Omenn syndrome (OS) is an inflammatory condition characterized by erythroderma, desquamation, alopecia, chronic diarrhea, failure to thrive, lymphadenopathy, and hepatosplenomegaly, associated with severe combined immunodeficiency (SCID; see this term).

Summary:
Epidemiology
Prevalence is unknown.
Clinical description
OS presents during the first year of life with features of SCID including chronic diarrhea, pneumonitis and failure to thrive. In addition, patients present with inflammatory symptoms including lymphadenopathy, hepatosplenomegaly and generalized erythroderma, which may often cause alopecia and loss of eyebrows and eyelashes; protein loss may lead to generalized edema and metabolic disturbances. The signs and symptoms of OS can evolve over time and may not appear simultaneously. Some patients present with some but not all of these symptoms and may be described as having atypical Omenn syndrome. OS may also be associated with syndromic disorders including cartilage-hair hypoplasia (CHH), adenosine deaminase (ADA) deficiency, monosomy 22q11, coloboma of the eye, CHARGE syndrome and ligase 4 deficiency (see these terms).
Etiology
OS is not caused by a defined genetic defect. Rather than a distinct form of SCID, it is a distinct inflammatory phenotype that can be associated with genetically diverse SCIDs. The majority of cases reported to date have hypomorphic mutations in RAG1 and RAG2 genes (11p13). The other cases have mutations in the RMRP, ADA, IL2RG, IL7RA, DCLRE1C, CHD7 and LIG4 genes (9p21-p12, 20q13.11, Xq13, 5p13, 10p, 8q12.2 and 13q22-q34).
Diagnostic methods
OS may pose a diagnostic challenge because lymphocyte counts may be normal or high, unlike in typical SCID. Diagnosis is based on inflammation with evidence of abnormal expansion of one or more T-cell clones in peripheral blood and tissue, skin biopsies showing acanthosis and parakeratosis on staining with hematoxylin and eosin, evidence of dysplastic thymus with few remnant lymphoid cells and lymphadenopathy. Typically B cells are absent, as are immunoglobulins apart from IgE which is often raised. Eosinophilia is also observed.
Differential diagnosis
Differential diagnoses include graft-versus-host disease, histiocytosis, Job syndrome, Netherton syndrome, and severe combined immunodeficiencies (see these terms), particularly those associated with maternal T-cell engraftment.
Antenatal diagnosis
OS is not a single genetic disorder, but if the causative gene is identified in the index patient, prenatal diagnosis may be offered, although subsequent individuals are likely to have SCID.
Genetic counseling
Transmission is autosomal recessive.
Management and treatment
Initial treatment is based on immunosuppressive drugs including prednisone and cyclosporin followed by hematopoietic stem cell transplantation, in a centre recognized as treating such disorders ideally using HLA-identical family donors or, if this is not available, other appropriate donors after use of appropriate conditioning regimens.
Prognosis
If untreated, prognosis is poor and the disease is fatal. Skin inflammation worsens with time leading to severe barrier problems that facilitate life-threatening and overwhelming bacterial and fungal infections in already severely immunocompromised patients. Viral infections are most severe and life-threatening. Survival rates with treatment have been reported as greater than 80%.

                            Last update:
                            July 2012

                            - Expert reviewer(s):
                            Pr Andrew GENNERY


Omodysplasia is a rare skeletal dysplasia characterized by severe limb shortening and facial dysmorphism. Two types of omodysplasia have been described: an autosomal recessive or generalized form (also referred to as micromelic dysplasia with dislocation of radius) marked by severe micromelic dwarfism with predominantly rhizomelic shortening of both the upper and lower limbs, and an autosomal dominant form in which stature is normal and shortening is limited to the upper limbs.

Summary:
Epidemiology
In total, less than 40 cases of omodysplasia have been described in the literature so far, with the majority of reported cases concerning the autosomal recessive form of the disease.
Clinical description
The facial dysmorphism is characterized by frontal bossing, a depressed nasal bridge with a short nose and a long and prominent philtrum. Decreased mobility of the elbows and knees is also a common feature. Other less frequent manifestations include midline hemangiomas, congenital heart defects, craniosynostosis and cryptorchidism in males.
Etiology
The etiology remains unknown but a paternally-inherited paracentric inversion of 15q13 to q21.3 has been detected in one family.
Diagnostic methods
Diagnosis is based on the clinical and radiological phenotype with major radiological findings including shortening and club-like tapering of the humeri and femora, proximal radioulnar diastasis and proximal radial head dislocation. Although the hands are generally considered to be normal in omodysplasia, short first metacarpals have been reported in the majority of patients with the autosomal dominant form.
Differential diagnosis
The differential diagnosis for the autosomal recessive form should include diastrophic dysplasia, atelosteogenesis and Larsen syndrome (see these terms), whereas the major differential diagnosis for the autosomal dominant form is Robinow syndrome (see this term).
Antenatal diagnosis
For affected families, detection of long bone anomalies by ultrasonography may allow prenatal diagnosis as early as at 13 weeks of gestation.
Genetic counseling
Genetic counseling should be recommended.
Management and treatment
Treatment is symptomatic only, involving mainly orthopedic management for recurrent joint dislocation.
Prognosis
The prognosis is variable.

                            Last update:
                            November 2008

                            - Expert reviewer(s):
                            Dr Martine LE MERRER


Omphalocele syndrome, Shprintzen-Goldberg type

ShprintzenGoldberg omphalocele syndrome is a very rare inherited malformation syndrome characterized by omphalocele, scoliosis, mild dysmorphic features (downslanted palpebral fissures, s-shaped eyelids and thin upper lip), laryngeal and pharyngeal hypoplasia and learning disabilities.


Omphalocele-diaphragmatic hernia-cardiovascular anomalies-radial ray defect syndrome

A rare multiple congenital anomalies/dysmorphic syndrome characterized by a large omphalocele containing liver and small intestine, diaphragmatic hernia, cardiovascular anomalies (e. g. aortic coarctation), variable limb malformations (including radioulnar synostosis, agenesis of the radius and/or thumb, generalized syndactyly, and numerical reduction of toes), and dysmorphic facial features. Additional reported manifestations are unilateral absence of umbilical artery, intestinal malrotation, hypoplastic ovaries, and unilateral renal agenesis, among others. The condition is mostly fatal in the neonatal period.


A rare, non-syndromic, abdominal wall malformation characterized by a hernia of the abdominal wall, centered on the umbilical cord, in which the protruding viscera are protected by a sac.

Summary:
Epidemiology
In Europe, the prevalence at birth of omphalocele (isolated and syndromic forms combined) is estimated at about 1/8,000 births. At least half of patients have other abnormalities associated.
Clinical description
Omphalocele occurs very early in development and is typically detected prenatally. The hernia occurs at the umbilical ring allowing protrusion of the abdominal organs (midgut, liver, spleen and gonads) through the umbilical cord. The protruding viscera is encased in a sac consisting of three layers: the outer amniotic layer, a middle layer of Wharton's jelly and the inner peritoneal layer. The defect is classified based in the predominant location (epigastric, umbilical or hypogastric) and further classified into small, giant and ruptured. A small omphalocele is less than 5 cm with a sac that may contain a few intestinal loops. A giant omphalocele is greater than 5 cm with a whole or large part of the liver and bowel protruding. Membrane rupture, resulting in evisceration, can occur in utero, during delivery or postnatally, although it is a rare complication. Almost half of patients with omphalocele have other malformations associated, including cardiac, gastrointestinal, genitourinary, musculoskeletal and central nervous system malformations.
Etiology
While the exact pathogenic mechanism of omphalocele is unknown, there is a wide consensus that it is due to the defective closure of the abdominal wall in the embryo before 9 weeks of gestation.
Diagnostic methods
Diagnosis is usually made before birth by ultrasound, and can be detect as early as 11 to 14 weeks gestation in tertiary level referral centers. Associated malformations can then be sought for and management of the infant can be timely prepared in specialized units.
Differential diagnosis
Differential diagnosis includes gastroschisis, especially when the covering sac is damaged, and other celosomias that can be associated. Omphalocele can be part of polymalformative syndromes including Beckwith-Wiedemann syndrome, and trisomy 13, 18 or 21.
Antenatal diagnosis
Prenatal diagnosis is usually made in the first trimester. Fetal karyotype must then be assessed, and accurate screening for associated malformations has to be repeated along pregnancy.
Management and treatment
Management is surgical and aims to close the abdominal opening and return the protruding viscera to the abdomen. Various techniques can be applied when primary closure is not possible.
Prognosis
The prognosis for isolated omphalocele depends on the size of the defect; prognosis for small omphalocele is very good; however, giant omphalocele have a risk of pulmonary hypoplasia. Recent improvements to resuscitation and surgical techniques (through abdominal prostheses) have notably improved the prognosis of giant isolated omphaloceles, who present with some degree of pulmonary hypoplasia, over the last three decades. In syndromic cases, the main prognostic factor is the associated anomalies, especially cardiac defects.

                            Last update:
                            March 2020

                            - Expert reviewer(s):
                            Dr Sylvie BEAUDOIN


A rare non-syndromic diaphragmatic or abdominal wall malformation, a remnant of omphalomesenteric duct, characterized by cuboidal or columnar epithelium with gastrointestinal differentiation. Patients may be asymptomatic or present with infraumbilical mass, umbilical lesion with secretions, abdominal pain, hernia, abscess, gastrointestinal tract bleeding, intestinal obstruction, and acute abdomen.


Omsk hemorrhagic fever (OHF), caused by Omsk hemorrhagic fever virus (OHFV), is a zoonotic disease characterized by fever, nausea, myalgia and moderately severe hemorrhagic manifestations as well as in some cases meningitis, pneumonia and nephrosis.


A form of filariasis, caused by the parasitic worm  Onchocerca volvulus, transmitted by the black fly. The infection can either be asymptomatic or manifest as an ocular disease (river blindness) with itchy eyes, erythema, photophobia, onchodermatitis or onchocercal skin disease (classified into acute papular, chronic papular, lichenified, atrophic, and depigmentated) and onchocercomas (over bony prominences). Other classic clinical manifestations are ichthyosis-like lesions (''lizard skin'') and ''hanging groin'', which may be associated with lymphadenopathy.


A rare paraneoplastic syndrome characterized by renal phosphate wasting and bone demineralization due to a phosphaturic mesenchymal tumor of the mixed connective tissue variant. It causes osteomalacia in adults with bone pain and pathological fractures, and rickets in children.

Summary:
Epidemiology
The prevalence of the disease is not known. Since the association between phosphate reabsorption and tumor was first made, approximately 400 cases of oncogenic osteomalacia have been reported in the literature.
Clinical description
Disease onset typically is in adulthood, with mean age of 45 years of age, although a few pediatric cases have been reported. Typical features are chiefly related to chronic hypophosphatemia caused by hyperphosphaturia. The causative tumors are typically small and benign, occur in either bone or soft tissue, and cause no local symptoms. Patients usually present with symptoms of isolated hypophosphatemia. This means that the diagnosis is usually made late, and even when it is, the tumors are often not found. Typically, both calcium and parathyroid hormone levels are normal, as is the serum 25 hydroxyvitamin D (25OH vitamin D) concentration. Osteomalacia causes bone pain and can lead to pathological fractures or rickets in young patients where the epiphyses have not matured. Severe hypophosphatemia can cause muscle weakness.
Etiology
This syndrome is caused by phosphatonin secretion by the causative tumor. Classically the phosphatonin is FGF-23 (Fibroblast Growth Factor 23), other phosphatonins (Matrix Extracellular Phosphoglycoprotein - MEPE and secreted frizzled-related protein 4 - sFRP4) appear to have the same biochemical effect, and were, in fact discovered by examination of patients with these tumors. FGF-23 causes urinary phosphate wasting by downregulating the main renal phosphate reabsorption transporter, the type 2 sodium-phosphate cotransporter (NaPi2a), localized in the proximal tubule. FGF-23 overexpression may also affect bone mineralization by suppressing osteoblast differentiation.
Diagnostic methods
The finding of isolated hypophosphatemia, urinary phosphate wasting in the absence of the renal Fanconi syndrome and without hereditary hypophosphatemic rickets, should prompt the search for a causative tumor. As these mesenchymal tumors generally express somatostatin receptors, they can be demonstrated by somatostatin/octreotide scanning. All imaging should be whole body (vertex to toes).
Differential diagnosis
Differential diagnosis may include other forms of hypophosphatemic osteomalacia (X-linked, autosomal dominant or recessive hypophosphatemic rickets) as well as primary or acquired renal Fanconi syndrome.
Management and treatment
Definitive treatment is with surgical resection of the tumor. If the tumor cannot be found or removed, medical treatment involves the supplementation of phosphate and active vitamin D (e.g. alfacalcidol). Radiotherapy may be helpful if the tumor is located but is non-resectable for anatomical reasons. A new anti-FGF23 monoclonal antibody has been promising in the treatment of X-linked hypophosphatemic rickets, and may therefore be effective in FGF-23 mediated oncogenic osteomalacia; however, this remains to be proven.
Prognosis
Excellent recovery after complete tumor excision with complete resolution of symptoms and biochemical abnormalities. Long term monitoring is required as local recurrence and metastases have been reported, even if rarely.

                            Last update:
                            May 2019

                            - Expert reviewer(s):
                            Dr Laura CESCA  - Pr T. [Tom] NIJENHUIS | ERKNet* - Dr Stephen WALSH | ERKNet*

                                * European Reference Network


A rare, benign, nail tumor originating in the nail matrix characterized by localized pachyonychia and variable degrees of pigmentation: pigmented, melanocytic (common, longitudinal melanonychia that may simulate a foreign body) or hypopigmented. Histopathology demonstrates a purely epithelial tumor with endokeratinization in the deep portion and concentrically arranged nests of prekeratogenous and keratogenous cells.


Onychomatricoma is a rare, benign nail tumor originating in the nail matrix characterized by localized or diffuse thickening of the nail plate, increased transverse or longitudinal overcurvature, a yellow longitudinal band of variable width, swelling of the proximal nail fold, multiple splinter hemorrhages and the presence of honeycomb-like cavities in the distal margin of the nail plate. Nail dystrophy and dorsal pterygium may be associated. Occasionally, a pigmented lesion has been reported.


Open spinal dysraphism with a myelomeningocele

A rare form of spina bifida cystica (saccular, open neural tube defect (NTD)) characterized by a non-neurulated spinal cord (neural placode) on the surface of the cystic extension of dysplastic meninges (non-epidermised posterior meningocele). The spinal cord extends through a spina bifida (posterior vertebral defect) with typically everted or parallel laminae. Nerve roots are connected to the borders of the neural placode and are visible inside the sac. Myelomeningocele is characteristically associated with a Chiari II malformation. It can be either isolated or associated with split cord malformation.


A rare neural tube closure defect characterized by a skin defect with exposed neural tissue in the area of the spinal column, with or without a protruding sac at the location of the defect. Signs and symptoms are variable depending on the content (only meninges or also spinal cord tissue), location, and severity of the lesion, but may include motor, sensory, and/or sphincter dysfunction, hydrocephalus, and/or skeletal anomalies (e. g. scoliosis, hemivertebrae), among others.


Ophthalmomandibulomelic dysplasia is characterized by complete blindness due to corneal opacities, difficult mastication due to temporomandibular fusion and anomalies of the arms.

Summary:
Epidemiology
Three cases in one family have been described so far (two males, one female).
Clinical description
Micrognathia, shortening and bowing of the forearm, ulnar deviation and bowed radius, short fibula, genu valgum and coxa vara have been reported. Intelligence is normal.
Etiology
The causative gene has not yet been identified.
Genetic counseling
Autosomal dominant inheritance has been suggested.

                            Last update:
                            November 2009


Ophthalmoplegia-intellectual disability-lingua scrotalis syndrome

A rare, genetic, syndromic intellectual disability disorder characterized by congenital, external, nuclear ophthalmoplegia, lingua scrotalis, progressive chorioretinal sclerosis and intellectual disability. Bilateral ptosis, bilateral facial weakness, Parinaud's syndrome, convergence paresis and myopia may be associated. There have been no further descriptions in the literature since 1975.


A rare X-linked congenital midline malformation syndrome characterized by hypertelorism, laryngo-tracheo-esophageal defects and hypospadias.

Summary:
Epidemiology
Whilst epidemiological data is limited, the prevalence of X-linked Optiz GBBB syndrome (GBBB) has been suggested to range from 1/50,000 to 1/100,000. Males are more severely affected. More than 150 patients are reported with MID1 mutation. The clinical diagnostic is unreliable in older literature due to phenotypic confusion.
Clinical description
GBBB syndrome usually presents with characteristic facial dysmorphism: prominent forehead, hypertelorism (>95% of cases) and telecanthus, cleft lip/palate (50%), broad nasal bridge, broad nasal tip and anteverted nares. Malformations include hypospadias (80%), imperforate or ectopic anus (20%), laryngeal cleft (50%), dysphagia, reflux and other esophageal problems (30%) and, less commonly, congenital heart malformations (20%) and agenesis of the corpus callosum or hypoplasia of the vermis. Developmental delay or intellectual deficiency (ID) affect one-third of males. Female carriers mostly show only hypertelorism (>90%) and rarely other manifestations. A mild form of GBBB has been reported in a single family with a MID2 variant.
Etiology
Opitz GBBB is caused by mutations in the MID1 gene (Xp22) encoding the midline-1 protein which is an ubiquitin E3 ligase associated with microtubules. The original report described two distinct X-linked midline defects either with (G syndrome) or without (BBB syndrome) laryngeal malformations. Both phenotypes were later assigned to the same gene, without genotype/phenotype correlation; a wide variability in clinical manifestations is noted even among patients harboring the same mutation.
Diagnostic methods
Opitz GBBB syndrome is suspected on clinical findings: boy with ocular hypertelorism and at least one other of the major findings (hypospadias or laryngo-tracheoesophageal abnormalities). Diagnosis is confirmed by identification of a MID1 mutation.
Differential diagnosis
SPECC1L syndrome (Teebi hypertelorism syndrome) is the main differential diagnosis of GBBB syndrome. SPECC1L syndrome has strikingly overlapping craniofacial phenotype, leading to confusion in the past literature between MID1-confirmed GBBB and various overlapping conditions. Earpits, uterine malformations, omphalocoele, diaphragmatic herniae and, rarely, craniosynostosis and aortic root dilation are specific to SPECC1L, whereas laryngeal and anorectal defects are specific to GBBB. ID is more common in the latter. Further nosologic confusion came from exceptional observation of ''BBBG-like'' phenotype in patients with 22q11.2 deletion syndrome. Baraitser-Winter cerebrofrontofacial syndrome (ACTB and ACTG1), craniofrontonasal dysplasia (EFNB1), frontonasal dysplasia and Aarskog syndrome (FGD1) share marked hypertelorism.
Antenatal diagnosis
Prenatal testing is possible for at-risk pregnancies if a MID1 mutation has been identified in a family member.
Genetic counseling
The pattern of inheritance is X-linked. Genetic counseling is recommended for young adults who are affected, are carriers, or are at risk of being carriers. Where the female is the carrier, there is a 50% risk of future male offspring being affected and a 50% risk for future female offspring to be a carrier. For affected males, future male offspring are always unaffected, whereas future female offspring are always a carrier.
Management and treatment
Multidisciplinary medical support with a pediatrician, craniofacial, ENT (ear, nose and throat) and urologic surgeons, cardiologist, and medical geneticist is required. Neurodevelopmental support and speech therapy may be necessary.
Prognosis
Prognosis is variable but usually favorable, depending on the severity of malformations and associated ID.

                            Last update:
                            November 2020

                            - Expert reviewer(s):
                            Pr Alain VERLOES | ITHACA*

                                * European Reference Network


Opsismodysplasia is a skeletal dysplasia characterized by congenital dwarfism and facial dysmorphism.

Summary:
Epidemiology
Twenty five cases (16 males and 9 females) have been reported in the literature so far.
Clinical description
The disorder is evident at birth. The facial dysmorphism includes macrocephaly, prominent brow, large fontanels, depressed nasal bridge, a small nose, anteverted nares and a long philtrum, hypertelorism, and exophthalmos. Additional features include a short neck, narrow thorax, predominantly rhizomelic micromelia with very short long bones, short feet and hands, muscular hypotonia, severe platyspondyly, marked delay of bone maturation, and increased susceptibility to respiratory infections.
Etiology
Etiology remains unknown.
Genetic counseling
Autosomal recessive transmission has been suggested.

                            Last update:
                            September 2009

                            - Expert reviewer(s):
                            Dr Martine LE MERRER


Opsoclonus myoclonus syndrome (OMS) is a rare neuroinflammatory disease of paraneoplastic, parainfectious or idiopathic origin, characterized by opsoclonus, myoclonus, ataxia, and behavioral and sleep disorders.

Summary:
Epidemiology
The annual incidence is estimated at around 1/5,000,000.
Clinical description
OMS typically presents between 1 and 3 years of age, although it can occur earlier or later in childhood. It is characterized by opsoclonus (rapid, multi-directional, conjugate eye movements), myoclonic jerks, ataxia, irritability and sleep disturbances. The clinical course may be monophasic or chronic relapsing. OMS is associated in approximately 50% of pediatric cases with a neuroblastoma (see this term); this tumour is usually (but not always) of low grade with a good oncological outcome. A similar adult-onset condition also occurs but is associated with different types of cancer, most commonly small-cell lung cancer (see this term) and adenocarcinoma of the breast.
Etiology
OMS may have a paraneoplastic, parainfectious or idiopathic origin. In the majority of pediatric paraneoplastic cases, a neuroblastoma is found. Infections triggering OMS include a variety of viral and bacterial agents including streptococci, mycoplasma and varicella zoster. The exact pathomechanism is unknown but an autoimmune-mediated brainstem and/or cerebellar dysfunction has been suggested; the opsoclonus may reflect disinhibition of the fastigial nucleus of the cerebellum or disordered interaction between the omnipause and burst neurons, but the cognitive and behavioral elements of the condition, as well as recent imaging studies, suggest a wider neurological process.
Diagnostic methods
The diagnosis is clinical, based on the presence of 3 out of the 4 following criteria: 1) neuroblastoma, 2) opsoclonus, 3) a movement disorder with myoclonus and/or ataxia, and 4) behavioural and/or sleep disturbance. Brain MRI in the acute presentation is normal. Neuroblastoma is detected by detailed MRI with particular focus on the whole length para-spinal regions, the carotids, the mediastinum, the adrenals, the abdomen and pelvis. Functional tests, including urinary vanillylmandelic and homovanillic acid tests and a metaiodobenzylguanidine scan, should be performed but may produce a false negative result as neuroblastomas in OMS are usually low grade and therefore not metabolically active. Serological tests may allow for the identification of a parainfectious etiology. No consistent neural antibody has yet been identified in pediatric OMS, in contrast to adult OMS in which Hu anti-neuronal nuclear antibodies (anti-Hu) have been found.
Differential diagnosis
Differential diagnosis includes acute inflammatory cerebellar ataxia that is differentiated from OMS by the type of eye movement (nystagmus), the absence of irritability, and the usually rapid recovery without treatment.
Management and treatment
Treatment usually includes resection of the neuroblastoma if present; occasionally, higher grade neuroblastoma may require chemotherapy. Treatment also includes immunomodulation. Treatment regimens have not been standardized but may include corticosteroids, adrenocorticotropin hormone, cyclophosphamide, intravenous immunoglobulin, and/or rituximab.
Prognosis
Outcome is variable. Some children have a monophasic illness, respond well to steroids and have little or no sequelae. Others may be treatment-resistant, have a chronic relapsing course and motor, cognitive and/or behavioral sequelae. Opsoclonus usually remits. The presence or absence of neuroblastoma does not seem to affect outcome.

                            Last update:
                            November 2014

                            - Expert reviewer(s):
                            Dr Mark GORMAN  - Dr Michael PIKE  - Pr Marc TARDIEU


Optic atrophy-ataxia-peripheral neuropathy-global developmental delay syndrome

A rare mitochondrial disease characterized by a variable clinical phenotype with the core features of optic atrophy, ataxia, and hypotonia. Additional common manifestations include global developmental delay with or without regression, neuropathy, spasticity, and microcephaly, less frequently seizures, movement disorder, hearing loss, and respiratory failure. Brain imaging may show abnormalities of the corpus callosum, basal ganglia, and midbrain, cerebral or cerebellar atrophy, or white matter abnormalities. The condition is frequently fatal at an early age.


Optic atrophy-intellectual disability syndrome is a rare, hereditary, syndromic intellectual disability characterized by developmental delay, intellectual disability, and significant visual impairment due to optic nerve atrophy, optic nerve hypoplasia or cerebral visual impairment. Other common clinical signs and symptoms are hypotonia, oromotor dysfunction, seizures, autism spectrum disorder, and repetitive behaviors. Dysmorphic facial features are variable and nonspecific.


A rare ophthalmic disorder characterized by a usually congenital and unilateral round or oval, gray, white, or yellowish depression in the optic disc. There may be more than one pit present in one eye, and the anomaly is most commonly found in the inferotemporal region of the optic disc, although any sector may be involved. Patients are often asymptomatic, or may present with visual field defects, in particular paracentral arcuate scotoma connected to an enlarged blind spot. A number of patients develop serous macular detachment, with loss of vision typically becoming apparent in the third or fourth decade of life.


Optic pathway glioma (OPG) is a benign tumor that develop along the optic nerve (chiasm, tracts, and radiations) characterized by impairment or loss of vision and may be accompanied by diencephalic symptoms such as reduced growth and alteration in sleeping patterns. OPG are often linked to neurofibromatosis type 1 (NF1, see this term).


Oral submucous fibrosis (OSMF) is a chronic, progressive disease that alters the fibroelasticity of the oral submucosa, prevalent in India and Southeast Asia but rare elsewhere, and characterized by burning and pain in the oral cavity, loss of gustatory sensation, the presence of blanched fibrous bands and stiffening of the oral mucosa and oro-pharynx (leading to trismus and a progressive reduction in mouth opening) and an increased risk of developing oral squamous cell cancer (3-19%). It is usually associated with the chewing of the areca nut (an ingredient in betel quid) but the exact etiology is unknown and there is currently no effective treatment.


Oral-facial-digital syndrome with short stature and brachymesophalangy

A rare ciliopathy characterized by oral anomalies (multiple oral frenula, missing incisors), facial dysmorphism (such as square face with small forehead, upslanting palpebral fissures, and cleft lip, among other features), digital anomalies (brachydactyly, brachymesophalangy, polydactyly), and short stature. Additional reported manifestations include short femoral neck, bilateral cervical ribs, abnormal vertebral bodies, and gracile long bones.


Orbital leiomyoma is a rare benign smooth muscle tumor arising from the walls of orbital vessels characterized by its slow growth and well encapsulated nature. It is usually located in an extraconal position, commonly manifesting with painless proptosis. The tumor is composed of spindle cells arranged in a fibrous stroma rich in dilated sinusoidal capillaries. The nuclei of tumor cells are oval with blunted ends and there are no mitotic figures. Orbital leiomyoma when excised has excellent prognosis for vision and life. One case of orbital leiomyosarcoma that possibly represents sarcomatous change in an orbital leiomyoma following radiation treatment has been reported.


Orgasm-induced seizures is a rare neurologic disease characterized by complex partial seizures with or without secondary generalization, or idiopathic primarily generalized epilepsy, triggered by sexual orgasm. Seizures usually start immediately, shortly after or a few hours after the achievement of orgasm, last a few seconds or minutes, and are followed, in very rare cases, by intense migraine.


A rare, genetic disorder of urea cycle metabolism and ammonia detoxification characterized by either a severe, neonatal-onset disease found mainly in males, or later-onset (partial) forms of the disease. Both present with episodes of hyperammonemia that can be fatal and which can lead to neurological sequelae.

Summary:
Epidemiology
Ornithine transcarbamylase deficiency (OTCD) is the most common type of urea cycle disorder. Worldwide prevalence estimates range between 1/56,500 to 1/113,000 live births.
Clinical description
Males with the severe, neonatal-onset type are normal at birth but develop poor sucking, hypotonia and lethargy after a few days, rapidly progressing into somnolence and coma. Seizures and hyperventilation may also be present. If untreated, severe encephalopathy will develop with a high risk for death. Patients with a milder form can present at any age. In infants, symptoms can be induced when switching from breast milk to whole milk. In children and adults, environmental stressors (i.e. fasting, high protein diet, pregnancy and the postpartum period, intercurrent illness, surgery) can trigger episodes of hyperammonemic encephalopathy along with nausea, vomiting, headaches, erratic behavior, delirium and combativeness. These episodes can also result in hyperammonemic coma. Neurological complications of hyperammonemic coma include developmental delay and, sometimes, severe cognitive impairment. Many female carriers are asymptomatic; however, they can be affected to the same extent as males if the degree of X-inactivation of the disease allele is unfavorable. Coagulopathy is a frequent finding during metabolic decompensation and sometimes evolves into acute liver failure.
Etiology
OTCD is due to mutations in the OTC gene (Xp21.1) which encodes OTC, responsible for catalyzing the synthesis of citrulline (in liver and small intestine) from carbamoyl phosphate and ornithine. Mutations that abolish OTC activity completely result in the severe, neonatal-onset form while mutations leading to decreased OTC activity result in the late-onset phenotypes.
Diagnostic methods
Diagnosis is based on clinical manifestations and plasma ammonia levels are typically high (>200 µmol/L) when encephalopathy is present. Plasma amino acid analysis reveals low citrulline and arginine levels and high glutamine. Urine organic acid analysis usually reveals elevated orotic acid levels. Molecular genetic testing confirms diagnosis.
Differential diagnosis
Differential diagnoses include carbamoyl-phosphate synthetase deficiency, argininosuccinic aciduria, hyperammonemia due to N-acetylglutamate synthase deficiency, citrullinemia type 1 and argininemia.
Antenatal diagnosis
Prenatal diagnosis is possible in families with a known disease causing mutation.
Genetic counseling
OTCD is inherited in an X-linked manner. Where the female parent is a carrier, male offspring have a 50% risk of inheriting the disease. Where the male is affected, male offspring are unaffected and females are obligate carriers. Female heterozygotes may be symptomatic due to skewed X-chromosome inactivation.
Management and treatment
Patients presenting with a hyperammonemic coma must be treated immediately in a tertiary care center where plasma ammonia levels must be lowered (by hemodialysis or hemofiltration methods), ammonia scavenger therapy implemented, catabolism reversed (through glucose and lipid infusions) and special care taken to reduce the risk of neurological damage (electroencephalogram surveillance and treatment of seizures if necessary). Long-term therapy involves life-long restriction of protein intake and nitrogen scavenger therapy (with sodium benzoate and/or sodium or glycerol phenylbutyrate). A liver transplantation may also be considered in patients with severe, neonatal-onset OTCD (usually performed by 3-6 months of age) or those with frequent hyperammonemic episodes. Valproate, haloperidol, fasting and known stressors should be avoided. Pregnant women with OTCD should be carefully monitored, especially also in the postpartum period.
Prognosis
Prognosis depends on disease severity but is considered bleak in patients with early neonatal disease. Without early diagnosis and treatment of hyperammonemic episodes, the neurological outcome is poor.

                            Last update:
                            October 2019

                            - Expert reviewer(s):
                            Pr Johannes HÄBERLE


Oral-facial-digital syndrome type 1 (OFD1) is a rare neurodevelopmental disorder in the ciliopathy group that is lethal in males and characterized by variable anomalies including external malformations (craniofacial and digital), and possible involvement of the central nervous system (CNS) and of viscera (kidneys, pancreas and ovaries) in females.

Summary:
Epidemiology
Estimated annual incidence of 1/250,000 to 1/50,000 live births has been reported. Almost all patients are female. Exceptional cases of affected males have been described.
Clinical description
OFD1 is associated with prenatal male lethality in almost all cases. In female patients, there is a very high degree of phenotypic variability ranging from multiple severe malformations and visceral involvement to only renal cysts or dysmorphic features. Manifestations include oral malformations in >95% (lobed tongue, tongue hamartomas or lipomas, ankyloglossia, cleft or highly arched palate, accessory gingival frenulae, missing (hypodontia, see this term) or extra teeth, enamel dysplasia, and malocclusion), craniofacial abnormalities in about 87% including facial dysmorphism (ocular hypertelorism or telecanthus, hypoplasia of the alae nasi, median cleft or pseudocleft upper lip, micrognathia, downslanting palpebral fissures), abnormal hair/alopecia, evanescent facial milia, digital malformations in about 88% (brachydactyly, syndactyly, 5th finger clinodactyly, duplicated hallux/broad thumb, preaxial or postaxial polydactyly), involvement of the CNS in about 50% including brain abnormalities (intracerebral cysts, corpus callosum agenesis, cerebellar agenesis with or without Dandy-Walker malformation) and mild to moderate intellectual deficit. Visceral involvement includes polycystic kidney disease (at least 50%), and hepatic and pancreatic cystic disease. Hearing problems have also been described in about 6%.
Etiology
OFD1 is caused by mutations in the OFD1 gene (Xp22) encoding a protein localized in the centrosome and basal body of primary cilia, which play an important role in development. A fraction of cases displays genomic deletions. High penetrance has been reported but expression is highly variable.
Diagnostic methods
Diagnosis is often made at birth on the basis of characteristic oral, facial, and digital anomalies. In other affected individuals, diagnosis is suspected only in later childhood or adulthood after polycystic kidney disease is found. Diagnostic methods include direct sequencing of OFD1 and dosage analysis in negative cases to detect genomic rearrangements not identifiable by direct sequencing due to the presence of the wild-type allele.
Differential diagnosis
Differential diagnoses include other OFD syndromes and disorders (OFD2, 3, 4, 5, 6, 8 and 9), and familial cystic renal disease (see these terms). Meckel and Joubert syndromes (see these terms) should also be considered.
Antenatal diagnosis
Prenatal diagnosis and preimplantation genetic diagnosis are recommended for at-risk pregnancies and require identification of the disease-causing mutation in the family.
Genetic counseling
OFD1 follows an X-linked dominant pattern of inheritance. The gene mutations commonly occur de novo. About 75% of affected female cases involve a single family member. Carrier testing for at-risk relatives is recommended.
Management and treatment
Treatment involves cosmetic or reconstructive surgery for cleft lip and/or palate, tongue nodules, and accessory frenulae, removal of accessory teeth, orthodontia for malocclusion, surgery to repair syndactyly, as well as routine management of kidney disease and seizures. Management requires special educational evaluation for learning disabilities.
Prognosis
Male mortality usually occurs in the first or second trimester of pregnancy. The prognosis in affected females is variable and depends on the associated malformations and/or visceral involvement, severity, treatment, and the course of the disease.

                            Last update:
                            September 2012

                            - Expert reviewer(s):
                            Pr Brunella FRANCO


Orofaciodigital syndrome type 11 is an extremely rare, sporadic form of Orofaciodigital syndrome (OFDS; see this term) with only a few reported cases, and characterized by facial (blepharophimosis, bulbous nasal tip, broad nasal bridge, downslanting palpebral fissures and low set ears) and skeletal (post-axial polydactyly and fusion of vertebrae) malformations along with severe intellectual disability, deafness and congenital heart defects.


Orofaciodigital syndrome type 14 is a rare subtype of orofaciodigital syndrome, with autosomal recessive inheritance and C2CD3 mutations, characterized by severe microcephaly, trigonocephaly, severe intellectual disability and micropenis, in addition to oral, facial and digital malformations (gingival frenulae, lingual hamartomas, cleft/lobulated tongue, cleft palate, telecanthus, up-slanting palpebral fissures, microretrognathia, postaxial polydactyly of hands and duplication of hallux). Corpus callosum agenesis and vermis hypoplasia with molar tooth sign, on brain imaging, are also associated.


Oral-facial-digital (OFD) type 2 is characterized by hand and feet deformities, facial deformities, midline cleft of the upper lip and tongue hamartomas.

Summary:
Epidemiology
Less than 20 cases have been reported so far.
Clinical description
Main clinical features include bilateral preaxial polydactyly of hands and feet, partial duplication of hallux, brachydactyly, syndactyly, scoliosis, pectus excavatums, short stature, muscular hypotonia, conductive hearing loss. Facial dysmorphism may include midface hypoplasia, hypertelorism, antimongoloid slant, broad nasal root, bifid nasal tip, cleft palate, microglossia, lobulated tongue, thick frenulum and low set ears. Microcephaly, porencephaly and internal hydrocephalus are also observed. Intelligence is normal in the majority of cases. Intellectual deficit and increased susceptibility to respiratory infections have been described in some patients. Involvement of the central nervous system (cerebellar atrophy) seems to be a clinical feature of OFD2.
Etiology
The causative gene has not yet been identified.
Genetic counseling
Autosomal recessive inheritance has been suggested.

                            Last update:
                            November 2009

                            - Expert reviewer(s):
                            Pr Marie-Paule VAZQUEZ


Oral-facial-digital syndrome, type 4 is characterized by lingual hamartoma, postaxial polysyndactyly of hands and feet, and mesomelic shortening of the legs with supinate equinovarus feet.

Summary:
Epidemiology
Approximately 15 cases have been reported so far.
Clinical description
Additional features include hypoplastic mandible, micrognathia, cleft palate, prominent eyes, low-set ears and normal intelligence.
Etiology
The causative gene has not yet been identified.
Genetic counseling
Autosomal recessive inheritance has been suggested.

                            Last update:
                            November 2009

                            - Expert reviewer(s):
                            Pr Marie-Paule VAZQUEZ


A rare orofaciodigital syndrome characterized by median cleft of the upper lip, postaxial polydactyly of hands and feet, and oral manifestations (duplicated frenulum).


Joubert syndrome with orofaciodigital defect (or oral-facial-digital syndrome type 6, OFD6) is a very rare subtype of Joubert syndrome and related disorders (JSRD, see this term) characterized by the neurological features of JS associated with orofacial anomalies and often polydactyly.

Summary:
Epidemiology
Prevalence is unknown.
Clinical description
Typical oral findings include bifid or lobulated tongue, lingual hamartomas and multiple oral frenulae, but cleft lip and/or palate can also be present. Polydactyly is typically mesaxial with Y-shaped metacarpals, but can also be preaxial or postaxial. A subset of patients present with hypothalamic hamartoma that has never been reported in other JSRD subgroups.
Etiology
Two OFD6 patients, including one fetus, were found to carry a homozygous mutation in the TMEM216 gene (11q13.1), but mutations in this gene were excluded in several other patients, and the genetic basis of this condition still remains elusive.
Genetic counseling
Males and females are equally affected and an autosomal recessive pattern of inheritance was observed in familial cases.

                            Last update:
                            July 2011

                            - Expert reviewer(s):
                            Dr Francesco BRANCATI  - Pr Bruno DALLAPICCOLA  - Pr Enza Maria VALENTE


Oral-facial-digital syndrome, type 8 is characterized by tongue lobulation, hypoplasia of the epiglottis, median cleft upper lip, broad or bifid nasal tip, hypertelorism or telecanthus, bilateral preaxial and postaxial polydactyly, abnormal tibiae and/or radii, duplication of the halluces, short stature, and mild intellectual deficit.

Summary:
Epidemiology
The syndrome has been described in one family with four affected males in three generations.
Clinical description
Increased susceptibility to respiratory infections has been noted.
Etiology
X-linked recessive transmission has been suggested, but the causative gene has not yet been identified.

                            Last update:
                            November 2009


Oral-facial-digital syndrome, type 9 is characterized by highly arched palate with bifid tongue and bilateral supernumerary lower canines, hamartomatous tongue, multiple frenula, hypertelorism, telecanthus, strabismus, broad and/or bifid nasal tip, short stature, bifid halluces, forked metatarsal, poly- and syndactyly, mild intellectual deficit and specific retinal abnormalities (bilateral optic disc coloboma and retinal dysplasia with partial detachment).

Summary:
Epidemiology
Less than ten cases have been described in the literature.
Clinical description
Recurrent aspiration pneumonia and severe microcephaly have been reported occasionally.
Etiology
The causative gene has not yet been identified.
Genetic counseling
Autosomal and X-linked recessive inheritance were initially suggested. Taking into consideration all reported cases so far, autosomal recessive inheritance seems most likely.

                            Last update:
                            November 2009


A form of focal dystonia, affecting the lower part of the face and jaws. It is characterized by sustained or repetitive involuntary jaw and tongue movements and facial grimacing caused by involuntary spasms of the masticatory, facial, pharyngeal, lingual, and lip muscles.


Oromandibular-limb hypogenesis syndromes (OLHS) are a group of dysmorphic complexes (including Charlie M syndrome, Hanhart syndrome and glossopalatine ankylosis; see these terms) characterized by the association of severe asymmetric limb defects (primarily involving distal segments) and abnormalities of the oral cavity and mandible (hypoglossia, aglossia, micrognathia, glossopalatine ankylosis, cleft palate, and gingival anomalies).

Summary:
Epidemiology
Prevalence is estimated at 1:500,000.
Clinical description
The clinical features are evident at birth. Intelligence is normal.
Etiology
Etiology remains unknown.

                            Last update:
                            September 2009


Osgood-Schlatter disease is a traction apophysitis of the anterior tibial tubercle described in active adolescents and characterized by gradual onset of pain and swelling of the anterior knee causing limping that usually disappears at the end of growth.


A rare genetic disease characterized by the association of osteosarcoma with limb anomalies (such as bilateral radioulnar synostosis and clinodactyly, as well as other abnormalities of the hands and feet) and erythroid macrocytosis without anemia. There have been no further descriptions in the literature since 1977.


Ossification anomalies-psychomotor developmental delay syndrome

A rare primary bone dysplasia characterized by global developmental delay, hypotonia, ossification anomalies of the cranial vault, abnormalities of the long bones due to defective remodeling, thoracic deformity, and progressive osteopenia. Dysmorphic craniofacial features include microcephaly, hypertelorism, narrow mouth, cleft palate, and micrognathia.


A rare, neoplastic disease characterized by a typically benign, locally aggressive, non self-limiting, osteoblastic bone tumor, usually located on the spine, proximal humerus and hip (although any bone may be involved), generally manifesting with slowly progressive, dull aching pain which is difficult to localize and is not relieved by nonsteroidal anti-inflammatory drugs or aspirin. Neurologic symptoms, such as cranial nerve palsies, myelopathy, neuralgia, radiculopathy, paraparesis or paraplegia, may be associated if the spine is involved. Imaging reveals a lytic (or mixed lytic and blastic) lesion with a radiolucent nidus (> 2 cm) associated with reactive sclerotic bone.


Osteochondritis dissecans (OCD) is a rare bone disease characterized by an acquired idiopathic necrotic lesion of subchondral bone with the formation of a sequestrum, which may detach to form loose bodies in joints. OCD mainly affects the knee, ankle and elbow joints and can lead to pain, functional limitations and secondary osteoarthritis.


A rare bone disease characterized by avascular necrosis of a metatarsal head, most commonly involving the second, but also the third or fourth, metatarsal. Patients may present with pain on weight-bearing, swelling, and tenderness. Radiological features include widening of the metatarsophalangeal joint space and flattening of the affected metatarsal head, at later stages metatarsal head sclerosis, cortical thickening, and intra-articular loose bodies. The condition can be bilateral in some cases and shows a significant predilection for females in the second or third decade of life.


A rare bone disease characterized by avascular necrosis of the navicular bone in children. Patients present with sudden unexplained foot pain, inability to bear weight, and limping. Radiographic features include flattening, fragmentation, and patchy sclerosis of the navicular bone. Soft tissue swelling may be associated. The condition is most commonly unilateral and self-limiting. Boys are more often affected than girls.


Osteocraniostenosis is a lethal skeletal dysplasia characterized by a cloverleaf skull anomaly, facial dysmorphism, limb shortness, splenic hypo/aplasia and radiological anomalies including thin tubular bones with flared metaphyses and deficient calvarial mineralization.

Summary:
Epidemiology
First described in 1989, less than 30 cases have been reported so far.
Clinical description
'This multiple congenital anomalies syndrome is characterized by dysmorphic features of the fetus and the newborn: the skull is misshapen, combining acrocephaly and cloverleaf deformity, fontanelles are very large; facial dysmorphism includes midface hypoplasia with telecanthus, short upturned nose, short philtrum, small inverted V-shaped mouth and low-set ears; limbs are also affected with bowed forearms, micromelia and acromicria with brachydactyly.'
Etiology
Etiology of osteocraniostenosis is not well known, but some histological findings report growth plate disorganization and adjacent diaphyseal ossification. Recently, heterozygous mutations of the FAM111A gene, encoding a protein of unknown function and responsible of some autosomal dominant forms of Kenny-Caffey syndrome (see this term) with hypothyroidism and slender and dense bone, have been identified in patients with osteocraniostenosis. A clinical and genetic heterogeneity remains likely.
Diagnostic methods
Diagnosis is based mainly on radiological and pathological examination. Radiological examination reveals hypomineralisation of the skull, flat and dense vertebral bodies, thin tubular bones with flared and dense metaphyses, brachymetacarpia and brachyphalangy with ''diabolo appearance'' (very thin tubular bones with abrupt metaphyseal flare) and lack of ossification of the distal phalanges. The spleen is hypoplasic or even absent. Diaphyseal fractures are frequent at birth.
Differential diagnosis
Differential diagnosis includes the hypo/akinesia sequence, Hallermann-Streiff-FranÁois syndrome, Kenny-Caffey syndrome and other slender bone dysplasias, and some cases of osteogenesis imperfecta with slender bones (see these terms).
Antenatal diagnosis
Prenatal ultrasound observation reveals micromelic dwarfism, cranial deformity, mild intra-uterine growth retardation and sometimes fractures.
Genetic counseling
Cases with FAM111A gene mutations show an autosomal dominant mode of inheritance with a majority of de novo mutations.
Management and treatment
There is no treatment for osteocraniostenosis.
Prognosis
Prognosis is very poor as most cases are stillborn or die in their first days of life.

                            Last update:
                            May 2014

                            - Expert reviewer(s):
                            Dr Martine LE MERRER


Osteofibrous dysplasia is a rare, genetic primary bone dysplasia characterized by the presence of a benign, fibro-osseous, osteolytic tumor typically located in the tibia (occasionally the fibula, or both) and usually involving the anterior diaphyseal cortex with adjacent cortical expansion. It may on occasion be asymptomatic or may present with a palpable mass, pain, tenderness and/or anterior bowing of the tibia.


A mild form of osteogenesis imperfecta (OI) characterized by increased bone fragility and low bone mass that clinically manifests with increased susceptibility to bone fractures (including vertebral crush fractures), normal height or short stature (typically between 0 and -2.0 SD scores), mild (Cobb angle <30 degrees) or no scoliosis, blue sclera, and in dentinogenesis imperfecta, and mild long bone bowing bone deformities.


A lethal type of osteogenesis imperfecta (OI) characterized by increased bone fragility, low bone mass and susceptibility to bone fractures and presenting with multiple rib and long bone fractures at birth, marked deformities, broad long bones, low density skull on X-ray, and dark sclera.

Summary:
Epidemiology
The overall prevalence of OI is estimated at between 1/10,000 and 1/20,000 but the prevalence of type II is unknown.
Clinical description
There are three subtypes of OI type II (A, B and C) that are characterized by different radiological features. Patients with OI type IIA present with broad ribs with multiple fractures, continuous beaded ribs and severe under-modeling of the femur. OI type IIB presents with normal or thin ribs with some fractures, discontinuous beaded ribs and some under-modeling of the femur. OI type IIC presents with varying thickness of the ribs, discontinuous beading of the ribs, malformed scapulae and ischiae, and long bones with thin shafts and expanded metaphyses. Type IIC is extremely rare and its existence is even doubted.
Etiology
Variants in the COL1A1 and COL1A2 genes (17q21.31-q22 and 7q22.1 respectively) cause OI type IIA and IIB, and transmission is autosomal dominant. Type IIB can also be autosomal recessive, caused by mutations in the CRTAP gene (3p22; sometimes described as OI type VII) or the P3H1 gene (1p34; sometimes described as OI type VIII) or the PPIB gene (15q21-q22; sometimes described as OI type IX). OI type IIC appearances have been reported in fetuses with mutations in the MESD gene (15q25).
Diagnostic methods
Diagnosis is typically prenatal due to suspicious ultrasound findings.
Differential diagnosis
Differential diagnosis includes thanatophoric dwarfism, severe hypophosphatasia, and mucolipidosis type II.
Antenatal diagnosis
Prenatal diagnosis of type II OI may be suggested by fetal ultrasound appearances, and confirmed by genetic testing of amniocytes.
Genetic counseling
The disease is either autosomal dominant or autosomal recessive depending on the gene involved. Autosomal dominant cases occur either sporadically or due to germline mosaicism. The appropriate genetic counseling should be offered to affected families.
Management and treatment
Management is initially expectant; some infants with apparently very severe changes on ultrasound may nevertheless survive with intensive support and early institution of bone-directed therapy such as bisphosphonates.
Prognosis
The majority of those identified of having type II changes antenatally will die either before birth or in the perinatal period. A few may survive with continued intensive treatment.

                            Last update:
                            May 2021

                            - Expert reviewer(s):
                            Pr Nick BISHOP


A severe type form osteogenesis imperfecta characterized by increased bone fragility and low bone mass clinically manifesting as susceptibility to bone fractures, severe short stature, a triangular face, moderate to severe scoliosis, blue or blue-grey sclera, and dentinogenesis imperfecta.


A moderately severe form of osteogenesis imperfecta characterized by increased bone fragility and low bone mass that clinically manifests from infancy as susceptibility to bone fractures, short stature, mild to moderate scoliosis in most, gray-blue or white sclera, and dentinogenesis imperfecta.


A moderate form of osteogenesis imperfecta characterized by increased bone fragility and low bone mass that clinically manifests with susceptibility to bone fractures of variable severity, metaphyseal changes at birth, short stature, dislocation of the radial head, mineralized interosseous membranes, hyperplasic callus (occurring more often during periods of more rapid growth), white sclera and absence of dentinogenesis imperfecta.


Osteogenesis imperfecta-retinopathy-seizures-intellectual disability syndrome

A rare multiple congenital anomalies/dysmorphic syndrome characterized by severe global developmental delay, osteogenesis imperfecta, presence of wormian bones, seizures, ocular abnormalities (blue sclerae, optic atrophy, retinal detachment), and dysmorphic facial features (including frontal bossing, low anterior hairline, medial flare of the eyebrows, long eyelashes, hypertelorism, depressed nasal bridge, and low-set, large ears). There have been no further descriptions in the literature since 1994.


A rare, genetic, primary bone dysplasias characterized by increased bone fragility, low bone mass, and susceptibility to bone fractures. The clinical severity is heterogeneous.

Summary:
Epidemiology
Prevalence is estimated at between 1/10,000 and 1/20,000.
Clinical description
Age at diagnosis depends on the severity of the disease. Five clinically distinct types of osteogenesis imperfecta (OI) have been identified. The most clinically relevant characteristic of all types of OI is bone fragility, which manifests as multiple spontaneous fractures. Type I is mild and nondeforming with normal height or short stature, blue sclera, and no dentinogenesis imperfecta (DI). Patients with type II present multiple rib and long bone fractures at birth, marked deformities, broad long bones, low density on skull X-rays, and dark sclera. These patients die at birth, or shortly after. Type III is severe and the main signs include severe short stature, a triangular face, severe scoliosis, grayish sclera, and DI. Type IV and 5 are moderate or severe forms. Patients with type IV have moderate short stature, variable severity of scoliosis, grayish or white sclera, and some have DI. Type V is characterized by mild to moderate short stature, metaphyseal dysplasia at birth, dislocation of the radial head, mineralized interosseous membranes of the forearm and lower leg, hyperplastic callus (particularly when growth is more rapid e.g. during infancy or puberty), white sclera, and no DI. They have variable severity of scoliosis.
Etiology
In approximately 90% of cases, OI is caused by monoallelic variants in the COL1A1 and COL1A2 genes (17q21.33 and 7q21.3) encoding the alpha1 and alpha2 chains of type 1 collagen. These variants can cause types I-IV of OI. In Type V, the variant is in the promoter region of the IFITM5 gene (11p15.5). Over 15 causal genes have been identified and some geno-phenotypes are emerging: in children with BMP1 variants, high bone mass can be observed. Children with homozygous WNT1 variants have ptosis and neurodevelopmental delay; and craniosynostosis defects are associated with P4HB or SEC24D variants.
Diagnostic methods
Diagnosis is based on skeletal and extra-skeletal clinical findings. Radiological studies reveal osteoporosis and the presence of Wormian bones. Bone densitometry confirms the low bone mass.
Differential diagnosis
Differential diagnoses include in utero diagnosis of chondrodysplasia, idiopathic juvenile osteoporosis, osteoporosis-pseudoglioma syndrome, Cole-Carpenter and Bruck syndromes, hyper or hypophosphatasia, panostotic form of polyostotic fibrous dysplasia, non-accidental injury (multiple fractures without osteoporosis), and osteoporosis due to medication, nutritional deficiency, metabolic disease, or leukemia.
Antenatal diagnosis
Antenatal diagnosis may be suspected through ultrasonography and/or confirmed through molecular analysis of amniocytes or chorionic villus cells if the causative mutation in the family has been identified.
Genetic counseling
Transmission is autosomal dominant for both Type I Collagen and IFITM5 variants. Autosomal recessive forms are also observed and are caused by variants in at least 15 other genes, and are typically severe; however, variability in severity has been noted especially for Type VI due to SERPINF1 variants; and for OI due to BMP1 or PPIB variants. Transmission is X-linked for MBTPS2 variants. Genetic counselling is recommended for affected families.
Management and treatment
Management should be multidisciplinary involving experienced medical, orthopedic, physiotherapy and rehabilitation specialists. Bisphosphonates with potent antiresorptive properties are now considered as the standard of care for severe forms but do not constitute a cure. Prevention of vitamin D and calcium deficiency is essential throughout life. Surgical management is essential for the correction of bone and spinal deformities and the prevention of long bone fractures (insertion of intramedullary rods in long bones; spinal rods when growth is complete, or nearly complete). Early physiotherapy may improve autonomy by helping to evaluate any motor deficits, reducing the risk of falls and encouraging patients to take up a sporting activity. Occupational therapy and attendance to fine motor activities has strong relevance for school performance. Many families need psychological and social care support.
Prognosis
Functional prognosis depends on the severity of the disease and on the quality of management. Vital prognosis depends on the severity of any respiratory complications associated with spinal deformities.

                            Last update:
                            May 2021

                            - Expert reviewer(s):
                            Pr Nick BISHOP


A rare disorder characterized by dwarfism, severe craniofacial abnormalities and multiple unerupted teeth.

Summary:
Epidemiology
Less than ten cases have been reported so far.
Clinical description
Main clinical features include craniosynostosis, acrocephaly, a prominent forehead, depressed nasal bridge, hypertelorism, midface hypoplasia, macroglossia, unerupted teeth, short neck, short and bowed limbs, short and broad hands and fingers, and flat feet. The main radiographic features are craniostenosis, fibrous dysplasia, metaphyseal lucencies and platyspondyly. Intelligence is usually normal.
Etiology
Osteoglosphonic dysplasia (OGD) is caused by mutations in the FGFR1 gene (8p11.2-p11.1).
Genetic counseling
OGD is transmitted in an autosomal dominant manner.

                            Last update:
                            September 2009

                            - Expert reviewer(s):
                            Dr Martine LE MERRER


Osteomesopyknosis is a very rare benign bone disorder characterized by bone dysplasia manifested by patchy sclerosis of the axial skeleton and increased bone mineral content.

Summary:
Epidemiology
The prevalence and incidence of this disorder are not known. It has been reported in fewer than 5 families, primarily in France.
Clinical description
Osteomesopyknosis may be underdiagnosed due to confusion with autosomal dominant osteopetrosis (Albers-Schönberg osteopetrosis, see this term). The condition is usually found incidentally on radiological examination and is very mild, sometimes accompanied by pain. Increased density of the vertebral plates, pelvis and occasionally of the upper femur have been reported, as well as kyphoscoliosis and femoral cysts.
Etiology
The genetic basis underlying the disorder is not known.
Genetic counseling
The disorder appears to follow an autosomal dominant pattern of inheritance.

                            Last update:
                            June 2012


A rare osteonecrosis characterized by an exposed necrotic lesion in the mandible or maxilla present for more than eight weeks, arising as a complication of antiresorptive medication, dental interventions, or trauma and infections. Patients may present with pain, altered neurosensory functions, secondary infections, and (in advanced stages) pathological fractures, or fistulae.


Osteopathia striata-cranial sclerosis syndrome

Osteopathia striata with cranial sclerosis (OS-CS) is a bone dysplasia characterized by longitudinal striations of the metaphyses of the long bones, sclerosis of the craniofacial bones, macrocephaly, cleft palate and hearing loss.

Summary:
Epidemiology
Fewer than 100 cases have been reported in the literature.
Clinical description
The clinical presentation is highly variable even within the same family, ranging from mild skeletal manifestations to multisystem organ involvement. Cardiac malformations (ventricular septal defect, aortic stenosis), developmental delay, cranial nerve palsies, anal malformations, cataracts and nervous system malformations are frequent. Vertebral anomalies (scoliosis, spondylolisthesis), anomalies of extremities (clubfoot, unusually long and thin fingers with clinodactyly of distal phalanges), hypertelorism, frontal bossing, broad nasal bridge, prominent occipital bony protrusion and mild intellectual impairment have also been documented. In rare cases, OS-CS has been reported in association with Hirschsprung disease, Pierre Robin sequence, coronal craniostenosis, hydrocephalus and laryngotracheomalacia (see these terms).
Etiology
OS-CS is associated with mutations in the Wilms tumour gene on the X chromosome (WTX), a repressor of WNT signaling (beta-catenin pathway implicated in control of target genes in the nucleus).
Diagnostic methods
Diagnosis is based on clinical and radiological examination, which reveals cranial sclerosis, longitudinal striations in the widened metaphyses of the long bones, and sclerosis of the ribs. Genetic testing is available to confirm the diagnosis.
Differential diagnosis
Differential diagnosis includes a large number of conditions with primary or secondary bone sclerosis. As the macrocephaly seems to be an early and constant clinical feature, OS-CS should be considered in the differential diagnosis of fetuses/infants with unexplained macrocephaly.
Antenatal diagnosis
In the most severe cases, the disorder can be diagnosed prenatally by detection of increased biparietal diameter of the fetal head on ultrasound examination. Prenatal genetic diagnosis is available if the disease-causing mutation in the family is known.
Genetic counseling
OS-CS follows an X-linked dominant pattern of inheritance, with frequent lethality in males.
Management and treatment
Management is supportive and aims at providing multidisciplinary surveillance and symptomatic management of complications.
Prognosis
Cases with severe multiple manifestations and those associated with Hirschsprung disease, Pierre Robin sequence and coronal craniostenosis have poor prognosis.

                            Last update:
                            October 2012

                            - Expert reviewer(s):
                            Dr Ravi SAVARIRAYAN  - Dr Zornitza STARK


Osteopathia striata-pigmentary dermopathy-white forelock syndrome

A rare primary bone dysplasia characterized by the association of osteopathia striata (longitudinal striations through most of the long bones) with a macular, hyperpigmented dermopathy and a white forelock.


Osteopenia-intellectual disability-sparse hair syndrome

A rare syndrome characterized by sparse hair, osteopenia, intellectual disability, minor facial abnormalities, joint laxity and hypotonia. There have been no further descriptions in the literature since 1992.


Osteopetrosis, also known as marble bone disease, is a descriptive term that refers to a group of rare, heritable disorders of the skeleton characterized by increased bone density on radiographs.

Summary:
Epidemiology
The overall prevalence and incidence of these conditions is difficult to estimate but autosomal recessive malignant osteopetrosis (ARO; see this term) has an incidence of 1/ 250,000 births, and autosomal dominant osteopetrosis (ADO or Albers-Schönberg osteopetrosis; see this term) has an incidence of 1 in 20,000 births.
Clinical description
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; see this term), to the incidental finding of osteopetrosis on radiographs (e.g. osteopoikilosis; see this term). Classic ARO is characterized by fractures, short stature, compressive neuropathies, hypocalcemia with attendant tetanic seizures, and life-threatening pancytopenia. The presence of primary neurodegeneration, intellectual deficit, skin and immune system involvement, or renal tubular acidosis may point to rarer osteopetrosis variants, whereas onset of primarily skeletal manifestations such as fractures and osteomyelitis in late childhood or adolescence is typical of ADO.
Etiology
Osteopetrosis is caused by failure of osteoclast development or function, and mutations in at least ten genes have been identified as causative in humans, accounting for 70% of all cases.
Diagnostic methods
Diagnosis is largely based on clinical and radiographic evaluation and should be confirmed by gene testing where applicable. Once the diagnosis of a primary osteopetrotic condition is made, it is important to distinguish between different subtypes. Correct diagnosis is essential for predicting and understanding the natural history of the disease, providing specific treatments where available, and offering adapted counseling regarding recurrence risks and prenatal diagnosis for severe forms.
Differential diagnosis
Alternative diagnoses include fluorosis; beryllium, lead and bismuth poisoning; myelofibrosis; Paget's disease (sclerosing form); and malignancies (lymphoma, osteoblastic cancer metastases) (see these terms).
Antenatal diagnosis
Antenatal diagnosis is possible if the mutations causing the condition in the family are known.
Genetic counseling
These conditions can be inherited as autosomal recessive, dominant or X-linked traits with the most severe forms being autosomal recessive.
Management and treatment
Treatment of osteopetrotic conditions is largely symptomatic, although hematopoietic stem cell transplantation is employed for the most severe forms associated with bone marrow failure, and currently offers the best chance of longer-term survival for patients in this group.
Prognosis
The severe infantile forms of osteopetrosis are associated with diminished life expectancy, with most untreated children dying in the first decade as a consequence of bone marrow suppression. Life expectancy in the adult-onset forms is normal.

                            Last update:
                            October 2012

                            - Expert reviewer(s):
                            Dr Ravi SAVARIRAYAN  - Dr Zornitza STARK


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.

Summary:
Epidemiology
Prevalence of this disorder is not known. Fewer than 100 cases have been reported to date. Many reports involved families of North African and Middle Eastern descent, but cases have been documented worldwide.
Clinical description
Patients present a triad of mild osteopetrosis, mixed proximal and distal RTA, and intracerebral calcifications. Other clinical manifestations include fractures, growth failure and short stature, developmental delay, intellectual deficit, dental malocclusions/malalignment, cranial nerve compression and hearing impairment.
Etiology
Osteopetrosis with renal tubular acidosis is caused by mutations in the CA2 gene (8q22) encoding carbonic anhydrase II.
Diagnostic methods
Diagnosis is based on radiological findings in the presence of acidosis and intracerebral calcifications, and can be confirmed by molecular genetic testing.
Antenatal diagnosis
Antenatal diagnosis is possible if the mutation(s) causing the condition in the family are known.
Genetic counseling
Transmission is autosomal recessive.
Management and treatment
Treatment is symptomatic. Referral to a renal physician to manage the acidosis is recommended.
Prognosis
Severity is variable but the disorder has a milder course than in patients with classic osteopetrosis.

                            Last update:
                            October 2012

                            - Expert reviewer(s):
                            Dr Ravi SAVARIRAYAN  - Dr Zornitza STARK


Osteopetrosis-hypogammaglobulinemia syndrome is an extremely rare primary bone dysplasia with increased bone density disorder characterized by severe osteoclast-poor osteopetrosis associated with hypogammaglobulinemia. Patients typically present infantile malignant osteopetrosis (manifesting with increased bone density, bone fractures, abnormal eye movements/visual loss, nystagmus), hematologic abnormalities with bone marrow failure (e.g. anemia, hepatosplenomegaly) and immunological deficiency (manifesting as recurrent respiratory infections) associated with reduced immunoglobulin levels due to impaired peripheral B cell differentiation.


A rare genetic disease characterized by congenital oculocutaneous hypopigmentation, visual impairment, generalized osteoporosis with skeletal anomalies such as short stature, short neck and trunk, kyphosis, scoliosis, and platyspondyly, and dysmorphic facial features (including long philtrum, small mouth, micrognathia, and prominent ears). Moderate joint hyperelasticity and muscular hypotrophy have also been reported.


A rare bone disease characterized by congenital or infancy-onset blindness and juvenile-onset osteoporosis with spontaneous and low trauma fractures.

Summary:
Epidemiology
The estimated prevalence is 1/2,000,000 but is higher in some founder populations (eg. Old Order Mennonites in Pennsylvania; 1.4/1000). Less than 100 cases have been reported.
Clinical description
Osteoporosis-pseudoglioma (OPPG) syndrome patients have reduced bone formation and poor bone quality. Fractures typically occur in both long bones and vertebrae, after age 2 until puberty. Some patients have eye pain severe enough to require enucleation. Additional clinical manifestations may include microphthalmos, cataracts, persistence of fetal fibrovascular system and absent retinal development, vitreoretinal dysplasia, pseudogliomatous retinal detachments and phthisis bulbi, short stature, microcephaly, ligamental laxity, and hypotonia. Cognitive difficulty and behavioral issues have been reported but most patients have neither.
Etiology
The disease is caused by biallelic mutations in the low-density lipoprotein receptor related protein 5 gene (LRP5). The severity of the osteoporosis varies by mutation but most patients have complete blindness by early infancy. With less severe mutations, some vision may persist into childhood. Heterozygotes may have reduced bone density or osteoporosis but have normal vision.
Diagnostic methods
Diagnosis is suspected on clinical presentation (typically congenital blindness and white pupils) and confirmed by genetic testing. Fragility fractures are generally not diagnosed < age 2 and normative bone density data are not available for children < age 3, so fragility fractures and osteoporosis by bone density are not required for diagnosis.
Differential diagnosis
Osteogenesis imperfecta is the primary differential diagnosis for osteoporosis. Familial exudative vitreoretinopathy and Norrie disease are the differential diagnoses for congenital blindness and pseudoglioma.
Antenatal diagnosis
Prenatal diagnosis is possible where the pathogenic LRP5 variant has been identified in a family member.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation). Heterozygote carriers have normal vision but may have low bone mass or osteoporosis.
Management and treatment
Examination by an ophthalmologist is recommended as soon as possible. In rare patients who have retained light perception at birth, laser therapy (for retinal detachment) may be successful in maintaining some vision, at least temporarily. For osteoporosis, intravenous (pamidronate) and oral (alendronate) bisphosphonates have been used successfully to increase bone density and appear to reduce fracture risk. However, due to the rarity of OPPG, no placebo-controlled trial has been reported. Maintenance of vitamin D sufficiency is important. Age of initiation and duration of treatment need to be individualized. Treatment can be delayed until after age 3 since fractures typically do not occur prior to age 2. Treatment can generally be stopped at puberty when fracture risk decreases. In patients treated from childhood until puberty, it is possible that treatment may need to be restarted when bone aging starts (after menopause in women and after 50 in men). Anabolic bone agents are contraindicated in children, but teriparatide has been reported to be successful in an adult and an adolescent with OPPG. As in other forms of juvenile osteoporosis, leg bowing may occur in childhood and may require surgical management.
Prognosis
Besides blindness and osteoporosis there are no other chronic medical problems that have definitively been associated with OPPG. There is no known impact on life expectancy. With appropriate osteoporosis treatment, ambulation is maintained in most patients. Chronic pain due to compression fractures of the spine can occur. Morbidity in most patients is due to blindness, which is complete (no light perception) in most. There have been no quality of life studies reported in OPPG.

                            Last update:
                            July 2023

                            - Expert reviewer(s):
                            Dr Elizabeth STREETEN


A rare radiation-induced disorder characterized by exposed irradiated bone that fails to heal over a period of three months without evidence of persisting or recurrent tumor. Patients present with pain, dysesthesia, dysgeusia, fetor oris, trismus, ulceration or necrosis of the mucosa with exposure of necrotic bone, and local suppuration. Complications include pathological fractures, formation of intra- or extra-oral fistulae, and infection. MRI shows cortical destruction, abnormal bone marrow signal, and irregular contrast enhancement.


Osteosarcoma is a primary malignant tumour of the skeleton characterised by the direct formation of immature bone or osteoid tissue by the tumour cells.

Summary:
Epidemiology
Classic osteosarcoma is a rare (0.2% of all malignant tumours) highly malignant tumour, with an estimated incidence of 3 cases/million population/year.
Clinical description
Osteosarcoma arises predominantly in the long bones and rarely in the soft tissues. The age at presentation ranges from 10 to 25 years of age.
Diagnostic methods
Plain radiographs, computed tomography, magnetic resonance imaging, angiography and dynamic bone scintigraphy are used for diagnosis, evaluation the extent of tumour involvement and for making decisions about the type of operation and, if necessary, the type of reconstruction required.
Management and treatment
In the past, all patients with osteosarcoma were treated by amputation but the cure rate was under 10% and almost all patients died within a year from diagnosis. At present, the percentage of patients cured varies between 60% and 70% for localised osteosarcoma at onset (80% of cases) treated in specialised bone tumour centres with pre- and postoperative chemotherapy associated with surgery. Surgery is conservative (limb salvage) in more than 90% of patients.
Prognosis
Prognosis is more severe (cure rate about 30%) for tumours located in the axial skeleton and in patients with metastasis at onset.

                            Last update:
                            January 2007

                            - Expert reviewer(s):
                            Dr Piero PICCI


This newly described syndrome is characterized by osteosclerosis, developmental delay and craniosynostosis (see this term).

Summary:
Epidemiology
It has been reported in 13 patients from a four-generation family.
Clinical description
Osteosclerosis was constant and most pronounced in the cranial base and calvarium. Craniosynostosis was reported in four patients and a mild developmental delay in three patients. Dysmorphic features were constant and included macrocephaly, brachycephaly, wide and high forehead, hypertelorism, prominent cheekbones and prominent jaw.
Etiology
A missense mutation A214T in the low-density lipoprotein receptor related protein 5 gene, LRP5, was found in all analyzed affected individuals. In this family, findings are consistent with autosomal dominant inheritance.

                            Last update:
                            November 2010


Osteosclerosis-ichthyosis-premature ovarian failure syndrome

A rare genetic disease characterized by sclerosing dysplasia affecting the diaphyseal and metaphyseal regions of the long bones, as well as the skull and metacarpals, in association with skin changes like those seen in ichthyosis vulgaris and premature ovarian failure with bilateral hypoplasia of the ovaries. Patients present in adulthood, primarily with swelling of the extremities and occasional mild pain in the legs.


A rare disorder defined by generalized osteosclerosis with periosteal bone formation, characteristic facial dysmorphism, brain abnormalities including intracerebral calcifications, and neonatal lethal course.

Summary:
Epidemiology
Ten cases in eight families have been reported, the majority of a Middle East origin. Parental consanguinity was frequently present.
Clinical description
The cranial features are a wide anterior fontanelle, expressed proptosis with everted lower eyelids, severely depressed nasal bridge, small nose, low-set ears, and severe midface hypoplasia leading to choanal atresia. The mouth is usually triangular, gum hypertrophy is expressed, and there may be natal teeth and cleft palate/uvula. The radiological findings include generalized osteosclerosis of all bones and the base of the skull, with cortical hyperostosis and periosteal new bone formation. An obtuse mandibular angle is characteristic, as are irregularly formed ribs. Radiologically, widespread bilateral calcification in the periventricular white matter, basal ganglia, and thalamus is found and in some cases calcifications are also seen in the corpus callosum, falx, tentorium, and meninges. Extra-skeletal features can be hydronephrosis and ureteral stenosis.
Etiology
Mutations in the FAM20C gene have a causative role in lethal osteosclerotic bone dysplasia.
Diagnostic methods
Diagnosis is based on clinical presentation and calcification demonstrable by ultrasound, plain X-rays and computing tomography (CT).
Antenatal diagnosis
Prenatal diagnosis by ultrasound or molecular testing is feasible.
Genetic counseling
The condition is transmitted in an autosomal recessive manner.

                            Last update:
                            February 2008

                            - Expert reviewer(s):
                            Pr Raoul HENNEKAM


Otodental syndrome is a very rare inherited condition characterized by grossly enlarged canine and molar teeth (globodontia) associated with sensorineural hearing loss.

Summary:
Epidemiology
Prevalence of this disorder is not known. It has been described in about 10 families of European, Chinese and Brazilian descent.
Clinical description
Patients have striking pathognomonic dental features characterized by globodontia of the primary and secondary dentition, sparing the incisors. Missing teeth, especially premolars, are also reported. Due to abnormal crown morphology, there is a great propensity to formation of caries. There is a high rate of endodontic-periodontic lesions due to the aberrant coronal and pulpal morphology. The dental conditions are associated with bilateral sensorineural high-frequency hearing deficit with an age of onset that varies from early childhood to middle age. Variable facial dysmorphism has also been reported. One family was found to have an associated bilateral iris and retinal ocular coloboma.
Etiology
Haploinsufficiency in the fibroblast growth factor 3 (FGF3) gene (11q13) has been reported in patients with otodental syndrome and is thought to cause the phenotype. In the family with the associated ocular coloboma, a microdeletion in the Fas-associated death domain (FADD) gene (11q13.3) was found to be responsible for ocular features.
Diagnostic methods
The dental findings are diagnostic. Molecular genetic testing confirms the diagnosis.
Differential diagnosis
Although the association of sensorineural hearing loss and dental anomalies can be found in other syndromes, none display the striking dental manifestations of otodental syndrome.
Genetic counseling
The condition appears to be inherited in an autosomal dominant manner with complete to variable penetrance and variable expressivity. Genetic counseling should be offered to affected families.
Management and treatment
Dental management is complex, interdisciplinary and requires regular follow up, scheduled tooth extraction and eventually orthodontic treatment. Monitoring of hearing and, if necessary, hearing aids are mandatory. A preventive program is mandatory in order to maintain proper oral hygiene and health. Endodontic therapy can be difficult due to duplicated pulp canals in the affected posterior teeth. Multiple extractions may be needed and fixed or removable prostheses should be constructed. Implants are also a potential consideration.
Prognosis
The functional prognosis is mostly good with appropriate dental treatment and hearing aids. Quality of life may be affected by psychological and functional aspects.

                            Last update:
                            November 2012

                            - Expert reviewer(s):
                            Pr Agnès BLOCH-ZUPAN


Otofaciocervical syndrome is a rare, genetic developmental defect during embryogenesis syndrome characterized by distinct facial features (long triangular face, broad forehead, narrow nose and mandible, high arched palate), prominent, dysmorphic ears (low-set and cup-shaped with large conchae and hypoplastic tragus, antitragus and lobe), long neck, preauricular and/or branchial fistulas and/or cysts, hypoplastic cervical muscles with sloping shoulders and clavicles, winged, low, and laterally-set scapulae, hearing impairment and mild intellectual deficit. Vertebral defects and short stature may also be associated.


A rare multiple congenital anomalies/dysmorphic syndrome characterized by the association of dysplastic external ears, nail hypoplasia, and variable skeletal malformations, such as hypoplastic or absent fibulae, abnormalities of the scapula, clavicle, and acromioclavicular joint, and talipes equinovarus, among others. Joint contractures and mild facial dysmorphism have also been reported.


Otopalatodigital syndrome spectrum disorder is a primary bone dysplasia and encompasses a group of congenital anomalies that are characterized by skeletal dysplasia of varying clinical severity and an X linked dominant pattern of inheritance. This group includes otopalatodigital syndrome type 1 and 2 (OPD1, OPD2) which are characterized in affected males by cleft palate, conductive hearing loss, craniofacial abnormalities and skeletal dysplasia; Melnick-Needles syndrome (MNS) which displays skeletal deformities in females and embryonic or perinatal lethality in most males; frontometaphyseal dysplasia (FMD); and terminal osseous dysplasia - pigmentary defects.


A disorder that is the mildest form of otopalatodigital syndrome spectrum disorder, and is characterized by a generalized skeletal dysplasia, mild intellectual disability, conductive hearing loss, and typical facial anomalies.

Summary:
Epidemiology
To date, more than 100 cases have been described in the world literature.
Clinical description
OPD1 is a congenital disorder characterized by generalized skeletal dysplasia which include camptodactyly, long spatulate fingers, short first digits (''tree frog'' hands and feet), pectus carinatum, mild campomelia, mild femoral bowing, limitation of joint movement (elbow extension, wrist abduction) and malformed auditory ossicles leading to conductive hearing loss in some individuals. Additional features include typical craniofacial anomalies (occipital prominence, frontal bossing with prominent supraorbital ridges, flat nasal bridge, hypertelorism, microstomia, dental abnormalities, and cleft palate (pugilistic face)). In affected females, a similar but usually milder spectrum of expressivity is observed.
Etiology
OPD1 is caused by gain of function mutations in the gene FLNA (Xq28) that encodes filamin A. However the pathogenesis of OPD1 is still elusive. OPD1 is allelic with 4 other skeletal dysplasias (OPD2, Melnick-Needles syndrome (MNS), terminal osseous dysplasia - pigmentary defects (TOD) and frontometaphyseal dysplasia (FMD)).
Genetic counseling
OPD1 is inherited in an X-linked dominant manner. Male-to-male transmission has not been reported. The risk of transmitting the mutation in each pregnancy is 50%; males inheriting the mutation will be affected while females who inherit the mutation have a broad range of phenotypic expression.

                            Last update:
                            May 2015

                            - Expert reviewer(s):
                            Pr Stephen ROBERTSON


A severe form of otopalatodigital syndrome spectrum disorder, and is characterized by dysmorphic facies, severe skeletal dysplasia affecting the axial and appendicular skeleton, extraskeletal anomalies (including malformations of the brain, heart, genitourinary system, and intestine) and poor survival.

Summary:
Epidemiology
To date, more than 40 cases of Otopalatodigital syndrome type 2 (OPD2) have been described in the literature.
Clinical description
OPD2 is a congenital disorder. Intrauterine growth is usually normal and affected infants have large anterior fontanels, and facial dysmorphism including broad forehead and lateral fullness of the supraorbital ridge, hypertelorism, downslanting palpebral fissures, stubby nose with a flat root, midfacial hypoplasia, microstomia (with typical down turned bow of the upper lip), micrognathia, Pierre Robin sequence, posterior cleft palate (submucosal cleft palate or cleft velum), glossoptosis, malformed and/or apparently low-set ears. Additional features include skeletal anomalies: pectus deformity, short limbs, campomelia, fibular agenesis, flexion contractures of elbows, knees, rocker bottom or equinovarus feet, syndactyly (usually involving fingers III and IV in the hands and toes II to V in the feet), camptodactyly of fingers, and absent halluces. Extraskeletal malformations include malformations of the central nervous system (myelomeningocele /encephalocele, cerebellar hypoplasia, hydrocephalus), heart (congenital valvular heart defects), intestine, genitourinary system (hydronephrosis ± urethral valve/reflux, hypospadias, epispadias). Congenital corneal opacities, bilobed tongue, deafness, and Dandy-Walker malformation have been reported in a minority of OPD2 cases. Congenital glaucoma and cataracts have been described in one patient. Psychomotor development varies from normal to mild intellectual disability. Carrier females with OPD2 can be asymptomatic or exhibit a phenotype that can extend from a mild subclinical osteodysplasia to a presentation indistinguishable from that of affected males. Prognosis of OPD2 is poor and perinatal death is common, secondary to cardio respiratory failure.
Etiology
OPD2 is caused by gain of function mutations in the gene FLNA (Xq28) that encodes filamin A. However the pathogenesis is still elusive. OPD2 is allelic with 4 other skeletal dysplasias (OPD1, Melnick-Needles syndrome (MNS), terminal osseous dysplasia - pigmentary defects (TOD) and frontometaphyseal dysplasia (FMD)).
Genetic counseling
OPD2 is inherited in an X-linked dominant manner. Male-to-male transmission has not been reported. The risk of transmitting the mutation in each pregnancy is 50%; males inheriting the mutation will be affected while females who inherit the mutation are less severely affected.

                            Last update:
                            May 2015

                            - Expert reviewer(s):
                            Pr Stephen ROBERTSON


Otospondylomegaepiphyseal dysplasia (OSMED) is an inborn error of cartilage collagen formation characterized by sensorineural hearing loss, enlarged epiphyses, skeletal dysplasia with disproportionately short limbs, vertebral body anomalies and a characteristic facies.

Summary:
Epidemiology
The prevalence is unknown but less than 30 cases have been described in the literature so far.
Clinical description
Typical facial features include midface hypoplasia, a short nose with anteverted nares and a flat nasal bridge, a long philtrum, cleft palate/bifid uvula, micrognathia, and hypertelorism. Joint pain and restricted mobility of the metacarpophalangeal joints appear during the second decade of life. The sensorineural hearing loss is generally described as moderate and nonprogressive. Early onset of osteoarthritis has also been reported.
Etiology
OSMED is classed among the type XI collagenopathies as the majority of reported cases have been associated with homozygous mutations in the COL11A2 gene (6p21.3), encoding the alpha2 chain of type XI collagen.
Diagnostic methods
Diagnosis is made on the basis of the clinical phenotype and typical radiographic findings: shortening of the long bones (humerus, radius, ulna, tibia, and fibula) with large epiphyses and metaphyseal flaring, coronal clefting and mild to moderate platyspondyly.
Differential diagnosis
OSMED shows significant clinical overlap with Weissenbacher-Zweymuller syndrome (WZS) and Stickler syndrome (see these terms). Whilst OSMED and Stickler syndrome can be distinguished early in life due to the absence of ocular anomalies in OSMED, differentiation of OSMED and WZS (also associated with heterozygous mutations in the COL11A2 gene) may be more problematic.
Genetic counseling
OSMED is inherited as an autosomal recessive trait.
Management and treatment
Treatment is symptomatic only, involving closure of the cleft palate, audiometry and adapted management of the hearing loss, and treatment of the joint pain.
Prognosis
The prognosis depends on the severity of the osteoarthritis (which may require early joint replacement), hearing loss and joint pain.

                            Last update:
                            November 2008

                            - Expert reviewer(s):
                            Dr Martine LE MERRER


A rare malignant germ cell tumor of ovary characterized by a solid, lobulated mass, usually with a diameter of more than 10 cm, generally occurring in children or young women who present with abdominal pain or an abdominal mass and elevated serum LDH. It is bilateral in about 20% of cases, although the contralateral tumor may not be evident on macroscopic examination. Histopathologically, tumor cells are uniform rounded primitive germ cells with clear cytoplasm and macronucleoli, arranged in nests or cords separated by thin fibrous septa containing lymphocytes. Immunohistochemistry should be positive for OCT4 or SALL4, KIT (CD117), and/or D2-40.


A rare benign ovarian tumor of sex cord / stromal origin characterized by an abdominal mass which may present with abdominal pain, distension, or menorrhagia, among others, or may also be asymptomatic. Association with ascites and hydrothorax is known as Meigs syndrome. The tumor can be solid and/or cystic in nature. Histologically it features bundles of spindle cells forming variable amounts of collagen, without cellular atypia or atypical mitoses.


Ovarian fibrothecoma is a rare, benign, sex cord-stromal neoplasm, with a typically unilateral location in the ovary, characterized by mixed features of both fibroma and thecoma. Patients may be asymptomatic or may present with pelvic/abdominal pain and/or distension and, occasionally, with post-menopausal bleeding. Large tumors (>10cm) are often associated with pleural effusion and ascites (the Meigs syndrome triad).


A rare non-malformative gynecological disease affecting pre-menopausal women usually following treatment with ovarian stimulating hormones, characterized by ovarian enlargement and, to varying degrees, shift of serum from the intravascular space to the third space, mainly into the peritoneal, pleural, and to a lesser extent to the pericardial cavities. Presenting symptoms include abdomen distention, pain, nausea, and vomiting. Severity ranges from mild to life-threatening and is complicated by increased risk of thrombosis, acute hepato-renal failure, acute respiratory distress syndrome, and ovarian torsion and rupture.


Overgrowth syndrome with 2q37 translocation

A rare overgrowth syndrome with skeletal involvement characterized by long and slim body habitus and multiple skeletal manifestations, such as scoliosis, macrodactyly of the big toes, arachnodactyly of fingers and toes, camptodactyly and clinodactyly, and progressive valgus deformities of the feet. Epimetaphyseal dysplasia, bowing of the tibiae, and dysmorphic facial features (hypertelorism, high palate, or micrognathia), as well as aortic root dilatation and umbilical hernia have also been reported.