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Osteopathia Striata with Cranial Sclerosis

Synonyms: Horan-Beighton Syndrome, OS-CS

, MBChB and , MBBS, MD, FRACP, ARCPA (Hon).

Author Information

Initial Posting: .

Estimated reading time: 25 minutes

Summary

Clinical characteristics.

Most females with osteopathia striata with cranial sclerosis (OS-CS) present with macrocephaly and characteristic facial features (frontal bossing, hypertelorism, epicanthal folds, depressed nasal bridge, and prominent jaw). Approximately half have associated features including orofacial clefting and hearing loss, and a minority have some degree of developmental delay (usually mild). Radiographic findings of cranial sclerosis, sclerosis of long bones, and metaphyseal striations (in combination with macrocephaly) can be considered pathognomonic.

Males can present with a mild or severe phenotype.

Mildly affected males have clinical features similar to affected females, including macrocephaly, characteristic facial features, orofacial clefting, hearing loss, and mild-to-moderate learning delays. Mildly affected males are more likely than females to have congenital or musculoskeletal anomalies. Radiographic findings include cranial sclerosis and sclerosis of the long bones; Metaphyseal striations are more common in males who are mosaic for an AMER1 pathogenic variant.

The severe phenotype manifests in males as a multiple-malformation syndrome, lethal in mid-to-late gestation, or in the neonatal period. Congenital malformations include skeletal defects (e.g., polysyndactyly, absent or hypoplastic fibulae), congenital heart disease, and brain, genitourinary, and gastrointestinal anomalies. Macrocephaly is not always present and longitudinal metaphyseal striations have not been observed in severely affected males, except for those who are mosaic for the AMER1 pathogenic variant.

Diagnosis/testing.

The diagnosis of OS-CS is established in a female proband with characteristic features and a heterozygous pathogenic variant in AMER1 identified by molecular genetic testing. The diagnosis of OS-CS is established in a male proband with characteristic features and a hemizygous pathogenic variant in AMER1 identified by molecular genetic testing.

Management.

Treatment: Scoliosis management per orthopedic surgeon; physiotherapy may be helpful for joint contractures; management of oral facial clefts per otolaryngologist; hearing loss is managed by audiology, speech and language therapy, and otolaryngology; vision loss management per ophthalmologist and neurosurgery for nerve compression as indicated; early intervention services and special education as indicated; standard treatments for cardiac, genitourinary, and gastrointestinal anomalies and Wilms tumor or other malignancy.

Surveillance: Annual clinical assessment for skeletal manifestations such as scoliosis, joint contractures, stress fractures, and persistent bone pain. Annual audiology and ophthalmology evaluations for evidence of cranial nerve compression due to sclerotic bone disorder. Consider abdominal ultrasound every three months until age seven years to screen for Wilms tumor.

Genetic counseling.

OS-CS is inherited in an X-linked manner. The risk to sibs of a male proband depends on the genetic status of the mother. The risk to sibs of a female proband depends on the genetic status of the mother and the father. If the mother of the proband has an AMER1 pathogenic variant, the chance of transmitting it in each pregnancy is 50%. If the father of the proband has an AMER1 pathogenic variant, it should be presumed he will transmit the AMER1 pathogenic variant to all his daughters and none of his sons (to date, paternal transmission has only been reported in mosaic fathers). Females who inherit an AMER1 pathogenic variant will be heterozygotes and will have variable manifestations of OS-CS. Males who inherit a pathogenic variant will be hemizygotes and will have variable manifestations ranging from mid-late gestation and neonatal lethality to the mild phenotype. Once the AMER1 pathogenic variant is identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Diagnosis

No consensus clinical diagnostic criteria for osteopathia striata with cranial sclerosis (OS-CS) have been published, however the combination of macrocephaly, cranial sclerosis, and longitudinal metaphyseal striations of the long bones are considered highly characteristic of this condition.

Suggestive Findings

OS-CS should be suspected in individuals with the following clinical and radiographic findings.

Females and Mosaic and/or Mildly Affected Males

Clinical findings

  • Characteristic facial features (e.g., frontal bossing, hypertelorism, epicanthal folds, depressed nasal bridge, prominent jaw)
  • Macrocephaly and stature short for mid-parental height
  • Orofacial clefting
  • Hearing loss (conductive and sensorineural) and progressive hearing loss
  • Poor or reduced vision
  • Normal intellect or mild developmental delays

Radiographic findings

  • Sclerosis of the cranium and skull base
  • Sclerosis of lamellar and trabecular bones
  • Metaphyseal, longitudinal striations of the long bones and pelvis (Note: Metaphyseal striations are typically absent in mildly affected constitutional males but present in mosaic males.)
  • Fibular aplasia or hypoplasia
  • Small exostoses

Severely Affected Males

Clinical findings

  • Fetal or neonatal death
  • Macrocephaly (50%)
  • Orofacial clefting (cleft palate or cleft lip and palate)
  • Facial features (frontal bossing, hypertelorism, depressed nasal bridge, and micrognathia)
  • Multiple congenital malformations:
    • Skeletal anomalies (polysyndactyly, talipes)
    • Genitourinary anomalies (echogenic or enlarged kidneys, nephrogenic rests)
    • Gastrointestinal anomalies (omphalocele, intestinal malrotation)
    • Congenital heart disease (hypoplastic left or right heart, septal defects, patent ductus arteriosus)
    • Brain anomalies (ventriculomegaly, abnormal corpus callosum)

Imaging findings

  • Cranial sclerosis
  • Sclerosis of pelvis and long bones
  • Bilateral absent or hypoplastic fibulae

Establishing the Diagnosis

Female proband. The diagnosis of OS-CS is established in a female proband with suggestive findings and can be confirmed with a heterozygous pathogenic variant in AMER1 identified by molecular genetic testing (see Table 1).

Male proband. The diagnosis of OS-CS is established in a male proband with suggestive findings and can be confirmed with a hemizygous pathogenic variant in AMER1 identified by molecular genetic testing (see Table 1).

Note: Identification of a heterozygous/hemizygous AMER1 variant of uncertain significance does not establish or rule out a diagnosis of this disorder.

Molecular genetic testing approaches can include single-gene testing, chromosomal microarray analysis, multigene panel, and comprehensive genomic testing:

  • Single-gene testing. Sequence analysis of AMER1 is performed first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.
  • Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including AMER1) that cannot be detected by sequence analysis.
  • A multigene panel that includes AMER1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • When the phenotype is indistinguishable from many other skeletal dysplasias, comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.
    For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Osteopathia Striata with Cranial Sclerosis

Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method
AMER1 Sequence analysis 3~75% 4
Gene-targeted deletion/duplication analysis 5~25% 4
CMA 6See footnote 7.
1.
2.

See Molecular Genetics for information on variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Review of approximately 90 pathogenic variants in the published literature [Author, personal observation], correlation with smaller published case series [Jenkins et al 2009, Perdu et al 2011], and data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2017]

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including AMER1) that cannot be detected by sequence analysis. The ability to determine the size of the deletion/duplication depends on the type of microarray used and the density of probes in the Xq11.2 region. CMA designs in current clinical use target the Xq11.2 region.

7.

Several contiguous deletions including AMER1 have been reported in individuals with features of OS-CS [Chénier et al 2012, Herman et al 2013, Holman et al 2013]. Contiguous gene deletions that include AMER1 and neighboring genes ARHGEF9 and MTMR8 appear to cause OS-CS with intellectual disability in females. Deletions including AMER1 and ASB12 only are not reported to be associated with intellectual disability [Holman et al 2013].

Clinical Characteristics

Clinical Description

To date, approximately 90 individuals with a pathogenic variant in AMER1 have been reported in the medical literature [Jenkins et al 2009; Perdu et al 2011; Author, personal observation]. The following description of the phenotypic features associated with this condition is based on these reports.

Table 2.

Osteopathia Striata with Cranial Sclerosis: Frequency of Select Features in Females and Mildly Affected Males

Feature% of Persons with Feature 1Comment
Cranial sclerosis100%
Sclerosis of long bones100%
Metaphyseal striations~95%In females & mosaic males; not seen in constitutional males
Characteristic facial features~90%Frontal bossing, hypertelorism, epicanthal folds, depressed nasal bridge
Macrocephaly~80%Absolute or relative macrocephaly
Orofacial clefting~50%Cleft palate or cleft lip and palate
Hearing loss~50%Conductive &/or sensorineural
Mild developmental delays~30%Severe developmental delay is rare.
Congenital heart disease~25%
Wilms tumor 2~5% 3Additional malignancies reported: hepatoblastoma, adult-onset colorectal cancer, adult-onset ovarian cancer
1.

Review of approximately 90 individuals reported with OS-CS and an AMER1 pathogenic variant

2.

Association with Wilms tumor (and possibly other cancers) is an emerging feature and a significant departure from what was previously understood about the disorder.

3.

Extrapolated from recently published data [Bach et al 2021]

Affected Females

Most females with osteopathia striata with cranial sclerosis (OS-CS) present with macrocephaly and characteristic facial features (frontal bossing, hypertelorism, epicanthal folds, and a depressed nasal bridge). Approximately half have associated features including orofacial clefting and hearing loss, and a minority have some degree of developmental delay (usually mild). Radiographic findings of cranial sclerosis, sclerosis of long bones, and metaphyseal striations (in combination with macrocephaly) can be considered pathognomonic.

  • Cranial sclerosis. Observed on radiographs of the skull, most notably in the vault. It can be present at birth, and is typically progressive.
  • Sclerosis of the pelvis and long bones. Best observed on radiographs of the pelvis and diaphyses of the femora and humeri. It can be present at birth, and is typically progressive.
  • Metaphyseal striations. Best observed on radiographs of the pelvis, proximal and distal femora, proximal tibiae, and humeri. It can be present antenatally, but usually develops during childhood.
  • Characteristic facial features. Most commonly include frontal bossing, hypertelorism, epicanthal folds, and a depressed nasal bridge. These features can be present at birth, and typically become more exaggerated with age, particularly frontal bossing.
  • Macrocephaly is usually of postnatal onset and is associated with cranial sclerosis. It is usually absolute (>+2.5 SD), but can be relative to height or weight.
  • Stature. Unlike in many other skeletal dysplasias, short stature is not commonly associated with OS-CS.
  • Orofacial clefting. Typically cleft hard palate; bifid uvula has also been observed.
  • Hearing loss. Both conductive and sensorineural hearing loss have been observed; hearing loss occurs in approximately 50% of females [Jenkins et al 2009, Perdu et al 2011].
  • Cranial nerve palsies. Rarely, compression of the optic nerve due to bony sclerosis can lead to vision loss, and facial palsies have been reported. This can be progressive, and typically occurs in late adolescence and early adulthood.
  • Cognition. Most females with OS-CS have normal intellect and a minority (30%) have mild learning delays [Jenkins et al 2009, Perdu et al 2011]. One female with severe learning delays has been reported [Jenkins et al 2009].
  • Congenital heart disease. Approximately 25% of females with OS-CS have a structural heart defect [Jenkins et al 2009, Perdu et al 2010]. Atrial septal defects, ventricular septal defects, and patent ductus arteriosus are the most commonly described structural anomalies.
  • Association with cancer. An association of OS-CS with cancer is emerging in the literature. To date, cancer has only been reported in females with OS-CS, including four instances of pediatric-onset Wilms tumor: one female with bilateral tumors [Sperotto et al 2017, Bach et al 2021], one with a pediatric-onset hepatoblastoma [Fujita et al 2014], one with an adult-onset colorectal cancer [Jenkins et al 2009], and one with adult-onset ovarian cancer [Perdu et al 2010].

Affected Males

There appear to be two distinct phenotypes in males: mild and severe.

Mild phenotype. Mildly affected males have clinical features similar to affected females, including macrocephaly, characteristic facial features, orofacial clefting, hearing loss, and mild-to-moderate learning delays. Mildly affected males are more likely than females to have congenital or musculoskeletal anomalies. Males with the mild phenotype may have a mosaic or constitutional AMER1 pathogenic variant, each with distinct radiographic features. Shared radiographic findings include cranial sclerosis and sclerosis of the long bones, however metaphyseal striations are more common in mosaic males.

  • Cranial sclerosis and sclerosis of the pelvis and long bones. Best observed on radiographs of the skull, pelvis, femora, and humeri. Sclerosis appears to be more marked compared with females, possibly due to the hemizygous nature of the pathogenic variant in males.
  • Metaphyseal striations have only been observed in one constitutional male [Holman et al 2011], a number of mosaic males [Joseph et al 2010, Perdu et al 2011, Chénier et al 2012], and a male with Klinefelter syndrome [Fradin et al 2017]. They are best observed on radiographs of the pelvis, femora, and humeri (see Pathophysiology).
  • Characteristic facial features most commonly include frontal bossing, hypertelorism, epicanthal folds, and a depressed nasal bridge.
  • Macrocephaly is usually of postnatal onset and is associated with cranial sclerosis. It is usually absolute, (>+3 SD), but can be relative to height or weight.
  • Stature. Proportionate short stature of <‒2 SD is commonly associated with OS-CS in males [Holman et al 2011].
  • Orofacial clefting, typically hard cleft palate, is observed in approximately 66% of mildly affected males [Holman et al 2011, Perdu et al 2011].
  • Hearing loss. Both conductive and sensorineural hearing loss have been reported. Hearing loss is more common in mildly affected males (~85%) compared with females [Holman et al 2011, Perdu et al 2011].
  • Cranial nerve palsies. Rarely, compression of the optic nerve due to bony sclerosis can lead to vision loss, and facial palsies have been reported. This can be progressive, and typically occurs in late adolescence and early adulthood.
  • Cognition. Learning problems are more common in surviving males than females, with approximately 80% of males having mild-to-moderate developmental delays [Holman et al 2011, Perdu et al 2011, Chénier et al 2012, Hague et al 2017].
  • Musculoskeletal. Scoliosis (which can be progressive) and joint contractures are commonly observed in mildly affected males [Holman et al 2011].
  • Congenital anomalies. Congenital heart disease is observed in approximately half of mildly affected males [Perdu et al 2011]. Brain malformations including ventriculomegaly and partial agenesis of the corpus callosum are also observed in this cohort [Holman et al 2011].

Severe phenotype. The severe phenotype manifests as a multiple-malformation syndrome, and is lethal in mid-to-late gestation or in the neonatal period [Holman et al 2011, Perdu et al 2011, Quélin et al 2015, Vasiljevic et al 2015]. Severely affected males typically have fewer of the characteristic features described in females, in part due to early mortality. In particular, macrocephaly is not always present, and longitudinal metaphyseal striations have not been observed. Severely affected males typically have multiple congenital malformations including limb patterning and skeletal defects (e.g., polysyndactyly, absent or hypoplastic fibulae), congenital heart disease, and brain, genitourinary, and gastrointestinal anomalies.

Pathophysiology

Metaphyseal striations are hypothesized to be due to the presence of two independently acting osteoblast cell lines [Rott et al 2003]. This can occur either through differential X-chromosome inactivation in a female or mosaicism for an AMER1 pathogenic variant in a male. This hypothesis would explain why constitutionally affected males with a hemizygous AMER1 pathogenic variant and only one osteoblast cell line do not have metaphyseal striations on radiographs.

Genotype-Phenotype Correlations

No genotype-phenotype correlations for AMER1 have been confirmed.

Initial reports of truncating variants at the 5' end of AMER1 predicting a severe phenotype have been disproven [Perdu et al 2010, Perdu et al 2011].

Penetrance

Penetrance appears to be 100%, albeit with variable expressivity and severity of the phenotype, even within families.

Nomenclature

Previous gene names for AMER1 include WTX and FAM123B.

OS-CS is also known as hyperostosis generalisata with striations.

Prevalence

Approximately 90 individuals with molecularly confirmed OS-CS have been reported [Author, personal observation].

Differential Diagnosis

Females and mildly affected males. Disorders that may present with sclerotic bone disease similar to that observed in females (and mildly affected males) with OS-CS are summarized in Table 3. See also the Nosology and Classification of Genetic Skeletal Disorders: 2019 Revision, Group 23 – "Osteopetrosis and related disorders" and Group 24 – "Other sclerosing bone disorders" [Mortier et al 2019] for a review of additional disorders that may be considered in the differential diagnosis of OS-CS.

Males with a severe phenotype present with a multiple-malformation syndrome, usually without metaphyseal striations, making the differential diagnosis very broad. AMER1 should be included within the gene list for any fetal or neonatal multiple-malformation presentation.

Table 3.

Genes of Interest in the Differential Diagnosis of Osteopathia Striata with Cranial Sclerosis

Gene(s)DiffDx DisorderMOIClinical Features of DiffDx Disorder
Overlapping w/OS-CSDistinguishing from OS-CS
ANKH Craniometaphyseal dysplasia, autosomal dominant ADBony sclerosis of cranial bones
  • Metaphyseal flaring
  • Absence of metaphyseal striations
CA2
CLCN7
LRP5
OSTM1
PLEKHM1
SNX10
TCIRG1
TNFRSF11A
TNFSF11
Osteopetrosis 1 (OMIM PS259700 & PS607634)AR
AD
Bony sclerosis of cranial and long bones
  • Absence of dysmorphic features
  • More diffuse sclerosis of long bones
  • Absence of metaphyseal striations
GJA1 Craniometaphyseal dysplasia, autosomal recessive (OMIM 218400)ARBony sclerosis of cranial bones
  • Metaphyseal widening
  • Absence of metaphyseal striations
LRP4 Sclerosteosis 2 (OMIM 614305)AD
AR
Bony sclerosis
  • Absence of dysmorphic features
  • Absence of metaphyseal striations
PORCN Focal dermal hypoplasia (Goltz syndrome)XLMetaphyseal striations
  • Ectodermal manifestations
  • Limb malformations
  • Ocular manifestations
SOST Endosteal hyperostosis, van Buchem type (van Buchem disease; see SOST-Related Sclerosing Bone Dysplasias.)ARBony sclerosis
  • Absence of metaphyseal striations
  • Progressive skeletal overgrowth
  • Hyperphosphatasemia
Craniodiaphyseal dysplasia (OMIM 122860)ADBony sclerosis; progressive overgrowth of craniofacial bones w/cranial nerve entrapment
  • Absence of metaphyseal striations
  • Diaphyses of long bones expanded within the cortices
  • Choanal stenosis a common complication
Sclerosteosis (See SOST-Related Sclerosing Bone Dysplasias.)ARBony sclerosis
  • Absence of metaphyseal striations
  • 2-3 finger syndactyly, nail dysplasia
TGFB1 Camurati-Engelmann disease (progressive diaphyseal dysplasia)ADBony sclerosis of cranial and long bones
  • Absence of metaphyseal striations
  • Pronounced diaphyseal hyperostosis of long bones
  • Proximal muscle weakness & wide-based waddling gait
TONSL Spondyloepimetaphyseal dysplasia, sponastrime type (OMIM 271510)ARMetaphyseal striations
  • Spondylar changes
  • Absence of OS-CS facial characteristics
  • Absence of sclerosis

AD = autosomal dominant; AR = autosomal recessive; DiffDx = differential diagnosis; MOI = mode of inheritance; XL = X-linked

1.

See also the Nosology and Classification of Genetic Skeletal Disorders: 2019 Revision, Group 23 – "Osteopetrosis and related disorders" and Group 24 – "Other sclerosing bone disorders" [Mortier et al 2019].

Voorhoeve disease (osteopathia striata) is characterized by isolated metaphyseal striations. Unlike OS-CS, Voorhoeve disease is not associated with cranial sclerosis or macrocephaly. Voorhoeve disease may be inherited in an autosomal dominant manner or occur in a single family member; the genetic cause(s) of the disorder are unknown.

Management

No consensus clinical diagnostic criteria for osteopathia striata with cranial sclerosis (OS-CS) have been published.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with OS-CS, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 4.

Recommended Evaluations Following Initial Diagnosis in Individuals with Osteopathia Striata with Cranial Sclerosis

System/ConcernEvaluationComment
Musculoskeletal Skeletal survey – long bones & skullTo assess for sclerosis &/or metaphyseal striations
Clinical assessment for scoliosis & joint contractures
ENT ENT assessmentTo assess for orofacial clefting
Hearing Hearing assessmentTo evaluate hearing loss
Eyes Ophthalmology assessmentTo evaluate for optic nerve compression
Constitutional Growth assessmentTo assess for short stature in surviving males (less common in females)
Cognition Developmental assessment
Cardiac Cardiology assessment incl echocardiographyTo assess for structural heart defects in females & surviving males
Renal Renal ultrasound exam
  • To assess for renal anomalies in surviving males
  • To evaluate for nephrogenic rests &/or Wilms tumor in females & males
Neurology Neurology assessment incl brain MRITo assess for CNS anomalies in surviving males
Gastroenterology Imaging for malrotation performed as clinically indicated
Genetic
counseling
By genetics professionals 1To inform affected persons & families re nature, MOI, & implications of OS-CS in order to facilitate medical & personal decision making
Family support/
resources
Assess:

CNS = central nervous system; MOI = mode of inheritance; OS-CS = osteopathia striata with cranial sclerosis

1.

Medical geneticist, certified genetic counselor, certified advanced genetic nurse

Treatment of Manifestations

Management by multidisciplinary specialists, including pediatrician, clinical geneticist, orthopedic surgeon, ENT specialist, and, in the presence of congenital malformations, relevant additional subspecialists, is recommended.

Table 5.

Treatment of Manifestations in Individuals with Osteopathia Striata with Cranial Sclerosis

Manifestation/
Concern
TreatmentConsiderations/Other
Scoliosis Management per orthopedic surgeon
Joint contractures PT may be helpful.
Orofacial clefting Management per ENT surgeon
Hearing loss
  • Management per audiologist
  • Speech/language therapy
  • Surgical management per otolaryngologist should be considered on a case-by-case basis if underlying pathology involves foraminal compression.
  • Community & support groups for hearing loss
  • Sclerotic bone poses surgical challenges [Katsevman et al 2016], and the success of surgical decompression of cranial nerve foramina in OS-CS is not established.
Vision loss Management per ophthalmologistCommunity & support groups for vision loss
Surgical management per neurosurgeon should be decided on a case-by-case basis.Sclerotic bone poses surgical challenges [Katsevman et al 2016], and the success of surgical decompression of cranial nerve foramina in OS-CS is not established.
Cognition Early intervention services & special education services as indicated
Cardiac anomalies Treatment per cardiologist
Genitourinary
anomalies
Treatment per urologist &/or nephrologist
Gastrointestinal
anomalies
Treatment per gastroenterologist &/or surgery
Wilms tumor &/or
other malignancy
Standard treatment

PT = physical therapy

Surveillance

Table 6.

Recommended Surveillance for Individuals with Osteopathia Striata with Cranial Sclerosis

System/ConcernEvaluationFrequency
Musculoskeletal Clinical assessment for scoliosis & joint contracturesAnnually or as indicated
Hearing Audiology eval
Vision Ophthalmology eval
Cognition Developmental assessment
Wilms tumor Abdominal ultrasoundEvery 3 mos until age 7 yrs as per Beckwith-Wiedemann syndrome guidelines until OS-CS specific guidelines are established 1
1.

The association of OS-CS with Wilms tumor has only recently been established [Bach et al 2021]. Until there is an evidentiary base for OS-CS-specific surveillance guidelines, surveillance based on Beckwith Wiedemann syndrome guidelines is recommended [Brioude et al 2018; Bach et al 2021; Author, personal communication with Professor Stephen Robertson].

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from early diagnosis and treatment of hearing and/or vision loss and congenital heart disease, from cancer surveillance, and from review for congenital anomalies (males).

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

No specific OS-CS pregnancy management is described, but guidelines for management of pregnant individuals with a skeletal dysplasia should be consulted [Savarirayan et al 2018].

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Osteopathia striata with cranial sclerosis (OS-CS) is inherited in an X-linked manner.

Risk to Family Members

Parents of a male proband

  • The father of an affected male will not have the disorder nor will he be hemizygous for the AMER1 pathogenic variant; therefore, he does not require further evaluation/testing.
  • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the AMER1 pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
  • If a male is the only affected family member (i.e., a simplex case):
  • Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment.

Sibs of a male proband. The risk to sibs depends on the genetic status of the mother:

  • If the mother of the proband has an AMER1 pathogenic variant, the chance of transmitting it in each pregnancy is 50%.
    • Females who inherit the pathogenic variant will be heterozygotes and will have variable manifestations of OS-CS (see Clinical Description, Affected Females)
    • Males who inherit the pathogenic variant will be hemizygotes and will have variable manifestations ranging from mid-late gestation and neonatal lethality to the mild phenotype (see Clinical Description, Affected Males).
      Of the males reported in the literature, approximately half died in mid-late gestation or the neonatal period. However, the incidence of lethality is likely to be under-reported, due to the nonspecific multiple-malformation presentation of males, increasing the likelihood of a missed diagnosis. The low number of reported males suggests that early fetal loss is also possible.
  • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the AMER1 pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is presumed to be low but greater than that of the general population because of the possibility of maternal germline mosaicism.

Parents of a female proband

  • A female proband may have inherited the AMER1 pathogenic variant from either her mother or her father, or the pathogenic variant may be de novo. About 45% of affected females have the disorder as the result of a de novo pathogenic variant.
  • Note: Paternal inheritance has only been reported in mosaic fathers [Ciceri et al 2013, Mi et al 2020].
  • Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a de novo pathogenic variant from those with an inherited pathogenic variant. Molecular genetic testing of the mother (and subsequently the father) can help to determine if the pathogenic variant was inherited.

Sibs of a female proband. The risk to sibs depends on the genetic status of the parents:

  • If the mother of the proband has an AMER1 pathogenic variant, the chance of transmitting it in each pregnancy is 50%.
    • Females who inherit the pathogenic variant will be heterozygotes and will have variable manifestations of OS-CS (see Clinical Description).
    • Males who inherit the pathogenic variant will be hemizygotes and will have variable manifestations ranging from mid-late gestation and neonatal lethality to the mild phenotype (see Clinical Description).
      Of the males reported in the literature, approximately half died in mid-late gestation or the neonatal period. However, the incidence of lethality is likely to be under-reported, due to the nonspecific multiple-malformation presentation of males, increasing the likelihood of a missed diagnosis. The low number of reported males suggests that early fetal loss is also possible.
  • If the father of the proband has an AMER1 pathogenic variant, it should be presumed he will transmit the AMER1 pathogenic variant to all his daughters and none of his sons. Only two instances of paternal vertical transmission have been reported; in both families the fathers were mosaic [Ciceri et al 2013, Mi et al 2020].
  • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the AMER1 pathogenic variant cannot be detected in the leukocyte DNA of either parent, the risk to sibs is greater than that of the general population because of the possibility of parental germline mosaicism.

Offspring of a male proband. Men with an AMER1 pathogenic variant will transmit the AMER1 pathogenic variant to all of their daughters and none of their sons.

Offspring of a female proband. Women with an AMER1 pathogenic variant have a 50% chance of transmitting the pathogenic variant to each child:

Other family members. If the mother of the proband is heterozygous for an AMER1 pathogenic variant (or, theoretically, the father is hemizygous for the AMER1 pathogenic variant), her (or his) family members may be at risk of being affected.

Note: Molecular genetic testing may be able to identify the family member in whom a de novo pathogenic variant arose, information that could help determine genetic risk status of the extended family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, heterozygous, or at increased risk of being affected or heterozygous.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).

Prenatal Testing and Preimplantation Genetic Testing

Once the AMER1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Alexander Graham Bell Association for the Deaf and Hard of Hearing
    Phone: 866-337-5220 (toll-free); 202-337-5221 (TTY)
    Fax: 202-337-8314
    Email: info@agbell.org
  • American Society for Deaf Children
    Phone: 800-942-2732 (ASDC)
    Email: info@deafchildren.org
  • National Association of the Deaf
    Phone: 301-587-1788 (Purple/ZVRS); 301-328-1443 (Sorenson); 301-338-6380 (Convo)
    Fax: 301-587-1791
    Email: nad.info@nad.org
  • International Skeletal Dysplasia Registry
    UCLA
    615 Charles E. Young Drive
    South Room 410
    Los Angeles CA 90095-7358
    Phone: 310-825-8998
    Fax: 310-206-5266
    Email: Salon@mednet.ucla.edu

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Osteopathia Striata with Cranial Sclerosis: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
AMER1 Xq11​.2 APC membrane recruitment protein 1 FAM123B @ LOVD AMER1 AMER1

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Osteopathia Striata with Cranial Sclerosis (View All in OMIM)

300373OSTEOPATHIA STRIATA WITH CRANIAL SCLEROSIS; OSCS
300647APC MEMBRANE RECRUITMENT PROTEIN 1; AMER1

Molecular Pathogenesis

AMER1 (also known as FAM123B or WTX) encodes adenomatous polyposis coli membrane recruitment protein 1.

The AMER1 protein acts as an inhibitor of the canonic WNT signaling pathway, through the ubiquitination and degradation of beta-catenin [Tanneberger et al 2011]. The WNT signaling pathway acts on a range of cellular processes including body axis patterning and bone morphogenesis. Up- or downregulation of this pathway can have a broad range of phenotypic effects [Huybrechts et al 2020].

Reduced expression of AMER1 (e.g., through a loss-of-function variant) leads to an accumulation of beta catenin in the nucleus. This in turn causes upregulation of the WNT pathway and osteoblastic function, leading to bony sclerosis [Mi et al 2020].

Metaphyseal striations are hypothesized to be due to the presence of two independently acting osteoblast-cell lines [Rott et al 2003]. This can occur either through differential X-chromosome inactivation in a female or mosaicism for an AMER1 pathogenic variant in a male. This hypothesis would explain why constitutionally affected males with a hemizygous AMER1 pathogenic variant and only one osteoblast cell line do not have metaphyseal striations on radiographs.

Mechanism of disease causation. Loss of function

AMER1-specific laboratory technical considerations. AMER1 contains two exons, the first of which is noncoding. To date, almost all reported pathogenic variants causing osteopathia striata with cranial sclerosis (OS-CS) are germline truncating variants in exon 2 or whole-gene deletions [Author, personal observation].

However, two pathogenic variants in the noncoding exon 1 of AMER1 have been reported, which may not be captured by traditional sequencing methods [Mi et al 2020].

Mosaicism has also been reported in several males [Joseph et al 2010, Holman et al 2011, Perdu et al 2011, Chénier et al 2012, Hague et al 2017], and in a male with Klinefelter syndrome [Fradin et al 2017]. Alternative cell lines, alternative technologies, or an increased depth of sequencing should be considered to identify suspected mosaic pathogenic variants.

Cancer and Benign Tumors

Somatic AMER1 variants are found in 15%-30% of Wilms tumors, evenly divided between mesenchymal- and epithelial-derived tumors [Fukuzawa et al 2009].

Early studies suggested that germline AMER1 variants did not predispose to Wilms tumors; however, a recent association has been reported in four individuals including one with bilateral Wilms tumors [Bach et al 2021].

Chapter Notes

Acknowledgments

Thank you to Professor Stephen Robertson and his working groups for their significant contributions to the OS-CS literature and for communications regarding cancer surveillance recommendations.

Revision History

  • 15 April 2021 (sw) Review posted live
  • 4 February 2021 (rs) Original submission

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