Infantile osteopetrosis, craniosynostosis, and Chiari malformation type I with novel OSTEM1 mutation

Abstract

We report a case of a 9-month-old Arab infant, with novel OSTEM mutation and unpublished triad of osteopetrosis (OP), craniosynostosis (CS), and Chiari malformation type I (CM1). The index presented with progressive irritability, abnormal movements, following an accidental fall. The history revealed early onset of irritability, progressive visual loss, and global developmental delay, more prominent at the gross motor level and a suspected congenital cytomegalovirus infection. The pregnancy was uneventful with subsequent unremarkable delivery. The parents are Arabs′first cousins with no apparent symptoms or signs of bone disease. Three dimensional brain computed tomography (CT) showed ventriculomegaly, thick calvaria, and CS of the coronal and sagittal sutures. Patient had signs of left lower motor neuron facial palsy, and CT of petrous bones confirms the presence of osteopetrotic petrous with slim mastoid portions of the facial nerve canals both sides. Brain magnetic resonance imaging showed CM1. Skeletal survey showed sclerotic skeleton. He needed ventriculoperitoneal shunt and died at 18 months of age. Molecular testing for OSTEM1 gene revealed novel homozygous mutation that segregated from his parents. This novel OSTEM1 gene novel mutation and the combination of OP, infantile CS, and CM1 is to our knowledge never been reported.

Introduction

Osteopetrosis (OP) is a heterogeneous group of rare, inherited disorders of the skeleton that results in neurological manifestations due to restriction of growth of cranial foramina and calvarial thickening.[1] It is a heterogeneous group of osteosclerotic bone dysplasias in which the entire skeleton is unusually dense.[2] It is divided into several subgroups which differ in their onset of symptoms, severity, and associated extraskeletal manifestations. Craniosynostosis (CS) is the premature fusion or abnormal development of one or more cranial sutures. Causation divides the group into primary and secondary CS (vide infra). Chiari malformation (CM) describes a group of structural defects of the cerebellum, characterized by brain tissue protruding into the spinal canal. The association of OP with CM and CS has been previously reported.[1,3] The triad of the three abnormalities has been published only once, however, with no genetic study.[4] Herein, we describe another patient with malignant OP, CS, and CM1. Molecular testing revealed novel mutation homozygous in OSTEM1 gene.

Materials and Methods

The index is 9-month-old Arab infant, who was a product of full-term gestation following uneventful pregnancy delivered via normal vertex delivery with no postnatal complications and average birth weight. He is the only child of first cousin parents.

They are apparently healthy and the mother has no history of abortions, unexplained neonatal deaths, or mental retardation in their close family members.

The patient started to have irritability at 2^nd week of life increasing with time. He fed well; however, his irritability was not related to feeds. There was no history of vomiting and his parents did not report any abnormal movements. At the age of 3 months, congenital cytomegalovirus infection was considered by different clinics due to abnormal cerebrospinal fluid analysis and brain atrophy shown on his brain computed tomography (CT). Despite receiving gancyclovir for 3 weeks, the patient′s irritability did not improve and eventually presented to emergency with continuous irritability and abnormal movements for 2 days after falling down from his cot (50 cm height). Six hours later he started to have up rolling of eyes with cessation of breathing, followed by generalized stiffness and clonic jerks in all limbs that increased in frequency lasting from seconds to 5 minutes. The baby was initially able to fix and follow; however, roving eye movements were noted at 3 months of age. Motor, cognitive, and speech functions were impaired, mainly at gross motor aspect. Evoked visual potential testing at 8 months of age revealed evidence of bilateral optic atrophy.

Clinical evaluation at 9 months showed an irritable baby, microcephaly (below third centile), closed anterior fontanel and ridging of coronal and sagittal sutures. The weight and the length were at 10^th centile. He had bilateral proptosis with roving eye movements and dilated pupils with sluggish reaction to light. Other cranial nerves were intact. He had mild hypertonia in all limbs with axial hypotonia. Power was normal in all muscle groups. Deep tendon reflexes were +2 in all limbs. He had no apparent bony deformity and there was no evidence of fractures. He had no organomegaly and other systemic examination was unremarkable.

Baseline CBC showed mild microcytic hypochromic anemia, leukocytosis. Serum electrolytes, liver transaminases, and blood gas were normal.

CT of brain showed presence of dilated ventricles with thick skull bones. Skeletal survey showed sclerotic bone [Figure 1].

Figure 1.

Skeletal survey showed features of osteopetrosis with generalized increased bone density, sclerosed medullary spaces

His seizures were controlled and ventriculoperitoneal shunt was inserted on 2^nd day of admission. Preinsertion skull three dimensional CT showed fusion of coronal and sagittal sutures [Figure 2]. Postoperative magnetic resonance imaging brain showed decompression of ventricles with presence of CMI [Figure 3].

Figure 2.

CT of skull showed CS of coronal and sagittal sutures

Figure 3.

Postoperative MRI T1brain showed decompression of ventricles with presence of CM1

Patient had signs of left lower motor neuron facial palsy, which was evident on 2^nd day postinsertion. A repeat CT of petrous bones showed osteopetrosis with slim mastoid portions of the facial nerve canal on both sides.

Molecular genetic analysis for OSTEM1 gene revealed two homozygous mutations in the OSTEM1 gene. This has not, to the best of our knowledge, been reported previously. The first mutation involves exon1; c. 365 T < A, (Val122Asp). The comparison of OSTEM1 amino acid sequences derived from numerous species indicates that the Val122 is not well-conserved (conserved in 9/16 species). Valine and aspartic acids are dissimilar amino acids. However, the lack of high conservation suggests that the Val122Asp may represent a neutral variant. The second mutation of OSTEM1 exon1c. 108C < T transition does not result in an amino acid substitution (GGC and GGT are both codons for glycine). However, the c. 108C > T transition may create a new donor splice site (GT) and result in aberrant mRNA processing. Analysis of the exon 1 of OSTEM 1 gene in both parents revealed a heterozygous c. 108C > T transition and a heterozygous OSTEM1 exon 1c. 365T > A transversion. CLCN7 and TCIRG1 genes were normal.

Discussion

OP was first described in 1904, by German radiologist Albers-Schönberg.[5] It is a clinical syndrome characterized by dynamic imbalance of the bone cells and failure of osteoclasts to resorb bone. As a consequence, bone modeling and remodeling are impaired. The defect in bone turnover characteristically results in skeletal fragility despite increased bone mass, and it may also cause hematopoietic insufficiency, disturbed tooth eruption, nerve entrapment syndromes, and growth impairment.

Although human OP is a heterogeneous disorder encompassing different molecular abnormalities and a range of clinical features, all forms share a single pathogenic nexus in the osteoclasts.[6] Infantile OP is an autosomal recessive disorder, which is considered the most severe of OP spectrum with four genes (TCIRG1, OSTEM1, CLCN7, RANK, and RANKL) known up-to-date.[7]

CS is a developmental abnormality in which one or more of the fibrous sutures in an infant skull prematurely fuses by ossification,[8] thereby changing the developmental growth pattern of the skull. Because the skull cannot expand perpendicular to the fused suture, it compensates by growing more in the direction parallel to the closed sutures.[9] Sometimes the resulting growth pattern provides the necessary space for the growing brain but results in an abnormal head shape and abnormal facial phenotype.[9] In cases where the compensation does not effectively provide enough space for the growing brain, CS results in increased intracranial pressure leading possibly to visual impairment, sleeping disturbances, eating difficulties, or impairment of mental development combined with a significant reduction in IQ.[10] CS occurs in one in 2000 births. It is a part of a syndrome in 15% to 40% of the patients, but it usually occurs as an isolated condition.[11,12]

The CM, also known as the Arnold-Chiari malformation (or deformity), was first described by Cleland in 1883 in a child with spina bifida, hydrocephalus, and alterations of the cerebellum and brainstem.[13,14] Clinical presentations resulting from CM vary along a spectrum of severity and depend on an anatomic involvement. Many individuals with CM1 do not have symptoms and go undiagnosed until adolescence. Headache and neck pain are the most common presenting symptoms of CM1.[15]

Our patient had clinical, radiological, and hematological manifestations of OP, with autosomal recessive inheritance highly possible in the presence of first cousin consanguineous parents.

The child had bilateral optic atrophy, left lower motor neuron facial palsy, and anemia. Genetic mutational studies confirmed the presence of OP. The early irritability of the baby could be explained on the basis of CS with subsequent increase in intracranial pressure. This was confirmed by CT of skull that showed CS of coronal and sagittal sutures [Figure 2]. The same applies to the finding of proptosis.

Hydrocephalus is a part of CM, which the child has. Headache and neck pain are the most common presenting symptoms of CM1.[15] The combination of OP with CM1 has been reported previously.[1] The association of CM1 with OP resulting in brain stem compression syndrome is extremely rare entity. The common neurological manifestations include cranial neuropathies involving optic, cochlear, facial, and trigeminal nerves.[16] As well the combination of CS with OP has been documented earlier.[17,18]

Reported cases of CS with CM1 have been encountered frequently.[19–21] CM is a frequent finding in multisutural and syndromic CS, occurring in 70% of patients with Crouzon′s syndrome, 75% with oxycephaly, 50% with Pfeiffer′s syndrome, and 100% with the Kleeblattschädel deformity.[22] Searching the literature indicated that the combination of the three abnormalities together (OP, CM1, and CS) was mentioned only once, with no mentioned genetic studies.[4]