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Abstract. To describe the clinical, radiological and biochemical features of 18 new Saudi Arabian children with the carbonic
anhydrase II deficiency syndrome, who have been in follow up at Al-Rass General Hospital in the period from September 2004
to September 2008. The medical records of these children were reviewed. The diagnosis was based on the...
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... is a heterogeneous group of heritable conditions in which there is a defect in bone resorption by osteoclasts [1]. Osteopetrosis is caused by failure of osteoclast development or function and mutations in at least 10 genes had been identified as causative in humans, accounting for 70% of all cases [2]. The severe, infantile autosomal recessive osteopetrosis (ARO) re- lies on loss of-function mutations of various genes, in- cluding the TCIRG1 gene, encoding for the a3 sub- unit of the H + ATPase and accounting for > 50% of cases, the CLCN7 and the OSTM1 genes, which have closely related function and account for approximately 10% of cases, in addition to others including RANKL and RANK genes. ARO may also have intermediate severity, with a small number of cases due to loss-of- function mutations of carbonic anhydrase II (CA II) or the PLEKHM1 genes. While, dominant negative mutations of the CLCN7, gene encoding on osteoclast specific chloride channel causes the so-called Albers- Schonberg disease, autosomal dominant osteopetrosis (ADO) [3]. Moreover, in the light of the common origin of osteoclasts and cells of the hematopoietic system, it is not surprising that mutations in molecules such as IKBKG (NEMO) and more recently CalDAG-GEF1 and kindlin-3 have been implicated in the pathogenesis of ARO variants associated with immune system dys- function [4,5]. The CA II deficiency, formerly called the syndrome of osteopetrosis with renal tubular acidosis (RTA) and cerebral calcifications, is an autosomal recessive inborn error of metabolism [6]. It was first described in 1972 [7]. In 1983, Sly et al. [8] reported a deficiency of CA II in three sisters with this disease. In the same year, Venta et al. [9] located the gene for CA II in the long arm of chromosome 8. Subsequently several case reports have been published [10–12], and also several gene mutations have been reported in patients with this syndrome [13,14]. The geographical distribution of the syndrome is striking, with more than half the known cases observed in families from the Middle East and Mediterranean region, such as North Africa, Kuwait and Saudi Arabia [6,15,16]. In this report, we describe the clinical features of 18 new Saudi Arabian cases with CA II deficiency syndrome. Eighteen Saudi children with the syndrome of osteopetrosis, and cerebral calcifications, who have been in follow up in the pediatric clinic at Al-Rass General Hospital, Qassim, Saudi Arabia, in the period from September 2004 to September 2008, are included in this study. The diagnosis was based on the typical clinical, radiological and biochemical evidence of the disease. However, due to lack of facilities, CA II level was not measured in these patients. The current age and the age at diagnosis of the patients, the gender, and the tribe of origin, family history, mode of presentation and the history and frequency of fractures were noted. All patients were evaluated clinically in the pediatric clinic. Each patient was observed for the typical facial features and the presence of other features. Anthropo- metric measurements were done by the first author at presentation and at each follow up visit. Weight and height were compared against standard growth charts. Development was measured by formal developmental scores. Each patient was assessed at the ophthalmol- ogy clinic for visual acuity and retinal examination. The presence of squint and nystagmus were also noted. Biochemical assessment included complete blood counts, renal function tests, and venous blood gases for determination of pH and HCO3 levels, urine analysis and urine pH when patients are acidotic. Radiological evaluation included skeletal surveys, serial bone age determinations and cranial computerized tomography (CT) scan. The association of osteopetrosis and RTA were noted and all patients were treated with sodium bicarbonate (NaHCO3) orally and followed for compliance and adjustment of the doses that correct the metabolic acidosis. Table 1 shows the clinical characteristics of the 18 patients. The current age of the patients ranged from 3 months to 22 years (median 7.5 years), and the age at diagnosis ranged from 0 to 15 years (median 3 years). These patients have been followed for a mean duration of 3 years (range 0.42 to 8.5 years). Twelve (66.6%) patients were males and six (33.3%) were females. The patients in this series are products of only 10 families; cases 3, 4 and 5 are from one family with three out of five children affected. Cases 6 and 7 are siblings with two out of eight children affected. Cases 8 and 18 are brothers with two out of 13 children affected, likewise, cases 11, 12, 13 and 14 are from the same family in which four out of seven are affected. Case 13 is one of twin, her co-twin -a boy- is normal. Also, cases 15 and 16 are siblings with two out of nine affected, case 17 has one sister affected with the disease but she is not included in this study as she is on follow up at another hospital, case 9 is the only affected child in a family of 10 children. The parents are first-degree cousins in six families, second-degree cousins in two families, far- relatives in two families and one child of unknown origin (an abundant child). The 18 patients represent only four tribes, eight families are originally from only two tribes and two families have more than two children affected. The majority of the patients have peculiar facial appearances. Sixteen had craniofacial dispropor- tion with large cranial vault, broad forehead, prominent nose, small mouth, thin upper lip and delayed den- tition (Fig. 1). Additional features include, squint in 10 patients (55.5%), nystagmus in eight (44.4%), impaired vision in seven patients (38.8%), optic atrophy and total blindness in two patients (11.1%). Abnormal peg-shaped teeth were noted in eight (44.4%) patients and two had recurrent dental abscess (Fig. 2). Four cases had spastic quadriplegia and three of them had severe mental retardation. Other five cases had mild to moderate psychomotor retardation. Three patients had pectus carinatum. Failure to thrive and growth retardation were seen in almost all patients, and 14 (77.7%) patients had height and weight at presentation below the third percentile. Short stature in these patients was proportionate. Bone age was retarded (more than the 2-SD below the mean) in 10 patients (55.5%). Most of the patients showed improvement in growth rate in response to sodium bicarbonate therapy. However, the majority remained short and underweight. In fact, only four cases (cases 2, 3, 6 and 7) maintained weight and height above the third percentile for age (Figs 3 and 4). Table 2 shows the biochemical and radiological features of the 18 patients at presentation. All patients had radiological features of osteopetrosis that are indistinguishable from other forms of osteopetrosis, which comprise diffuse sclerosis affecting skull, spine, pelvis and appendicular bones, bone modeling defects at metaphyses of long bones, such as the Er- lenmeyer Flask deformity and lucent bands, bone in bone appearance and focal sclerosis of the skull base, pelvis and vertebral end plates which form sandwich vertebrae and rugger- jersey spine. Seven (38.8%) had repeated fractures with normal healing. CT scan of the brain was performed in 15 (83%) patients and it showed cerebral calcifications in nine (60%). In case two the scan was done at, the age of 2 and 7.5 years and both were normal, in case nine, the 1st scan at the age 3.5 years was normal, a repeated scan at age 6 years showed basal ganglia calcifications. In cases 6, 15, 16, 17 and 18 the scans were done at the ages of 3, 5, 6, 4, one year and 10 days respectively and all did not show any calcification. The cerebral calcifications involved the basal ganglia and periventricular white matter of the frontal, parietal and occipital lobes and they were more extensive and apparent in the old patients (Fig. 5). All patients had a persistent normal anion gap metabolic acidosis. Distal renal tubular acidosis (DRTA) was suspected in 13 patients. In these patients HCO3 level ranged from 12.5 to 17.9 (15.3 ± 1.59 mmol/L), with a mean serum pH level of 7.23 ...
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... Autosomal recessive type of osteopetrosis is a rare inherited disorder of bone resorption characterized by increased bone density due to the failure of osteoclasts to resorb bone (Sly, Hewett-Emmett, Whyte, Yu, & Tashian, 1983). It is more common in highly consanguinity cultures such as Saudi Arabia (Suliman, Khedr, & Al Ruthae, 2010). The classical features of osteopetrosis, in general, is bone marrow failure, fractures, visual impairment or neurological abnormality (Suliman et al., 2010). ...
... It is more common in highly consanguinity cultures such as Saudi Arabia (Suliman, Khedr, & Al Ruthae, 2010). The classical features of osteopetrosis, in general, is bone marrow failure, fractures, visual impairment or neurological abnormality (Suliman et al., 2010). Because of the infrequency of this type of osteopetrosis, we report a case of a male neonate who presented with recurrent life-threatening episodes of poor feeding and thrombocytopenia at the age of 5 weeks old. ...
Osteopetrosis Type 3 with Renal Tubular Acidosis (OPTB3) is a rare inherited autosomal recessive disorder. It is manifested clinically with osteopetrosis, renal tubular acidosis (RTA), cerebral calcification, and growth retardation. Neonatal onset with life-threatening complications warrants a thorough clinical evaluation with an assessment of specialized tests such as x-ray. Here, we discuss a rare case of carbonic anhydrase II deficiency syndrome, presenting with poor feeding and thrombocytopenia, in which the diagnosis was initially missed in the first hospitalization. Upon second admission, re-exanimation of the CXR was suggestive of marble bone disease. Further tests confirmed OPTB3. Following conservative management and family counseling, the patient was discharged in a good general condition. In conclusion, this highlight the need of early identification of the disease, as early appropriate treatment is necessary to improve the patient outcome and prevent complications.
... Autosomal recessive type of osteopetrosis is a rare inherited disorder of bone resorption characterized by increased bone density due to the failure of osteoclasts to resorb bone (Sly, Hewett-Emmett, Whyte, Yu, & Tashian, 1983). It is more common in highly consanguinity cultures such as Saudi Arabia (Suliman, Khedr, & Al Ruthae, 2010). The classical features of osteopetrosis, in general, is bone marrow failure, fractures, visual impairment or neurological abnormality (Suliman et al., 2010). ...
... It is more common in highly consanguinity cultures such as Saudi Arabia (Suliman, Khedr, & Al Ruthae, 2010). The classical features of osteopetrosis, in general, is bone marrow failure, fractures, visual impairment or neurological abnormality (Suliman et al., 2010). Because of the infrequency of this type of osteopetrosis, we report a case of a male neonate who presented with recurrent life-threatening episodes of poor feeding and thrombocytopenia at the age of 5 weeks old. ...
Osteopetrosis Type 3 with Renal Tubular Acidosis (OPTB3) is a rare inherited autosomal recessive disorder. It is manifested clinically with osteopetrosis, renal tubular acidosis (RTA), cerebral calcification, and growth retardation. Neonatal onset with life-threatening complications warrants a thorough clinical evaluation with an assessment of specialized tests such as x-ray. Here, we discuss a rare case of carbonic anhydrase II deficiency syndrome, presenting with poor feeding and thrombocytopenia, in which the diagnosis was initially missed in the first hospitalization. Upon second admission, re-exanimation of the CXR was suggestive of marble bone disease. Further tests confirmed OPTB3. Following conservative management and family counseling, the patient was discharged in a good general condition. In conclusion, this highlight the need of early identification of the disease, as early appropriate treatment is necessary to improve the patient outcome and prevent complications.
... Nine patients had their initial diagnosis and maintained their metabolic follow-up at a regional hospital. One of these (Patient 12,Table 1) was diagnosed at birth (Suliman et al., 2010). Patients 16 and 19 (Table 1 ), who presented with floppy infant syndrome, were diagnosed at the Security Forces Hospital, Riyadh and followed-up for 14 and 15 years, respectively, by one of the authors (M.A.S.). ...
... Many were recorded to have infantile hypotonia and failure to thrive during infancy (Table 2 ), and when older, generally disproportionate large cranial vault and short stature. None was dysmorphic, although almost all had a broad head with prominent forehead, a long bulbous nose, a relatively thin upper lip and abnormal teeth, as previously described in CADS (Hu et al., 1992; Awad et al., 2002; Suliman et al., 2010) (Fig. 4 ). Motor milestones were delayed, with the typical individual beginning to sit between eight and 12 months and to walk after 2 years of age. ...
Carbonic anhydrase type II deficiency syndrome is an uncommon autosomal recessive disease with cardinal features including osteopetrosis, renal tubular acidosis and brain calcifications. We describe the neurological, neuro-ophthalmological and neuroradiological features of 23 individuals (10 males, 13 females; ages at final examination 2-29 years) from 10 unrelated consanguineous families with carbonic anhydrase type II deficiency syndrome due to homozygous intron 2 splice site mutation (the 'Arabic mutation'). All patients had osteopetrosis, renal tubular acidosis, developmental delay, short stature and craniofacial disproportion with large cranial vault and broad forehead. Mental retardation was present in approximately two-thirds and varied from mild to severe. General neurological examinations were unremarkable except for one patient with brisk deep tendon reflexes and two with severe mental retardation and spastic quadriparesis. Globes and retinae were normal, but optic nerve involvement was present in 23/46 eyes and was variable in severity, random in occurrence and statistically correlated with degree of optic canal narrowing. Ocular motility was full except for partial ductional limitations in two individuals. Saccadic abnormalities were present in two, while half of these patients had sensory or accommodative strabismus, and seven had congenital nystagmus. These abnormalities were most commonly associated with afferent disturbances, but a minor brainstem component to this disorder remains possible. All internal auditory canals were normal in size, and no patient had clinically significant hearing loss. Neuroimaging was performed in 18 patients and repeated over as long as 10 years. Brain calcification was generally progressive and followed a distinct distribution, involving predominantly basal ganglia and thalami and grey-white matter junction in frontal regions more than posterior regions. At least one child had no brain calcification at age 9 years, indicating that brain calcification may not always be present in carbonic anhydrase type II deficiency syndrome during childhood. Variability of brain calcification, cognitive disturbance and optic nerve involvement may imply additional genetic or epigenetic influences affecting the course of the disease. However, the overall phenotype of the disorder in this group of patients was somewhat less severe than reported previously, raising the possibility that early treatment of systemic acidosis with bicarbonate may be crucial in the outcome of this uncommon autosomal recessive problem.
