for three lysosomal enzymes (iduronate 2 sulfatase, total hexosaminidase and hexosaminidase A) were performed in the plasma sample. The plasma levels of all three enzymes were significantly elevated (more than 10 times above normal range). Based on the enzyme levels and the clinical features, the diagnosis of I-cell disease with craniosynostosis was established in the child. The parents were counseled about the underlying genetic basis and prognosis of the condition and in addition, about the autosomal recessive inheritance pattern and the 25% risk of recurrence in future offspring. On being explained about the co-existing skeletal dysplastic changes, intellectual disability, respiratory problems and the limited survival associated with the disorder, the parents opted not to get surgery done for the craniosynostosis.

Figure 1

(a) Clinical photograph of the child showing coarse facial features, bilateral proptosis, upturned tip of nose, micrognathia and low set ears. (b) Computed tomography (CT) head with 3D reconstruction image anterior view showing fused sagittal, bicoronal sutures. (c) Posterior view showing fused lambdoid sutures as well. (d) CT axial bony window showing sutural synostosis

Figure 2

Skeletal survey of the child. (a) X-ray chest anteroposterior (AP) view showing broad oak shaped ribs, (b) X-ray dorso lumbar spine lateral view showing inferior beaking of vertebrae, X-ray lower limb lateral view (c) and X-ray pelvis AP view (d), showing diaphyseal, metaphyseal and epiphyseal dysplasia, (e) clinical photograph showing bent limbs with skin folds

Discussion

Craniosynostosis occurs in 1 in 2500 births, with the non-syndromic subtype present in 0.4-1 in 1000 births.[2] Craniosynostosis is classified as simple if it involves a single suture and named according to the suture involved and the deformity of the skull vault. If multiple sutures are involved it is considered to be complex. Craniosynostosis is classified as syndromic craniosynostosis if it is associated with well-described genetic syndromes, or non-syndromic, when there are no associated anomalies. Most common syndromic associations with craniosynostosis are Crouzon, Apert, Pfeiffer, Muenke and Saethre-Chotzen syndromes. Patients with syndromic craniosynostoses are much more complicated to care for, requiring a multidisciplinary approach to address all of their needs effectively.[3] Non-syndromic craniosynostosis is also believed to have a strong genetic component with possible gene–gene or gene–environment interactions that remain to be identified.[4]

Our patient presented mainly with the complaints of global developmental delay and craniosynostosis. However, on thorough clinical genetic evaluation he was found to have numerous dysmorphic features including coarse facies and bent limb bones in addition to hepatomegaly. Skeletal survey revealed features of dysostosis multiplex and typical diaphyseal and epiphyseal changes consistent with the diagnosis of I-cell disease. The diagnosis of I-cell disease was confirmed by metabolic testing.

I-cell disease, also known as mucolipidosis Type II, is a rare genetic inborn error of metabolism. Most cases have clinical onset at birth and a fatal outcome by early childhood. It is associated with limited postnatal growth, joint contractures, thickening of the skin, coarsening of facial features and hypertrophic gingiva.[56] All cases have dysostosis multiplex and typically have small epiphyses with delayed ossification and shortening and widening of diaphyses with osteopenia, coarse trabeculations and periosteal cloaking. Craniosynostosis has been reported in some cases of I-cell disease, but may not be present in all cases. Orthopedic abnormalities are present at birth and may include thoracic deformity, kyphosis, clubfeet, deformed long bones and/or hip dislocation.[7] Cardiac involvements in the form of thickening and insufficiency of the mitral valve and sometimes of the aortic valve occur in almost all cases. The most common cause of death is respiratory insufficiency, which results from progressive mucosal thickening and narrowing of the airways and stiffening of the thoracic cage.[56]

I-cell disease is caused by mutations in the GNPTAB gene, which codes for the alpha and beta subunits of the N-acetylglucosamine-1-phosphotransferase protein. Mutations in the gene result in impairment of receptor-mediated transport of lysosomal enzymes through the Golgi network into the lysosomal compartment. As these enzymes are unable to enter the lysosomes, they accumulate in the plasma, which is why plasma shows several fold elevation of the lysosomal enzymes in this disorder. I-cell disease has an autosomal recessive pattern of inheritance. The risk of recurrence of the disease in each offspring of carrier parents is 25%.[568]

Our patient had primarily presented with craniosynostosis but before contemplating surgery the child was sent for genetic evaluation and was found to have I-cell disease, which significantly changed the prognosis and management plan. Until now, only few cases of I-cell disease associated with craniosynostosis have been reported.[9101112] Out of these, to the best of our knowledge, only one case presented primarily with craniosynostosis as was the scenario with our patient.[9]

Conclusion

Craniosynostosis can result in raised intra cranial pressure, ophthalmic and neurocognitive complications. It can be treated by skull bone reconstruction. However, before contemplating surgery, evaluation of syndromic craniosynostosis is advisable as it will significantly affect the prognosis and management. In addition, diagnosis of the exact underlying genetic syndrome is also important for appropriate genetic counseling of the family, in terms of recurrence risk in future pregnancies and prenatal diagnosis to prevent recurrence. We are hereby reporting a rare case of I-cell disease presenting with craniosynostosis.