OPTA1 patients may or may not present characteristic facial features. Most severe osteosclerotic changes are observed in the skull and may be associated with an enlargement of the cranial vault and mandibles. Torus palatinus has also been described [1] [2]. Regardless of the external appearance, the progressive thickening of the cranial bones may provoke sequelae such as increased intracranial pressure and neurological deficits. Although most patients remain asymptomatic until adulthood, symptom onset in childhood or adolescence has been reported [2] [3] [4].

Visual and hearing impairment are among the most common presenting symptoms, and patients may develop blindness or deafness [4] [5] [6]. Trigeminal and facial neuralgia have been described, too [7]. Patients may claim headaches, backaches, or bone pain, which is not necessarily restricted to the head. Severe pain may also originate from an osteomyelitis of the jaw. Others may vomit, present exophthalmos and papilledema [4]. In general, symptoms may develop acutely or be of insidious onset, whereby the latter often causes long delays in seeking health care [6].

The relative sparing of the appendicular skeleton, the spinal column, and rib cage is likely to account for the low incidence of pathological fractures in OPTA1 patients. While other types of hereditary osteoporosis present with an increased susceptibility to fractures, this does not apply to OPTA1 [5]. Likewise, bone marrow failure and ensuing hematological anomalies are not features of OPTA1.

• Anemia

  There may be obliteration of the marrow spaces, causing anemia. [medical-dictionary.thefreedictionary.com]

  It manifests with deformities, fractures, hepatosplenomegaly, anemia, and extramedullary hematopoiesis. [ncbi.nlm.nih.gov]

  Recessive osteopetrosis commonly manifests in early infancy with macrocephaly, feeding difficulties, evolving blindness and deafness, bone marrow failure, severe anemia, and hepatosplenomegaly. [nectarmutation.org]

  Phenotype Most patients are asymptomatic, although some may have mild anemia due to narrowed medullary. [iofbonehealth.org]

• Recurrent Infection

  Affected individuals also have a malfunctioning immune system (immunodeficiency), which allows severe, recurrent infections to develop. [ncbi.nlm.nih.gov]

  Other presentations include failure to thrive and recurrent infection, both secondary to the underlying anaemia and bone marrow involvement. [adc.bmj.com]

  Infants with MIOP have failure to thrive and are prone to recurrent infections. [1], [3] Our patient had gained only 0.5 kg weight over the period of 4 months since birth. A variety of radiological signs has been described in the literature. [wajradiology.org]

• Failure to Thrive

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

  pancytopenia; bleeding; infection; failure 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 [aafp.org]

  FAILURE TO THRIVE Failure to thrive is seen in many osteopetrotic children and is a result of the chronic anaemia, feeding problems caused by bulbar nerve involvement, nasal congestion, and recurrent infections.4 9 19 20 Many children require nasal gastric [adc.bmj.com]

• Vomiting

  Others may vomit, present exophthalmos and papilledema. In general, symptoms may develop acutely or be of insidious onset, whereby the latter often causes long delays in seeking health care. [symptoma.com]

• Hepatosplenomegaly

  Recessive osteopetrosis commonly manifests in early infancy with macrocephaly, feeding difficulties, evolving blindness and deafness, bone marrow failure, severe anemia, and hepatosplenomegaly. [nectarmutation.org]

  Extramedullary hematopoiesis leads to hepatosplenomegaly. [1] The extramedullary hematopoiesis leading to hepatosplenomegaly was noted in the index patient. [wajradiology.org]

  […] marble bones. os·te·o·pe·tro·sis ( os'tē-ō-pe-trō'sis ), [MIM*166600] Excessive formation of dense trabecular bone and calcified cartilage, especially in long bones, leading to obliteration of marrow spaces and to anemia with myeloid metaplasia and hepatosplenomegaly [medical-dictionary.thefreedictionary.com]

  It manifests with deformities, fractures, hepatosplenomegaly, anemia, and extramedullary hematopoiesis. [ncbi.nlm.nih.gov]

• Visual Impairment

  Only a small number of these are associated with anaemia and visual impairment.10Dysosteosclerosis is a very rare condition which can present with a very similar phenotype to osteopetrosis. [adc.bmj.com]

  Other symptoms include: Low levels of calcium (which can cause seizures) Pressure on the optic nerve in the brain (leading to visual impairment or blindness) Hearing loss facial paralysis Frequent bone fractures This form of osteopetrosis is rare, affecting [verywell.com]

  However, the father denied having any complaints including history of fracture, osteomyelitis, visual impairment and hearing problem. Radiographs of his bones were also normal (Figure 1D). [jcrpe.org]

  Visual impairment and central nervous system involvement is rare in autosomal dominant osteopetrosis type II [12]. Severe visual loss was reported in 19% of the patients by Waguespack et al. [21]. [hindawi.com]

• Visual Impairment

  Only a small number of these are associated with anaemia and visual impairment.10Dysosteosclerosis is a very rare condition which can present with a very similar phenotype to osteopetrosis. [adc.bmj.com]

  Other symptoms include: Low levels of calcium (which can cause seizures) Pressure on the optic nerve in the brain (leading to visual impairment or blindness) Hearing loss facial paralysis Frequent bone fractures This form of osteopetrosis is rare, affecting [verywell.com]

  However, the father denied having any complaints including history of fracture, osteomyelitis, visual impairment and hearing problem. Radiographs of his bones were also normal (Figure 1D). [jcrpe.org]

  Visual impairment and central nervous system involvement is rare in autosomal dominant osteopetrosis type II [12]. Severe visual loss was reported in 19% of the patients by Waguespack et al. [21]. [hindawi.com]

• Hearing Impairment

  While nerve damage leading to vision loss and impaired hearing is largely irreversible, OPTA1 patients have a normal life expectancy. [symptoma.com]

  Researchers often refer to this condition as OL-EDA-ID, an acronym derived from each of the major features of the disorder. https://ghr.nlm.nih.gov/condition/osteopetrosis From HPO Conductive hearing impairment MedGen UID: 9163 •Concept ID: C0018777 • [ncbi.nlm.nih.gov]

  impairment Conductive deafness Conductive hearing loss [ more ] 0000405 Generalized osteosclerosis 0005789 Headache Headaches 0002315 Osteopetrosis Harder, denser, fracture-prone bones 0011002 Thickened calvaria Increased thickness of skull cap Thickened [rarediseases.info.nih.gov]

• Hypertelorism

  A syndrome characterized by Noonan dysmorphic features such as macrocephaly, high forehead, hypertelorism, palpebral ptosis, low-set and posteriorly rotated ears, short and webbed neck, pectus anomalies, in association with pluckable, sparse, thin and [nectarmutation.org]

  Figure 2: Facial appearance with lower hyperplasic jaw, restricted temporomandibular joint, obliterated nasal passage, mandibular abnormalities with hypoplasia, macrocephaly, and hypertelorism Click here to view The equipment for difficult airway management [aeronline.org]

  Symptoms that affect the eyes may include wasting away (atrophy) of the retina, eyes that appear widely spaced (hypertelorism), eyes that protrude from their orbits (exophthalmos), cross-eyes (strabismus), involuntary rhythmic movements of the eyes (nystagmus [rarediseases.org]

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

• Neonatal 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]

  onset with life-threatening complications (such as bone marrow failure) to the incidental finding of osteopetrosis on X-ray. [rarediseases.info.nih.gov]

• Neonatal Seizures

  Seizures 1 1 Benign Familial Neonatal-Infantile Seizures 2 Benign Hereditary Chorea 1 Benign Recurrent Intrahepatic Cholestasis 1 2 Benign Recurrent Intrahepatic Cholestasis 2 2 Benign Scapuloperoneal Muscular Dystrophy With Cardiomyopathy 2 Bent bone [preventiongenetics.com]

A thorough anamnesis may help to draw a clearer picture with regard to the patient's medical and family history, provide important clues as to the underlying disorder. Symptom onset may have occurred years ago, but the link between past and current symptoms is easily overlooked [6]. Reports about similar symptoms in close relatives suggest a hereditary condition and may complement the idea of the disease' clinical presentation. In any case, diagnostic imaging is indicated to shed more light on the causes of clinical findings, while asymptomatic patients are typically identified when imaging is realized for non-related reasons [3] [5].

Radiological studies form the basis of OPTA1 diagnosis. Images usually show enhanced density of the cranial vault and thickened mandibles, whereas the bone density in the appendicular skeleton may be increased or within normal ranges [2]. Thickening of the cortices of the long bones has repeatedly been described, but OPTA1-related structural anomalies don't predispose to pathological fractures. Diagnostic imaging also reveals the causes of specific neurological deficits, such as vision and hearing loss. They are related to the obturation of the optical and auditory canals [6].

Finally, the tentative diagnosis of OPTA1 should be confirmed by means of genetic studies. The clinical differentiation of OPTA1 from other types of autosomal dominant osteopetrosis poses a major challenge, so patients are often screened for mutations in the LRP5 and CLCN7 genes.

• Increased Bone Density

  Overview A very rare dominantly inherited syndrome characterized mainly by increased bone density. The increased bone density results because old bone is not resorbed and replaced with new bone. Only 33 cases in 3 families have been reported. [checkorphan.org]

  […] iliac wings and near the ends of the long bones, and increased skull base density. [iofbonehealth.org]

  NIH Rare Diseases : 52 Osteopetrosis refers to a group of rare, inherited skeletal disorders characterized by increased bone density and abnormal bone growth. [malacards.org]

  The osteopetroses are a heterogeneous group of genetic disorders characterized by increased bone density due to impaired bone resorption by osteoclasts. [ncbi.nlm.nih.gov]

Owing to the benign nature of OPTA1, patients are provided supportive care and are not candidates for hematopoietic stem cell transplantation. What's more, given that the pathogenic defect is on the formative side of bone remodeling, the phenotype could not be reversed by this procedure. When deciding upon the optimum treatment regimen, the side effects of pharmacotherapies have to be taken into account. Glucocorticoids and glitazones, for instance, have been shown to diminish bone formation and promote bone resorption, but secondary effects to be expected during long-term treatment render them unacceptable for the management of OPTA1 [8].

The attenuation of the overactive Wnt cascade may possibly be achieved by applying inhibitors of LDL-receptor-related protein 5 or downstream elements of the signaling pathway. With regard to the former, patients may present with increased levels of sclerostin, without it being able to attach to the degenerated binding site of the receptor. Allosteric inhibitors might overcome this issue but have not yet been identified. Downstream components of the Wnt pathway have been proposed as alternative drug targets to achieve a regulated response on bone homeostasis, with further research being required to identify bone-specific targets. On the other hand, bone resorption may be stimulated by the administration of RANKL or parathyroid hormone, but long-term studies on the safety and efficacy of such strategies have not yet been conducted. Beyond pharmacotherapy, bed rest may aid to reduce bone formation and thus alleviate symptoms [8].

OPTA1 follows a progressive but usually mild course. Most patients are incidentally diagnosed before the onset of symptoms. Notwithstanding, more severe phenotypes have been described. Irreversible neurological damage may result in permanent vision or hearing loss, and treatment options for chronic headaches and other symptoms are limited. OPTA1 does not affect a patient's life expectancy.

OPTA1 is inherited in an autosomal dominant manner and is caused by mutations in the LRP5 gene. This gene, which is located at 11q13.2 and expressed in osteoblast-lineage cells, encodes for LDL-receptor-related protein 5 [9]. It localizes to the cell surface, where it binds and internalizes ligands in the process of receptor-mediated endocytosis. Distinct LRP5 mutations have been related to the disease, and they cluster in an open binding pocket near the surface of the first β-propeller of this protein's extracellular domain, a region of importance for binding inhibitory proteins [8]. Several missense mutations have been determined in OPTA1 patients, as well as a single in-frame deletion [2] [3] [6]. OPTA1 has been stated to be a fully penetrant disease [5].

LRP5 mutations have also been implied in other diseases related to abnormal bone remodeling, such as autosomal dominant osteosclerosis, endosteal hyperostosis, and van Buchem disease type 2. Patients suffering from primary osteoporosis or osteoporosis-pseudoglioma syndrome may similarly carry pathogenic variants of this gene [10]. In general, loss-of-function mutations give rise to low-bone-mass phenotypes, while any gain of function may induce osteosclerotic changes as observed in OPTA1. Genetic dichotomy, however, does not explain for the broad spectrum of phenotypes within either group of disorders. The presence of other factors, be them genetic or environmental, is likely to affect the expressivity and course of the disease [1] [8].

The overall incidence of hereditary osteopetrosis has been estimated at 5.5 in 100,000 live births [7]. It is generally assumed that most of these cases correspond to OPTA2, whereas OPTA1 and autosomal recessive osteopetrosis are considered rare entities. However, both OPTA1 and OPTA2 are most likely underdiagnosed. Many patients are diagnosed incidentally, while others may remain asymptomatic throughout life.

OPTA1 has been diagnosed in patients originating from distinct parts of the world and has been stated to affect men and women alike.

LRP5 and its gene product play key roles in skeletal homeostasis. LDL-receptor-related protein 5 is involved in Wnt/β-catenin signaling, and its activity is modulated by agonists, namely by Wnts, and antagonists, like DKK1 and sclerostin [9]. In the absence of agonists, intracellular β-catenin remains bound to a protein complex awaiting its degradation in the proteasome, but β-catenin is released from this complex upon the activation of LDL-receptor-related protein 5. It can then translocate to the nucleus, bind to transcription factors of the TCF/LEF family and influence gene expression [8].

Compounds like DKK1 and sclerostin bind to the functional protein and inhibit signaling through the Wnt pathway. In OPTA1 patients, though, antagonist binding to LDL-receptor-related protein 5 is largely impaired, giving rise to a gain of function and constitutive activity of the downstream signaling cascade [1]. Gene expression control by β-catenin, which is essential to the regulation and limitation of osteoblastogenesis, fails, with the cadherin-associated protein permanently contributing to the proliferation and survival of osteoblasts [9]. Accordingly, bone formation is pathologically increased, and patients develop osteopetrosis.

Minor alterations in bone resorption have been assumed to add to this phenotype. One hypothesis as to the underlying mechanism is that the stabilization and accumulation of β-catenin may lead to excessive secretion of osteoprotegerin. This osteoblast-derived protein is also referred to as osteoclastogenesis inhibitory factor and may hinder bone resorption in OPTA1 [8].

Families known to harbor pathogenic mutations of the LRP5 gene may be offered genetic counseling. As-of-yet asymptomatic carriers can be identified, including, but not limited to, unborn children within the setting of prenatal diagnosis. Unfortunately, though, few recommendations can be given to prevent or delay symptom onset in those carriers. Novel therapies would have to be developed to this end.

Decades ago, the distinction of two types of autosomal dominant osteopetrosis has been proposed based on the corresponding radiological findings [11]. On the one hand, patients presented with a pronounced sclerosis of the cranial vault and thickening of the mandibles. Others were found to have sclerotic changes mainly at the base of the skull, so-called "sandwich vertebrae" forming a "rugger jersey spine", and pelvic "bone within a bone". The first description corresponds to OPTA1; the latter variant of the disease has been designated autosomal dominant osteopetrosis type 2 (OPTA2). More recently, the underlying gene defects have been detected in the LRP5 and CLCN7 genes, respectively [2] [12].

OPTA1 is different from other types of hereditary osteoporosis, from OPTA2 and recessive variants, in that it does not result from disorders of osteoclast differentiation, maturation, or function. Indeed, some authors argue OPTA1 should therefore no longer be considered a "true form" of osteopetrosis [13] [14]. In line with the former, patients with OPTA1 are not to be diagnosed with Albers-Schönberg disease. The latter term is now reserved for OPTA2, the first described and more common variant of autosomal dominant osteopetrosis.

Autosomal dominant osteoporosis type 1 (OPTA1) is a rare disease. It is caused by mutations in the LRP5 gene and is inherited in an autosomal dominant manner, i.e., an affected individual has a 50% chance of having an affected child with each pregnancy. Notwithstanding, most patients are unaware of their condition. OPTA1 does not usually manifest until adulthood, and the majority of patients is identified when diagnostic imaging is realized for non-related reasons. Images of the head are particularly revealing: OPTA1 is characterized by increased density of the cranial vault and thickened mandibles. Enhanced bone density may also be recognized in other parts of the skeleton, albeit to a lesser extent.

In rare cases, excessive bone tissue interferes with the function of the brain, cranial nerves, and other structures. The obturation of the optical and auditory canals may result in visual and hearing impairment, and the compression of the trigeminal or facial nerves may provoke pain. Furthermore, OPTA1 patients may develop increased cranial pressure, suffer from recurrent headaches and vomiting. With regard to the appendicular skeleton, backaches and bone pain have been reported. The causes of severe phenotypes could not yet be clarified. Most likely, additional genetic and environmental factors affect the course of the disease.

Causal treatment is not available, hence patients are provided supportive care. Milder forms of the disease may not require any treatment at all, while pharmacological therapies are indicated to relieve those symptoms described in the previous paragraph. Optimum treatment regimens are designed according to the needs of the individual patients and aim at maintaining their quality of life. While nerve damage leading to vision loss and impaired hearing is largely irreversible, OPTA1 patients have a normal life expectancy.

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