Metabolic acidosis and mental retardation are the clinical hallmarks of OPTB3. They may manifest in infancy or childhood and be accompanied by susceptibility to fractures. Minor traumas may result in recurrent pathological fractures, and skeletal anomalies may also show in general growth failure and characteristic facial features. Patients have repeatedly been described to have a wide forehead, prominent ears, a narrow nose, and a small mouth. Dental malocclusion and/or malalignment have been observed in several cases. Cranial nerve compression is a dreaded complication of narrowing of the cranial nerve foramina due to abnormal skull growth and may lead to disabling sequelae. Compression of the second or eighth cranial nerve, for instance, may result in blindness or deafness [1] [2] [3]. Despite extensive skeletal involvement, bone marrow failure with subsequent cytopenias is not characteristic of this type of autosomal recessive osteopetrosis [1] [4].

Additional symptoms have been described in some families. In this context, OPTB3 patients have been stated to be prone to nephrolithiasis [1] [5]. Pulmonary hypertension has been reported in another case, but the causal relationship between this condition and OPTB3 could not be unequivocally proven [4].

• Short Stature

  Other clinical manifestations are: an high risk of fractures, dental abnormalities, cranial nerve compression, developmental delay and short stature. The radiographic exams can show cerebral calcifications by early childhood. [iofbonehealth.org]

  Other features include developmental delay, short stature, cognitive defects, and a history of multiple fractures by adolescence. [ncbi.nlm.nih.gov]

  We report here, three siblings of CAII deficiency syndrome presenting with short stature, distal renal tubular acidosis and cerebral calcification. [abstracts.eurospe.org]

  If OPTB3 is recognized before the final adult height is reached, short stature and skeletal anomalies may somewhat be compensated for by treatment-induced growth, but patients are unlikely to obtain a normal hight and phenotype. [symptoma.com]

  stature Decreased body height Small stature [ more ] 0004322 Visual loss Loss of vision Vision loss [ more ] 0000572 Showing of 35 Last updated: 3/1/2020 Making a diagnosis for a genetic or rare disease can often be challenging. [rarediseases.info.nih.gov]

• Developmental Delay

  Other clinical manifestations are: an high risk of fractures, dental abnormalities, cranial nerve compression, developmental delay and short stature. The radiographic exams can show cerebral calcifications by early childhood. [iofbonehealth.org]

  Other features include developmental delay, short stature, cognitive defects, and a history of multiple fractures by adolescence. [ncbi.nlm.nih.gov]

  delay 0001263 Hepatomegaly Enlarged liver 0002240 Intellectual disability Mental deficiency Mental retardation Mental retardation, nonspecific Mental-retardation [ more ] 0001249 Osteopetrosis Harder, denser, fracture-prone bones 0011002 Recurrent fractures [rarediseases.info.nih.gov]

• Fatigue

  Without treatment, RTA can affect a child's growth and cause kidney stones, fatigue, muscle weakness, and other symptoms. Over time, untreated acidosis can lead to long-term problems like bone disease, kidney disease, and kidney failure. [kidshealth.org]

  Carriers of Gitelman's syndrome-linked mutations are often asymptomatic while some complain of mild muscle cramps or weakness fatigue. Bartter's syndrome causes hypocalcaemia, but Gitelman's syndrome causes hypercalcaemia. [patient.info]

  The potential complications of Autosomal Recessive Osteopetrosis Type 1 may include: Severe anemia, which may lead to extreme fatigue and fainting spells Vision impairment; permanent loss of vision Problems with movement due to brittle bones susceptible [dovemed.com]

  SLC12A3 gene on chromosome 16p impaired function of the thiazide -sensitive sodium- chloride cotransporter in the distal convoluted tubule impaired Na and Cl - reabsorption mild natriuresis mild volume depletion mild RAAS activation Clinical features Fatigue [amboss.com]

• Splenomegaly

  0011002 Recurrent fractures Increased fracture rate Increased fractures Multiple fractures Multiple spontaneous fractures Varying degree of multiple fractures [ more ] 0002757 Reduced bone mineral density Low solidness and mass of the bones 0004349 Splenomegaly [rarediseases.info.nih.gov]

• Failure to Thrive

  Those who survive childbirth present with general failure to thrive, bone marrow failure or characteristic facies. [radiopaedia.org]

  […] to us with hematological abnormalities, failure to thrive and blindness. [wajradiology.org]

  Initial symptoms include failure to thrive, spontaneous bruising, abnormal bleeding, and anemia. Palsies of the 2nd, 3rd, and 7th cranial nerves and hepatosplenomegaly occur later. [msdmanuals.com]

  Osteopetrosis Albers-Schönberg Disease, Marble Bone Disease General Considerations Rare hereditary disorder Defective osteoclast function with failure of proper reabsorption produces sclerotic bone Structurally weak Types Infantile autosomal recessive type Failure [learningradiology.com]

  […] to thrive; growth retardation; proptosis; blindness; deafness; hydrocephalus Infancy Poor Marble bone disease Autosomal recessive Abnormal osteoclastic bone resorption No bone marrow failure; renal tubular acidosis; intracranial calcifications; sensorineural [aafp.org]

• Hepatomegaly

  […] anhydrase 2 deficiency See More Categories: Osteopetrosis refers to a group of rare, inherited skeletal disorders characterized by increased bone density and abnormal bone growth. 0001508 Genu valgum Knock knees 0002857 Global developmental delay 0001263 Hepatomegaly [rarediseases.info.nih.gov]

• Malocclusion

  Phenotype Intermediate form, renal tubular acidosis (typical sign), basal ganglion calcification (typical sign), early fractures, short stature, dental malocclusion, increased bone density (sclerosis) and generalized high bone mass, diaphyseal sclerosis [iofbonehealth.org]

  Dental malocclusion and/or malalignment have been observed in several cases. Cranial nerve compression is a dreaded complication of narrowing of the cranial nerve foramina due to abnormal skull growth and may lead to disabling sequelae. [symptoma.com]

  […] deformity Dental malformations Malformed teeth Misshapen teeth Misshapened teeth [ more ] 0006482 Carious teeth Dental cavities Tooth cavities Tooth decay [ more ] 0000670 Cerebral calcification Abnormal deposits of calcium in the brain 0002514 Dental malocclusion [rarediseases.info.nih.gov]

• Dental Caries

  Disease General Considerations Rare hereditary disorder Defective osteoclast function with failure of proper reabsorption produces sclerotic bone Structurally weak Types Infantile autosomal recessive type Failure to thrive Premature senility in facies Dental [learningradiology.com]

  The main complication in patients with autosomal dominant osteopetrosis type II is osteomyelitis, particularly affecting the mandible in association with dental caries and abscess [12]. [hindawi.com]

  caries One of the commonest presentations is with ocular disturbance: failure to establish fixation, nystagmus or strabismus 4. [radiopaedia.org]

  Some affected individuals may experience delayed tooth development or severe dental caries. [rarediseases.org]

  The patient developed pain in relation to the left mandibular second molar due to dental caries. Extraction was carried out in a private hospital 6 months back, following which the patient experienced pus and blood discharge from the socket. [ijdr.in]

• Prognathism

  Patients with this form have radiographic evidence of disease, short stature, macrocephaly, increased US/LS ratio decreased arm span, mandibular prognathism nerve compression and a tendency for developing fractures and osteomyelitis. [jpgmonline.com]

  Some affected individuals may experience abnormal protrusion of the lower jaw (mandibular prognathism), dental anomalies, baby teeth that do not fall out (deciduous retention), tooth crown malformation, dental caries, and facial paralysis. [rarediseases.org]

  On extraoral examination hypertelorism, exophthalmos, depressed nasal bridge, broad face, and a prognathic mandible were noted. [hindawi.com]

• Abnormal Teeth

  It is clinically characterized by mental retardation, stunted growth and abnormal teeth. [annsaudimed.net]

• Recurrent Fractures

  fractures Increased fracture rate Increased fractures Multiple fractures Multiple spontaneous fractures Varying degree of multiple fractures [ more ] 0002757 Reduced bone mineral density Low solidness and mass of the bones 0004349 Splenomegaly Increased [rarediseases.info.nih.gov]

• Genu Valgum

  […] acidosis; Guibaud Vainsel syndrome; Marble brain disease; Carbonic anhydrase 2 deficiency See More Categories: Osteopetrosis refers to a group of rare, inherited skeletal disorders characterized by increased bone density and abnormal bone growth. 0001508 Genu [rarediseases.info.nih.gov]

• Bone Pain

  Clinical signs include chronic bone pain and disorders of the cranial nerves (trigeminal neuralgia, facial palsy, hearing loss). The risk of fracture is not increased and patients show normal or even increased trabecular bone strength. [orpha.net]

  Patients present in childhood with complaints of bone pains, failure to thrive and growth retardation. Other clinical findings include severe anemia, hepatosplenomegaly, lymphadenopathy and thrombocytopenia. [mss-ijmsr.com]

  The other two (III:2 and IV:4, Figure 2(a)) complained of bone pain. One (III:2, Figure 2(a)) was diagnosed with osteoarthritis of the knees. [journals.sagepub.com]

  Other symptoms of RTA you might notice include: confusion, decreased alertness, or fatigue increased breathing and heart rates decreased urination muscle weakness muscle cramps and pain in the back and abdomen rickets (a disorder that can cause bone pain [kidshealth.org]

  Presentation: Hyperventilation, muscle weakness, cardiac arrhythmias (hypokalaemia) and bone pain (due to rickets or osteomalacia). Renal calculi, recurrent UTI, chronic kidney disease. [patient.info]

• Decrease in Height

  […] body height Small stature [ more ] 0004322 Visual loss Loss of vision Vision loss [ more ] 0000572 Showing of 35 Last updated: 3/1/2020 Making a diagnosis for a genetic or rare disease can often be challenging. [rarediseases.info.nih.gov]

• Long Arm

  This gene is located on the long arm of chromosome 8 and encodes for carbonic anhydrase II, an enzyme catalyzing the hydration of carbon dioxide into bicarbonate and a proton. More than two dozen mutations have been identified in OPTB3 patients. [symptoma.com]

• Narrow Nose

  Patients tend to have characteristic facial features, such as a broad forehead, prominent ears, a narrow nose, and a small mouth with dental anomalies. [symptoma.com]

  Facial appearance characteristically shows broad forehead, prominent narrow nose and slight epicanthic folds.7 The upper lip is relatively thin and the lower lip everted in association with micrognathia. [annsaudimed.net]

• Neonate-Onset

  Symptoms and severity can vary greatly, ranging from neonatal onset with life-threatening complications (such as bone marrow failure) to the incidental finding of osteopetrosis on X-ray. [malacards.org]

  ARO is characterized by neonatal onset with great likelihood of death within the first year of life. [research-journal.net]

  Osteopetrotic conditions vary greatly in their presentation and severity, ranging from neonatal onset with life-threatening complications such as bone marrow failure (e.g., classic or “malignant” ARO) to the incidental finding of osteopetrosis on radiographs [hindawi.com]

• Cerebral Calcification

  Lack of enzyme activity results in osteopetrosis, tubular acidosis, and cerebral calcifications or so-called marble brain disease. [symptoma.com]

  […] in 12 families with the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification. 61 56 Sly WS...Al-Mosawi M 3925334 1985 12 Carbonic anhydrase II deficiency identified as the primary defect in the autosomal [malacards.org]

  This disorder is characterized by a triad of osteopetrosis, renal tubular acidosis, and neurological disorders related to cerebral calcifications. [iofbonehealth.org]

  Osteopetrosis with renal tubular acidosis is a rare disorder characterized by osteopetrosis (see this term), renal tubular acidosis (RTA), and neurological disorders related to cerebral calcifications. [monarchinitiative.org]

  Abstract Osteopetrosis with renal tubular acidosis and cerebral calcification was identified as a recessively inherited syndrome in 1972. [nejm.org]

• Seizure

  In addition, some affected individuals may have seizures due to low blood calcium levels. Intellectual disability (usually mild to moderate) may result from recurrent seizures and/or brain abnormalities that may occur in some individuals with ARO1. [myriadwomenshealth.com]

  The first patient had episodes of seizure and spastic in extremities 2 weeks after birth. Gradually, the patient showed upper and lower respiratory problems and horizontal nystagmus. [ijmcmed.org]

  Depending on severity and age of onset, features may include fractures, short stature, compressive neuropathies (pressure on the nerves), hypocalcemia with attendant tetanic seizures, and life-threatening pancytopenia. [malacards.org]

• Peripheral Neuropathy

  neuropathy 0009830 Thrombocytopenia Low platelet count 0001873 5%-29% of people have these symptoms Optic atrophy 0000648 Visual impairment Impaired vision Loss of eyesight Poor vision [ more ] 0000505 Percent of people who have these symptoms is not [rarediseases.info.nih.gov]

• Average Intelligence

  Nevertheless, this hypothesis may not apply to all variants of CA2: Truncating mutation c.145_148delGTTT (V49fsX) is incompatible with residual enzyme activity and has been detected in a patient of average intelligence. [symptoma.com]

Genetic studies are the gold standard of OPTB3 diagnosis: Any suspicion of OPTB3 should be clarified by determining the underlying mutation in the CA2 gene. Before molecular biological techniques became widely available (and even before the causal gene defect had been identified), the diagnosis of OPTB3 was based on the measurement of carbonic anhydrase II activity [6]. To date, enzyme activity measurements play a tangential role only in the clinical workup of suspected cases, but they maintain their importance in research.

In any case, the rarity of the disease frequently entails a lack of awareness and clinical suspicion, so any possible clues must be gathered beforehand. Most important conclusions can Blood and from familial and personal history, clinical, laboratory and imaging findings:

• Parental consanguinity should raise suspicion as to the presence of recessive hereditary diseases. The medical history of relatives may allow to narrow down the list of differential diagnoses long before the index patient develops the characteristic symptom triad of osteopetrosis, renal tubular acidosis, and cerebral calcifications. Irreversible sequelae may thereby be avoided.
• Blood and urine tests may reveal several metabolic anomalies. Besides metabolic acidosis, hypokalemia, hypocalcemia, hyperchloremia, and alkaline urine are common [2] [5].
• Brain imaging typically reveals intracranial calcifications, preferentially affecting the basal ganglia and periventricular subcortical white matter. Such calcifications usually develop at the age of 2-5 [5]. Osteopetrosis is evidenced by a hyperdense, marble-like skeleton and signs of multiple healed fractures. Furthermore, renal sonography may demonstrate nephrolithiasis [1] [2].

• Parathyroid Hormone Increased

  Differential Diagnoses Hypoparathyroidism Myeloproliferative Disease Lead Toxicity in children Pseudohypoparathyroidism Lab Investigations Decreased calcium Elevated parathyroid hormone Increased acid phosphatase – due to increased release from defective [boneandspine.com]

Symptomatic treatment primarily aims at the correction of metabolic anomalies and alleviation of consequences. In this context, patients are administered sodium bicarbonate, potassium, calcium, and vitamin D according to their individual needs [1] [5]. Blood counts and biochemical parameters are likely to normalize, but irreversible damage to the nervous system will persist. Skeletal anomalies may be ameliorated, but orthopedic problems remain part of most patients' life. Specific interventions may help to resolve these problems, and patients should relationship orthopedic aids, physical therapy, or even surgery. Similarly, bone fractures, nephrolithiasis, and other conditions have to be treated in line with the respective guidelines. OPTB3 patients and their families may also benefit from psychological support.

Allogeneic bone marrow transplantation may be considered to improve osteopetrosis and to delay the development of cerebral calcifications, but is unable to revert neurological damage and has little or no effect on renal tubular acidosis [7]. Accordingly, possible benefits should be carefully weighed up against the risks inherent to this procedure. A mild phenotype and late diagnosis argue against this type of treatment.

OPTB3 is compatible with long-term survival [8]. However, the disease may progress and cause irreversible neurological damage. If OPTB3 is recognized before the final adult height is reached, short stature and skeletal anomalies may somewhat be compensated for by treatment-induced growth, but patients are unlikely to obtain a normal hight and phenotype. In line with these observations, a patient's prognosis largely improves if the disease is recognized early and treatment is provided without interruptions [5].

OPTB3 is caused by mutations in the CA2 gene [6]. This gene is located on the long arm of chromosome 8 and encodes for carbonic anhydrase II, an enzyme catalyzing the hydration of carbon dioxide into bicarbonate and a proton. More than two dozen mutations have been identified in OPTB3 patients [1] [3] [9]. One of them, namely splice site mutation c.232+1G>A at the 5' end of intron 2, has been nicknamed the "Arabic mutation". It has been shown to introduce a new Sau3A1 restriction site and has been linked to a more severe phenotype. In detail, mental retardation was stated to be more pronounced in patients of Arab descent, who are at the same time less likely to suffer from pathological fractures [10]. With regard to non-Arab patients, missense mutation c.319C>T (H107Y) has been identified in several families. This mutation results in the synthesis of carbonic anhydrase II with reduced but measurable enzymatic activity, which may be the cause of the rather mild phenotype. Nevertheless, this hypothesis may not apply to all variants of CA2: Truncating mutation c.145_148delGTTT (V49fsX) is incompatible with residual enzyme activity and has been detected in a patient of average intelligence [9]. Further research is necessary to elaborate on possible correlations between genotype and phenotype, and may include the search for modulating factors of genetic or environmental nature [11].

OPTB3 is a rare entity, with less than 100 cases reported to date. The disease is preferentially diagnosed in the Middle East and Mediterranean region. To date, about two-thirds of confirmed cases involved families of Arab descent [4] [10]. The high incidence of OPTB3 among Arabs is very likely owing to the widespread practice of consanguineous marriage, which allowed for the so-called "Arabic mutation" to be passed on from a common ancestor that settled in the Maghreb in the tenth century and be preserved to the present day [10] [12].

Beyond those patients of Arab origin, OPTB3 has occasionally been diagnosed in a number of European, African, Asian, and American ethnicities.

Carbonic anhydrase II is crucial in the generation of protons by mature osteoclasts. This enzyme actually catalyzes the reversible hydration of carbon dioxide into carbonic acid, which dissociates spontaneously to release protons and bicarbonate. These protons create the acidic environment required for the dissolution of bone minerals in the resorption lacunae. Carbonic anhydrase II deficiency therefore interferes with the physiological cycle of bone remodeling according to the physical demands. Bone formation is normal in OPTB3 patients, which is why signs of fracture healing can be recognized on radiological images. Bone resorption, however, is largely disturbed, which gives rise to diffuse sclerosis involving the skull, spine, ribs, pelvis, and appendicular skeleton [3].

The reabsorption of bicarbonate in proximal and, to a lesser degree, distal renal tubules also depends on the activity of carbonic anhydrase II. The reaction catalyzed by the enzyme takes places on both sides of the tubular membrane. In the lumen of the tubule, bicarbonate and a proton form carbon dioxide and water, and while the latter remains in the lumen, carbon dioxide diffuses into the adjacent cell. Within the cell, the reaction of carbon dioxide with water yields bicarbonate and a proton. Through a sodium-proton exchanger, the proton is returned to the lumen. Bicarbonate, however, leaves the cell via its basolateral membrane. Distinct transporters facilitate this process, such as sodium-bicarbonate symporters and sodium-bicarbonate-carbonate symporters. In sum, this mechanism assures the reabsorption of large shares of bicarbonate and sodium, and it explains why OPTB3 patients develop metabolic acidosis.

Finally, CA2 is expressed in the brain, mainly in glial cells. The molecular mechanisms behind cerebral calcifications and mental retardation remain poorly understood, but anomalies of skull growth may contribute to the latter [11] [13].

Of note, individuals who are heterozygous for pathogenic mutations of the CA2 gene are usually asymptomatic. Enzyme activity levels are about half of reference values but seem to suffice to assure the correct function of osteoclasts, renal tubule cells, and glial cells [6].

In Arab societies, the practice of consanguineous marriage increases the likelihood of homozygosity for pathogenic mutations and thus yields a higher incidence of OPTB3 and other hereditary disorders. Therefore, the first step towards a reduction of these diseases' incidence must be the appropriate education and information of the population. In second place comes the provision of genetic counseling to families known to harbor mutations of the CA2 gene. The identification of carriers is as feasible as the prenatal diagnosis of the disease [9], but both require the patients to have access to the corresponding services.

OPTB3 has first been described in the early 1970s, although its etiology was still unclear when Guibaud and colleagues reported two affected brothers of Northern African origin and Vainsel et al. presented a consanguineous Belgian family with similar signs and symptoms [14] [15]. The identification of the underlying mutation was achieved in 1983 and paved the way towards a better understanding of the molecular mechanisms behind the disease: OPTB3 patients are deficient of carbonic anhydrase II, an enzyme required for the maintenance of the acid-base balance [6]. Carbonic anhydrase II is expressed in a broad spectrum of tissues, e.g., in the skeleton, kidneys, and brain. While its functions in bones and kidneys are well understood, it is not yet clear how carbonic anhydrase II interferes with brain function. Further open questions regard the optimum management of the disease. To date, symptomatic treatment is provided, but carbonic anhydrase cannot be replaced, and most patients do develop some type of permanent damage.

Autosomal recessive osteopetrosis 3 (OPTB3) is also referred to as carbonic anhydrase II deficiency, whereby the latter term refers to the pathogenesis of this disease: OPTB3 patients suffer from the deficiency of an enzyme called carbonic anhydrase II, which is required as a catalyst of biochemical reactions in the bones, kidneys, brain, and other organs. The lack of carbonic anhydrase II is owing to mutations in the CA2 gene. As implied above, the disease is inherited in an autosomal recessive manner, i.e., only patients who inherit defective genes from both of their parents will manifest symptoms. Accordingly, children born to consanguineous parents are much more likely to develop OPTB3.

First symptoms manifest in infancy or childhood. Mental retardation, growth failure, and susceptibility to fractures are commonly observed. They may not be related to OPTB3, which is a very rare disease, until additional signs and symptoms are detected. Patients tend to have characteristic facial features, such as a broad forehead, prominent ears, a narrow nose, and a small mouth with dental anomalies. Abnormal skeletal growth may eventually provoke cranial nerve compression and neurological sequelae such as visual and hearing impairment. Laboratory analyses of blood samples and diagnostic imaging have to be carried out to recognize further hallmarks of the disease, notably metabolic acidosis and cerebral calcifications.

Most of the aforementioned symptoms are due to disease progression and irreversible damage to the nervous system or skeleton. While there is no cure for OPTB3, disease progression can be delayed and disabling consequences may possibly be avoided if the condition is diagnosed and treated early. Indeed, OPTB3 may be diagnosed prenatally, and families known to harbor pathogenic mutations of the CA2 gene are highly recommended to seek genetic counseling before having children.

At the level of society, one of the most effective measures to reduce the incidence of OPTB3 and many, many other hereditary diseases is the avoidance of consanguineous marriage.

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