Osteopetrosis, Autosomal Recessive 3

Alternative Names

  • OPTB3
  • Osteopetrosis with Renal Tubular Acidosis
  • Carbonic Anhydrase II Deficiency
  • Guibaud-Vainsel Syndrome
  • Marble Brain Disease

Associated Genes

Carbonic Anhydrase II
Back to search Result
WHO-ICD-10 version:2010

Congenital malformations, deformations and chromosomal abnormalities

Congenital malformations and deformations of the musculoskeletal system

OMIM Number

259730

Mode of Inheritance

Autosomal recessive

Gene Map Locus

8q21.2

Description

Osteopetrosis with renal tubular acidosis (carbonic anhydrase type II deficiency) is a rare autosomal recessive disorder characterised by osteopetrosis, renal tubular acidosis (RTA), cerebral calcification, and growth retardation. This disorder is caused by mutations in CA2  gene.

Epidemiology in the Arab World

View Map
Subject IDCountrySexFamily HistoryParental ConsanguinityHPO TermsVariantZygosityMode of InheritanceReferenceRemarks
259730.1.1Saudi ArabiaFemaleYesYes Osteopetrosis; Intellectual disability; ...NM_000067.3:c.232+1G>AHomozygousAutosomal, RecessiveMaddirevula et al. 2018
259730.1.2Saudi ArabiaFemaleYesYes Osteopetrosis; Intellectual disability; ...NM_000067.3:c.232+1G>AHomozygousAutosomal, RecessiveMaddirevula et al. 2018 Relative of 259730.1...
259730.1.3Saudi ArabiaFemaleYesYes Osteopetrosis; Intellectual disability; ...NM_000067.3:c.232+1G>AHomozygousAutosomal, RecessiveMaddirevula et al. 2018 Relative of 259730.1...
259730.2Saudi ArabiaFemaleYesNo Recurrent fractures; Renal tubular acido...NM_000067.3:c.232+1G>AHomozygousAutosomal, RecessiveMaddirevula et al. 2018
259730.3.1Saudi ArabiaMaleYesYes OsteopetrosisNM_000067.2:c.232+1G>THomozygousAutosomal, RecessiveMaddirevula et al. 2018
259730.3.2Saudi ArabiaFemaleYesYes OsteopetrosisNM_000067.2:c.232+1G>THomozygousAutosomal, RecessiveMaddirevula et al. 2018 Relative of 259730.3...
259730.3.3Saudi ArabiaFemaleYesYes OsteopetrosisNM_000067.2:c.232+1G>THomozygousAutosomal, RecessiveMaddirevula et al. 2018 Relative of 259730.3...
259730.4United Arab EmiratesFemaleYesYes Failure to thrive; Metabolic acidosis; G...NM_000067.3:c.232+1G>AHomozygousAutosomal, RecessiveAlabdullatif et al. 2017 Similarly affected s...
259730.G.1United Arab EmiratesNM_000067.3:c.232+1G>AHomozygousAutosomal, RecessiveAl-Shamsi et al. 2014 2 Emirati patients

Other Reports

Arab

Hu et al. (1992) studied all 39 reported cases of CA2 Deficiency. Almost 72% of these patients were of Middle Eastern or North African Arab origin.

Egypt

Nagai et al. (1997) described a 3.5-year-old Egyptian boy, born for unrelated parents, with osteopetrosis, cerebral calcification, a persistent normal anion gap type of metabolic acidosis (plasma pH 7.26), and a mild degree of hypokalemia. In addition, the patient had the following findings: impaired renal re-absorption of HCO3, decreased NH4+ excretion, low urine-blood PCO2 difference in alkaline urine, a high urinary citrate level unless he was severely acidotic, and a failure to achieve maximally low urine pH. These findings indicated that the renal acidification mechanisms of the patient were impaired in both the proximal and distal tubule as a result of CAII deficiency.

Kuwait

Bourke et al. (1981) reported two Kuwaiti Bedouin sibs with osteopetrosis with renal tubular acidosis. The major clinical manifestation in both was periodic hypokalemic paresis, while one sib showed basal ganglion calcification and mental subnormality.

Al Kordy (1989) (Kuwait Med J. 1899; 23(2):200-4) reported two sisters suffering from carbonic anhydrase II deficiency. The clinical features included osteopetrosis, renal tubular acidosis, cerebral calcification, mental retardation, typical facial features, abnormal teeth, and growth failure.

Abdel-Al et al. (1994) diagnosed 19 Arab children (six boys and 13 girls) in ten sibships as having osteopetrosis over a 5-year period in various hospitals in Kuwait. Eighteen patients had an isolated autosomal recessive form and one had autosomal recessive osteopetrosis associated with renal tubular acidosis. The mean age of diagnosis was 24 months. Parental consanguinity was high amongst them (68%). Anemia, hepatosplenomegaly, failure to thrive, recurrent infections and neurological manifestations were common. Associated congenital abnormalities were found in 26%. Deafness, hydrocephalus and dental caries were relatively less common. Abdel-Al et al. (1994) noted a high mortality rate (37%) owing to infection.

Samilchuk et al. (Med Princ Pract. 1996; 5(4):234-7) reported a Kuwaiti patient with ORTACC, yet without a splice junction mutation in the CA2 gene.

Palestine

Lotan et al. (2006) studied affected members of a family with the CA2 deficiency syndrome and having the "Egyptian mutation" in CA2 c.191delA (p.H64fsX90). One affected member, homozygote for the mutation, developed primary pulmonary hypertension. Lotan et al. (2006) added that primary pulmonary hypertension was never described before in patients with this unique syndrome and they speculated that there might be a possible etiologic link between these entities.

Saudi Arabia

Ohlsson et al. (1980) described four children from three Saudi Arabian families suffering from osteopetrosis, distal renal tubular acidosis and cerebral calcification associated clinically with mental retardation, stunted growth, abnormal teeth and a similar facial appearance. The syndrome was inherited as an autosomal recessive. Ohlsson et al. (1980) attributed the growth retardation to renal tubular acidosis but no metabolic link was evident between the other major features of the disorder. In addition, Ohlsson et al. (1980) could not define the fundamental defect in their patients. However, the disorder was radiologically indistinguishable from the classical recessive (malignant) and dominant (benign) forms of osteopetrosis but its other characteristics lead Ohlsson and colleagues (1980) to conclude that their patients exhibited a separate disease entity. In 1986, Ohlsson and colleagues described four new Saudi Arabian cases of the carbonic anhydrase II deficiency syndrome from two families. The disease was inherited as autosomal recessive and exhibited osteopetrosis with renal tubular acidosis and cerebral calcification. Additional features also included mental retardation, growth failure, typical facial appearance, and abnormal teeth. Two patients showed evidence of restrictive lung disease. One of the patients reported represented the first neonate reported to be affected with this syndrome. Intrauterine growth was normal, but metabolic acidosis was already evident in the neonatal period. Radiographic evidence of osteopetrosis was probably absent at birth but appeared during the late neonatal period. Carbonic anhydrase II deficiency was demonstrated in erythrocyte hemolysates from the older two siblings of this neonate, and a 50% normal level of carbonic anhydrase II was demonstrated in the erythrocyte hemolysate from their father.

In 1988, Al Rajeh et al. described two sisters with osteopetrosis associated with renal tubular acidosis and cerebral calcification, inherited as an autosomal recessive disorder. Features of the two patients included deficiency of carbonic anhydrase II. Significant reduction in blood levels of carbonic anhydrase II was also found in both parents and another sister, suggestive that these individuals are heterozygotic carriers.

An 11-year old girl with Marble Brain Syndrome was reported by Jacquemin et al. in 1998. The patient presented with short stature, multiple leg fractures, left optic atrophy, and anisometropia. CT brain showed cerebral calcifications in the cortical, subcortical, and basal ganglia. Urinalysis indicated tubular acidosis. X-rays of the long bones showed osteopetrotic changes and a diagnosis of Marble Brain Syndrome was made. A repeat CT after 4-years showed progression of the calcification, with involvement of the thalami and the caudate nucleus. The renal acidosis was corrected by then.

An 11-year-old Saudi female patient was reported by Al-Ibrahim et al. (2003). The child developed acute paralysis and was admitted to hospital subsequently. The parents of the girl belonged to the same tribe but she had six healthy siblings and no family history of similar symptoms. The child was fully conscious, well oriented apathetic and dysmorphic, with a prominent narrow nose, thin upper lip, poorly developed philtrum and everted lower lip. Biochemical indices were consistent with CAII deficiency so her serum potassium and bicarbonate levels were corrected. After the patient was discharged she was monitored for 4 years, during which she had two attacks of hypokalemic paralysis, each lasting less than twenty-four hours. Al-Ibrahim et al. (2003) highlighted this case to raise awareness about this disorder among pediatricians.

Muzalef et al. (2005) described two Saudi siblings from first-degree cousin parents with marble brain disease.  The first patient was an 8-year-old boy, he presented to the neurosurgery service due to a head and neck trauma resulting in fracture of the second and third cervical vertebra.  He was dull with slow response to instructions, he had slightly prominent forehead.  CT scan revealed diffuse parenchymal calcification.  He had increased bone density, medullary nephrocalcinosis in the kidneys, and increased skull density and fracture at the second and third cervical spines.  His 14-year-old sister had severely stunted growth with skeletal deformities involving long bones and moderate mental retardation.  Both siblings improved in somatic growth and mental development after they were treated with alkaline therapy and potassium supplementation.

Moammar et al. (2010) reviewed all patients diagnosed with inborn errors of metabolism (IEM) from 1983 to 2008 at Saudi Aramco medical facilities in the Eastern province of Saudi Arabia. During the study period, 165530 Saudi infants were born, of whom a total of 248 newborns were diagnosed with 55 IEM. Affected patients were evaluated based on clinical manifestations or family history of similar illness and/or unexplained neonatal deaths. Almost all patients were born to consanguineous parents. Three cases out of 248 were found to have CA II with an estimated incidence of 2 per 100,000 live births. The authors concluded that data obtained from this study underestimate the true figures of various IEM in the region. Therefore, there is an urgent need for centralized newborn screening program that utilizes tandem mass spectrometry, and offers genetic counseling for these families.

Tunisia

Fathallah et al. (1994) analyzed the genomic DNA of 10 Tunisian patients for the presence of a splice junction mutation at the 5' end of intron 2 in the carbonic anhydrase II gene (CAII) previously described in six CAII-deficient patients presumed to be of Arab origin. All the patients were homozygous for this mutation and were mentally retarded, a characteristic feature of the phenotype of patients with an Arabic background. Fathallah et al. (1994) concluded that this mutation is found exclusively in patients with an Arabic background and it may be confined to this ethnic group. In 1997, Fathallah et al. traced the origin of this disorder in 24 Tunisian patients from 14 families with CAII deficiency. All families had histories of osteopetrosis, renal tubular acidosis, mental retardation, and CA II deficiency. Fathallah et al. (1997) conducted a filiation study to trace these families back to a common Arabic tribe that settled in the Maghreb (North Africa) in the tenth century. By sequence-tagged site analysis, Fathallah et al. (1997) showed cosegregation of the Taq (-) allele with the mutation in 12 families out of 14. This observation supported a founder effect to explain the common CAII deficiency allele in the Tunisian population. In the remaining two families, a genomic recombination or gene conversion occurred between the TaqI restriction marker and the mutation causing the disease. Fathallah et al. (1997) suggested the presence of a hot spot for recombination or gene conversion at the CA II locus because of the relatively high recombination frequency observed.

© CAGS 2024. All rights reserved.