Sclerosing Bone Dysplasias (Sclerosteosis, Van Buchem, Pyknodysostosis and Others)

Literature and regulatory information updated: 29 October 2026.

Class of genetic skeletal disorders with increased bone density or volume without a primary osteopetrotic-type defect of osteoclastic resorption: SOST- and LRP4-related dysplasias (sclerosteosis, van Buchem disease, craniodiaphyseal dysplasia), endosteal hyperostosis and osteosclerosis due to LRP5 gain of function, pyknodysostosis (CTSK), Camurati-Engelmann disease (TGFB1, TGFB2), osteopathia striata with cranial sclerosis (AMER1), craniometaphyseal dysplasia (ANKH, GJA1), osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis (LEMD3; somatic MAP2K1 and SMAD3), Pyle disease (SFRP4), Lenz-Majewski dysplasia (PTDSS1) and related entities. The osteopetroses form part of the differential diagnosis.

0. Initial Reference Table

The table brings together the entities of the article, with the numbers of the Online Mendelian Inheritance in Man (OMIM) catalogue and of Orphanet (ORPHA). Orphanet prevalence figures expressed as a class («< 1/1,000,000») are upper limits and not estimates; counts of published cases are not equivalent to prevalence [1–3].

The European reference network for all these entities is ERN BOND (European Reference Network on Rare Bone Diseases) [45]. The other disorders of the class — dysosteosclerosis, osteomesopyknosis, Raine dysplasia, Ghosal haematodiaphyseal dysplasia, osteoectasia with hyperphosphatasia, sclerosteo-cerebellar syndrome, craniometadiaphyseal dysplasia wormian bone type and SP7-related craniodiaphyseal dysplasia — appear in the table in section 6.

1. Introduction

1.1. Definition of the class and terminology

Sclerosing bone dysplasias are genetic skeletal disorders in which radiographs show increased bone density, often associated with changes in bone shape and a progressive natural history [16]. The Oxford Desk Reference distinguishes sclerosis, a generalised change with increased density, from hyperostosis, overgrowth localised to one part of the bone, and recalls that in osteopetrosis cortex and cancellous bone can no longer be distinguished on radiographs [16]. The same text reproduces the division of the International Nomenclature of Constitutional Disorders of Bone into four groups: increased density without change in bone shape, increased density with diaphyseal involvement, increased density with metaphyseal involvement and severe neonatal osteosclerotic disorders [16]. The GeneReviews on SOST-related dysplasias proposes a complementary functional division: osteoscleroses, such as osteopetrosis, have increased density without overgrowth and with little change in contour; craniotubular dysplasias have abnormal skeletal modelling and moderate sclerosis of the vault and base; in craniotubular hyperostoses bone overgrowth predominates, altering contours and making the bones very resistant to trauma [5].

The 2023 revision of the Nosology of Genetic Skeletal Disorders places the osteopetroses and pyknodysostosis, renamed «CTSK-related pyknodysostosis», in group 24 (osteopetrosis and related osteoclast disorders), and the SOST-related dysplasias, AMER1-related osteopathia striata with cranial sclerosis and other entities in group 25 (osteosclerotic disorders) [5, 18, 26, 46]. The same revision renamed van Buchem disease «SOST-related van Buchem-type endosteal hyperostosis» and Camurati-Engelmann disease «TGFB1-related Camurati-Engelmann diaphyseal dysplasia» [5, 23]. Orphanet groups these entities in the category «primary bone dysplasia with increased bone density» (ORPHA:93444) [47]. This article follows this nomenclature, mentions the osteopetroses in the differential diagnosis and brings together the other sclerosing dysplasias in a uniform structure, with more detailed coverage of the most frequent or most severe entities.

1.2. Original descriptions

The clinical descriptions preceded the identification of the genes by several decades. According to the atlas by Spranger and colleagues, which cites the original works, van Buchem and colleagues described in 1962 seven patients with «hyperostosis corticalis generalisata», added eight in 1971 and published in 1970 the table of Dutch patients that still serves as an iconographic reference; the term «sclerosteosis» was used by Hansen in 1967, and Beighton and colleagues established autosomal recessive inheritance of sclerosteosis in 1977 [48]. GeneReviews adds that these disorders were grouped in the past under non-specific designations such as «marble bones», «osteopetrosis» or «Albers-Schönberg disease», until syndromic delineation established the current terms [5].

Pyknodysostosis was individualised by Maroteaux and Lamy in 1962, who chose the name from the Greek pyknos, dense; before that date, the association between cleidocranial dysostosis, osteosclerosis and bone fragility had already been noted [18, 49]. The designation «Maroteaux-Lamy syndrome», sometimes applied to pyknodysostosis, refers mainly to mucopolysaccharidosis type VI (gene ARSB), which requires care with nomenclature [18]. The name «Toulouse-Lautrec syndrome» reflects the retrospective hypothesis that the painter Henri de Toulouse-Lautrec (1864–1901) had this disease, because of short stature, parental consanguinity, facial dysmorphism, frequent fractures and large fontanelles; the hypothesis was proposed by Maroteaux and contested by the biographer J. Frey in 1995 [18, 50].

Camurati-Engelmann disease was described by Camurati in 1922 and, as a second observation, by Engelmann in 1929, under the name «osteopathia hyperostotica (sclerotisans) multiplex infantilis»; Neuhauser and colleagues coined the term «progressive diaphyseal dysplasia» in 1948 [23, 51]. Ribbing disease, with late, mild and asymmetric forms, was recognised as a phenotypic variant of the same disease when TGFB1 variants were found in these patients [23, 51]. Craniometaphyseal dysplasia was delineated by Jackson and colleagues in 1954, Pyle disease originates from the 1931 description, and Lenz-Majewski dysplasia was proposed as a distinct syndrome in 1974 [31, 42, 52]. Although Voorhoeve is usually credited with the first observation of osteopathia striata with cranial sclerosis, his original cases had no cranial radiographs [53].

1.3. Milestones of molecular discovery

The genes were identified in the following chronological order. In 1996, Gelb and colleagues showed that pyknodysostosis is a lysosomal disease caused by cathepsin K deficiency [54]. In 2000, Kinoshita and colleagues described domain-specific TGFB1 variants in Camurati-Engelmann disease [55]. In 2001, Brunkow and colleagues mapped sclerosteosis in Afrikaner families by homozygosity to an interval of about 2 cM at 17q12-q21 and identified a new gene, SOST, with a nonsense variant in Afrikaners and a splicing variant in a patient of Senegalese origin; in the same year, Balemans and colleagues related the increased bone density to deficiency of this secreted protein [56, 57]. Also in 2001, two groups identified heterozygous ANKH variants in autosomal dominant craniometaphyseal dysplasia [58, 59].

In 2002, Balemans and colleagues and, independently, Staehling-Hampton and colleagues showed that van Buchem disease results from a homozygous 52 kb deletion in the SOST–MEOX1 intergenic region, without change in the SOST coding sequence [60, 61]. In the same year, Boyden and colleagues and Little and colleagues linked the autosomal dominant high bone mass phenotype to LRP5 variants, and Van Wesenbeeck and colleagues described in 2003 six new LRP5 missense variants in different conditions with increased bone density [62–64]. In 2004, Hellemans and colleagues showed that loss-of-function LEMD3 variants cause osteopoikilosis, Buschke-Ollendorff syndrome and, in some patients, melorheostosis [65]. In 2009, Jenkins and colleagues identified germline WTX (now AMER1) variants in osteopathia striata with cranial sclerosis [66].

The following decade added allelic mechanisms and new genes: SOST signal peptide variants in autosomal dominant craniodiaphyseal dysplasia (2011), LRP4 variants that impair the facilitating function of sclerostin (2011), a recessive GJA1 variant in craniometaphyseal dysplasia (2013), PTDSS1 gain-of-function variants in Lenz-Majewski dysplasia (2014), biallelic truncating SFRP4 variants in Pyle disease (2016), activating somatic mosaicism of MAP2K1 (2018) and SMAD3 (2020) in melorheostosis, and a recessive form of craniodiaphyseal dysplasia due to SP7 (2023) [11, 38, 67–72]. In 2025, Mumm and colleagues described a family with Camurati-Engelmann disease type 2 due to a TGFB2 variant, after three sporadic cases published in 2024 [24].

1.4. Entities within scope

Sclerosteosis and van Buchem disease are autosomal recessive dysplasias due to sclerostin deficiency, with progressive bone overgrowth mainly of the skull and mandible; sclerosteosis is distinguished by tall stature, syndactyly and greater severity [5]. Craniodiaphyseal dysplasia is the most severe form of the SOST spectrum, autosomal dominant, with massive craniofacial hyperostosis from infancy [11, 13]. Worth-type endosteal hyperostosis and autosomal dominant osteosclerosis result from gain-of-function variants of LRP5, which lies at the opposite pole from the loss-of-function variants causing osteoporosis-pseudoglioma syndrome [8, 62]. Pyknodysostosis is an osteoclastic but not osteopetrotic disease, with short stature, acro-osteolysis and bone fragility [18]. Camurati-Engelmann disease is a dominant diaphyseal dysplasia with pain and muscle weakness [23]. Osteopathia striata with cranial sclerosis is an X-linked dominant disease with metaphyseal striations in women and a severe or lethal phenotype in many men [26]. Craniometaphyseal dysplasia combines craniofacial hyperostosis with metaphyseal widening [28]. Osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis form a group of focal or linear sclerotic lesions [34, 73]. Pyle disease and Lenz-Majewski dysplasia complete the group of entities covered in detail; the others fall within the differential diagnosis.

2. Molecular Genetics and Pathophysiology

2.1. The canonical Wnt pathway as a common axis

Most non-osteopetrotic sclerosing dysplasias converge on the canonical Wnt pathway of the osteoblast. Sclerostin, encoded by SOST, is a 190-amino-acid glycoprotein secreted mainly by osteocytes; it binds the co-receptors LRP5 and LRP6 and prevents binding of Wnt ligands, restraining bone formation; for this action it depends on its own co-receptor, LRP4 [5, 48]. Loss of sclerostin removes this brake and leads to progressive generalised hyperostosis [5]. Leupin and colleagues showed that LRP4 variants associated with bone overgrowth impair the facilitating function of sclerostin, which explains the phenotype of sclerosteosis 2 [67]. LRP5 gain-of-function variants, such as p.(Gly171Val), lie in the first β-propeller domain and make the receptor resistant to inhibition by Dickkopf-1 (Dkk-1), with increased Wnt signalling, very high formation markers and normal resorption markers [62]. AMER1 inhibits the same pathway by promoting ubiquitination and degradation of β-catenin; its loss of function accumulates β-catenin in the nucleus and increases osteoblast function [26]. SFRP4 is a secreted WNT inhibitor, whose deficiency in Pyle disease increases trabecular bone and thins cortical bone, through differential regulation of WNT and bone morphogenetic protein (BMP) in the two compartments [8, 70].

GeneGuidance summarises, from Littman and colleagues, the direction-of-effect rule in LRP5: total loss of function causes osteoporosis-pseudoglioma syndrome, partial loss is associated with other low bone mass phenotypes and gain of function produces the high bone mass phenotypes, so nothing written about one pole applies to the other [8]. The gain-of-function phenotypes listed include endosteal hyperostosis and osteosclerosis (OMIM 144750) and autosomal dominant osteopetrosis type 1 (OMIM 607634), an entry that OMIM maintains as osteopetrosis even though the mechanism is increased bone formation [8, 16].

2.2. SOST: sclerosteosis, van Buchem disease and craniodiaphyseal dysplasia

SOST is located at 17q21.31 (OMIM gene 605740 [74]; MANE Select transcript, Matched Annotation from NCBI and EMBL-EBI, NM_025237.3) [5, 8]. In sclerosteosis, the mechanism is loss of function due to biallelic variants of the coding sequence; GeneReviews identifies no phenotypic differences between the known variants [5]. In van Buchem disease, the 52 kb deletion results from homologous recombination between Alu sequences, begins about 35 kb downstream of SOST and removes a regulatory element required only for postnatal transcription of sclerostin; it contains no gene, and its consequence is downregulation of SOST by a cis or position effect [5, 60]. Because embryonic sclerostin expression is preserved, patients with van Buchem disease do not develop syndactyly [5].

Serum sclerostin follows gene dosage. It is undetectable in sclerosteosis, low but measurable in van Buchem disease (mean 8.0 pg/mL) and intermediate in heterozygous carriers (15.5–28.7 pg/mL), compared with about 40.0 pg/mL in controls, according to the studies by van Lierop and colleagues summarised in GeneGuidance [8, 75, 76]. Heterozygotes have increased bone mass and calvarial widening, without signs or symptoms of the disease [5, 77].

In autosomal dominant craniodiaphyseal dysplasia, Kim and colleagues found the variants NM_025237.3:c.61G>A p.(Val21Met) and NM_025237.3:c.61G>T p.(Val21Leu) in two children, both in the secretion signal; in transfected cells they greatly reduced sclerostin secretion, and the authors proposed a dominant-negative mechanism [11]. Up to the 2024 GeneReviews update no other patients with SOST-related craniodiaphyseal dysplasia had been published, and the disease is probably heterogeneous [5]. Hendrickx and colleagues described a recessive form of craniodiaphyseal dysplasia due to a homozygous missense variant of SP7 (Osterix) [5, 72].

The SOST variants cited in GeneReviews and in the literature were normalised in VariantValidator with the MANE transcript, according to Human Genome Variation Society (HGVS) nomenclature (following table) [78]. The South African founder variant appears in the older literature as «69C>T»; in the current transcript, c.69C>T would be a synonymous variant, p.(Gly23=), and the correct designation is c.70C>T p.(Gln24Ter) [5, 78].

2.3. LRP4 and LRP5

LRP4 (11p11.2; OMIM gene 604270) [80] is associated with three phenotypes with differing strength of evidence: congenital myasthenic syndrome 17 (OMIM 616304), Cenani-Lenz syndactyly syndrome (OMIM 212780) and sclerosteosis 2 (OMIM 614305) [8]. The SOST GeneReviews records LRP4-related sclerosteosis with autosomal dominant and recessive inheritance and an overlapping phenotype (hyperostosis of the long bones and skull, facial deformity, cranial nerve compression, hearing loss and tall stature), distinguishable by normal or increased serum sclerostin [5]. OMIM records sclerosteosis 2 as caused by heterozygous or homozygous LRP4 variants, with autosomal dominant and recessive inheritance, whereas GeneGuidance classifies it only as recessive; both patterns are documented [5, 7, 8]. OMIM also describes a 17-year-old Spanish patient with sclerosteosis who presented at 12 years with right facial palsy [7]. A 2026 report described a patient with cranial nerve compression and dense bones due to an LRP4 variant [81].

LRP5 (11q13.2; OMIM gene 603506) [82] is the Wnt co-receptor that determines bone mass by controlling osteoblast proliferation and differentiation and is also a co-receptor for norrin in retinal vascularisation [8]. Boyden and colleagues linked the autosomal dominant syndrome of high bone density, wide, deep mandible and torus palatinus to 11q12-13 in one family, with odds of linkage greater than one million to one, and identified the substitution of glycine by valine at codon 171 [62]. GeneReviews places Worth-type endosteal hyperostosis (OMIM 144750) in the differential diagnosis of the SOST-related dysplasias, with a milder phenotype, normal height, absence of syndactyly and torus palatinus [5]. In the United Kingdom, Gregson and colleagues found higher plasma sclerostin concentrations in high bone mass cases with an LRP5 variant (mean 130.1 pmol/L) and without an LRP5 variant (88.0 pmol/L) than in controls (66.4 pmol/L) [83].

2.4. CTSK and cathepsin K

CTSK is located at 1q21.3 (OMIM gene 601105) [84] and encodes cathepsin K, a lysosomal cysteine protease highly expressed in osteoclasts, also detected in macrophages and marrow dendritic cells [18]. It is synthesised as a pro-enzyme and cleaved in the lysosome; at acid pH it degrades type I and II collagen, osteopontin and osteonectin [18]. In pyknodysostosis, the number of osteoclasts is normal, as are the ruffled borders and clear zones, but the area of demineralised bone around each osteoclast increases: acidification of the lacuna is preserved and degradation of the organic matrix fails, which mechanistically separates pyknodysostosis from the osteopetroses due to acidification defects [8, 18]. The resulting bone is dense but structurally poor, with increased fragility [8].

The mechanism is loss of function. About 60 pathogenic variants have been described, 69% in the mature domain, 24% in the pro-region and 6% in the pre-region (signal sequence), with hotspots at residues Arg241 and Ala277 [18]. A 301 bp Alu insertion in intron 7, which creates a new splice acceptor site, is the only structural change described, and the choice of primers determines its detection [18]. There are several reports of pyknodysostosis due to uniparental disomy [49]. In Brazil, Araujo and colleagues found six variants in 33 families — NM_000396.4:c.436G>C p.(Gly146Arg), c.580G>A p.(Gly194Ser), c.721C>T p.(Arg241Ter), c.830C>T p.(Ala277Val), c.953G>A p.(Cys318Tyr) and the new c.83dup — with homozygosity in 83.3% of patients from Ceará and in half of patients from other states; c.83dup has a single origin in Ceará, according to haplotypes of the markers D1S2344, D1S442, D1S498 and D1S2715 [20]. GeneReviews identifies no clinically relevant genotype-phenotype correlations and knows of no other phenotypes associated with germline CTSK variants [18].

2.5. TGFB1, TGFB2 and LRP6: diaphyseal dysplasias

TGFB1 (19q13.2; OMIM gene 190180) [85] encodes a pro-protein with a 29-amino-acid signal peptide, cleaved after amino acid 278 into latency-associated peptide (LAP) and active TGFβ1; LAP dimerises through disulphide bonds at Cys223 and Cys225, and most cells secrete TGFβ1 in a large latent complex bound to the LTBP protein [23]. Most Camurati-Engelmann disease variants substitute an amino acid at the carboxy-terminal end of LAP, near these bonds, disrupt LAP dimerisation and binding to active TGFβ1 and increase release of active TGFβ1 [23]. In transcript NM_000660.7 (protein NP_000651.3), the variants p.(Arg218His), p.(Arg218Cys), p.(His222Asp) and p.(Cys225Arg) increased active TGFβ1 in culture, whereas p.(Leu11_Leu13dup) and p.(Tyr81His) reduced secretion but increased TGFβ1-dependent transcriptional activity, suggesting intracellular receptor activation [23]. GeneReviews classifies the mechanism as gain of function; the abstract by Mumm and colleagues describes the same variants as «loss of function» of LAP with increased TGFβ1 action, which corresponds to the same final effect expressed at another point in the chain [23, 24].

The variants p.(Arg218Cys) and p.(Arg218His) account for about 40% and 35% of patients [23]. Sequencing detects a variant in more than 90% of cases, and large deletions or duplications have not been described [23]. A family without a shared haplotype at the locus and several patients without a variant suggested heterogeneity, later confirmed for TGFB2: in 2024 three sporadic cases of Camurati-Engelmann type 2 (OMIM 606631) had TGFB2 variants, and in 2025 a Peruvian family with an affected father, son and daughter showed the variant NM_001135599.4:c.108G>T p.(Arg36Ser) in the LAP domain, absent from gnomAD and cosegregating in an autosomal dominant manner [23, 24]. Pickering and colleagues described a rare LRP6 missense variant in a woman with a similar picture, whose pathogenic role remains to be demonstrated [23, 86]. Biallelic loss-of-function TGFB1 variants cause a different phenotype, with inflammatory bowel disease, immunodeficiency and encephalopathy (OMIM 618213) [23].

2.6. ANKH and GJA1: craniometaphyseal dysplasia

ANKH (5p15.2; OMIM gene 605145) [87] encodes a multi-domain transmembrane protein, located in the outer membrane, that transports citrate and ATP into the extracellular matrix; for years it was described as a transporter of inorganic pyrophosphate, an inhibitor of calcification, mineralisation and resorption [28, 30]. The variants of autosomal dominant craniometaphyseal dysplasia are mainly single-amino-acid deletions, as well as missense variants and small in-frame deletions or insertions, located in presumed intracellular domains; studies in mice suggest a dominant-negative effect with gain of function and loss of transport function, and the mutant protein is rapidly degraded [28]. Sequencing detects about 90% of cases, and some simplex cases without a variant suggest heterogeneity [28]. Penetrance is 100%, with variable expressivity within families, and there is no clinically relevant genotype-phenotype correlation [28]. ANKH variants also cause calcium pyrophosphate deposition disease (familial chondrocalcinosis, OMIM 118600), and one family showed cosegregation of the two diseases; biallelic variants caused intellectual disability, deafness and ankylosis in one family [28, 31].

The autosomal recessive form results from homozygous variants of GJA1 (6q22.31; OMIM gene 121014; allelic to oculodentodigital dysplasia) [88], which encodes connexin 43, a component of the gap junctions of osteoblasts, osteocytes, osteoclasts and chondrocytes [31, 68]. A GJA1 variant was identified in an isolated case and confirmed in six individuals from three families [30].

In the MANE transcript NM_054027.6, the recurrent in-frame deletions of the dominant form are located in the carboxy-terminal cytoplasmic domain and include c.1129_1131del p.(Phe377del) and c.1124_1126del p.(Ser375del); the latter was identified in a North American infant girl with hypophosphataemic rickets and in a Turkish child, and a new variant in the same region, which segregated in a mother and two children, was classified as of uncertain significance for lack of functional data [78, 89, 90]. A 2026 review places the protein in a regulatory axis shared with ENPP1 and tissue-non-specific alkaline phosphatase: ATP exported by ANKH is hydrolysed by ENPP1 into AMP and inorganic pyrophosphate, an inhibitor of mineralisation, and alkaline phosphatase degrades pyrophosphate, maintaining the phosphate/pyrophosphate ratio required for normal mineralisation; citrate export influences matrix composition and the mechanical strength of bone, and gene expression is regulated by the Wnt, TNF-α and FGF pathways [91]. In the mouse homozygous for the p.Phe377del deletion, which reproduces the craniofacial hyperostosis, dense mandible, club-shaped femora and narrowing of the foramen magnum, osteoblast and osteoclast formation and function are reduced, the mutant protein is rapidly degraded and plasma pyrophosphate is reduced to about half (0.43 versus 0.94 µM in normal animals) [92, 93]. The available models reproduce the disease only in part [91].

The variant NM_054027.6:c.-11C>T, upstream of the initiation codon, causes an allelic disorder without a skeletal phenotype: autosomal dominant self-limited familial infantile epilepsy, described in a British family and in a second family of Italian origin with six affected members, with focal or bilateral tonic-clonic seizures, sometimes triggered by fever, beginning mainly before 2 years, with good response to antiepileptic drugs and complete remission before 4 years; a family history of chondrocalcinosis or recurrent acute joint attacks points to this gene [78, 94].

The recessive GJA1 variant described by Hu and colleagues is NM_000165.5:c.716G>A p.(Arg239Gln) [68, 78]. In the mouse homozygous for the equivalent variant there is thickening of the craniofacial bones, club-shaped femora and widening of the diaphyseal cortex, more marked in females with age, with periosteal bone deposition, more endosteal osteoclasts but with reduced resorption, fewer osteocyte dendrites, lower Sost expression and a lower RANKL/OPG ratio; gap junction and hemichannel activity is only slightly reduced and, since Cx43 ablation models lack this phenotype, loss of function does not appear to be the main mechanism of the recessive form [95].

2.7. AMER1: osteopathia striata with cranial sclerosis

AMER1 (Xq11.2; OMIM gene 300647 [96]; formerly WTX and FAM123B) has two exons, the first non-coding [26]. Almost all pathogenic variants are germline truncating variants in exon 2 or whole-gene deletions; two variants in the non-coding exon 1 may escape conventional sequencing [26]. The mechanism is loss of function [26]. The metaphyseal striations are thought to result from the coexistence of two independent osteoblast lineages, through differential X inactivation in women or mosaicism in men, which explains their absence in constitutional hemizygous men [26]. The initial hypothesis that truncating variants at the 5' end predict the severe male phenotype, still mentioned in Spranger's atlas, was refuted in later series [26, 53]. Contiguous deletions including AMER1, ARHGEF9 and MTMR8 cause osteopathia striata with intellectual disability in women, unlike deletions limited to AMER1 and ASB12 [26]. Somatic AMER1 variants are present in 15–30% of Wilms tumours; Jenkins and colleagues concluded in 2009 that germline variants did not predispose to tumours, a conclusion revised after Bach and colleagues gathered four Wilms tumours in patients with the disease [26, 66, 97].

In murine models, complete loss of Wtx causes midline fusion defects (cleft palate and ectopic synostosis of the skull base), whereas deletion of only the carboxy-terminal portion allows survival, with altered cranial morphology and increased bone density, similar to the mild male phenotype; the truncated protein still partially recruits β-catenin, through AXIN and AXIN2, which explains the partial retention of function of some truncating variants [98]. An adult Dutch woman with generalised high bone mass and typical metaphyseal striations, without an AMER1 variant, had a mosaic CTNNB1 missense variant, NM_001904.4:c.876A>C p.(Lys292Asn), at a residue required for the interaction of β-catenin with AXIN; in luciferase assays, the variant increased canonical Wnt signalling about 70-fold, without altering phosphorylation or cytoplasmic stability of the protein [78, 99]. Somatic CTNNB1 variants thus become a cause to consider in cases of osteopathia striata without an AMER1 variant [99].

2.8. LEMD3, MAP2K1 and SMAD3: focal and linear sclerotic lesions

LEMD3 (12q14.3; OMIM gene 607844) [100] encodes the inner nuclear membrane protein MAN1, which restrains SMAD signalling of TGFβ and BMP; haploinsufficiency causes osteopoikilosis and Buschke-Ollendorff syndrome, with a ClinGen haploinsufficiency score of 3 [8, 34, 65]. The absence of a LEMD3 variant in a family with Buschke-Ollendorff suggests genetic heterogeneity [34]. The coexistence of melorheostosis and osteopoikilosis in the same person or family led to the hypothesis of a second somatic event in the normal allele [34, 73]. In isolated melorheostosis, however, germline LEMD3 variants are rare [101].

OMIM classifies isolated melorheostosis (155950) as somatic mosaicism of MAP2K1 (15q22.31; OMIM gene 176872), and the name combines the Greek roots for «limb», «flow» and «bone» [35, 102]. Kang and colleagues found in 2018, by exome sequencing, somatic MAP2K1 mosaicism in the affected but not in the unaffected bone of eight patients with melorheostosis; the activating variants (NM_002755.4; NP_002746.1) p.(Gln56Pro), p.(Lys57Glu) and p.(Lys57Asn) cluster in the negative regulatory domain of MEK1, increase ERK1/2 phosphorylation and osteoblast proliferation and inhibit BMP2-mediated mineralisation, which explains the greatly increased osteoid; secretion of vascular endothelial growth factor (VEGF) contributes to bone formation in these lesions [103]; mosaicism was also present in the skin overlying the lesions in four of five patients [38]. Spranger's atlas estimates that about half of patients have this variant [73]. In 2020, the same group found somatic SMAD3 variants in four patients with endosteal-pattern melorheostosis, which activate the TGFβ pathway and stimulate differentiation and mineralisation, unlike the MAP2K1 variants, associated with the «dripping wax» radiological pattern [71]. Germline MAP2K1 variants cause cardiofaciocutaneous syndrome, an entity unrelated to melorheostosis [8].

2.9. SFRP4, PTDSS1 and other genes

Simsek Kiper and colleagues found biallelic truncating variants of SFRP4 (7p14.1; OMIM gene 606570) [104] in the four patients with Pyle disease studied and reproduced, in Sfrp4-null mice, the combination of increased trabecular bone with thin cortical bone [8, 70]. In 2026, Magnus and colleagues showed that three missense variants in the WNT-binding domain impair inhibition of the pathway as truncating variants do, according to GeneGuidance [8]. Heterozygotes have mild changes in metaphyseal modelling and, sometimes, mild tibial bowing [42].

PTDSS1 (8q22.1; OMIM gene 612792) [105] encodes phosphatidylserine synthase 1 [44]. Gain-of-function PTDSS1 variants abolish feedback inhibition of the enzyme by phosphatidylserine; excess phosphatidylserine, with high affinity for calcium, acts as a nucleus for hydroxyapatite crystal formation and impairs osteoclast formation [44, 69]. All cases tested occurred de novo [44]. The variant NM_014754.3:c.284G>A p.(Arg95Gln) has a smaller gain-of-function effect than NM_014754.3:c.284G>T p.(Arg95Leu) and is associated with the attenuated phenotype; NM_014754.3:c.1058A>G p.(Gln353Arg) was found in four patients with borderline to severe intellectual disability [44]. A loss-of-function PTDSS1 variant, NM_014754.3:c.409C>T p.(Leu137Phe), was described in a girl with developmental delay and autism, without dysplasia [44].

2.10. Penetrance, expressivity and correlations

3. Clinical Spectrum and Manifestations by System

3.1. SOST-related sclerosteosis

Sclerosteosis has a phenotype that builds up during childhood. Syndactyly, cutaneous or bony, is present at birth in 66% of patients, mainly affects the 2nd and 3rd fingers, is usually bilateral but not always symmetrical, and is accompanied by radial deviation of the terminal phalanges and dysplastic or absent nails [5, 48]. Linear growth accelerates from early childhood and stops at puberty, when some patients exceed 2 m in height [5]. Recurrent facial palsies, present in 93% of patients, are the characteristic complication: they begin in early childhood, in some cases in the first months, are initially intermittent and become permanent in adulthood, due to narrowing of the cranial nerve foramina [5]. Hearing loss affects 94%; it begins as conductive hearing loss in childhood and progresses to mixed hearing loss through compression of cranial nerve VIII and closure of the oval and round windows [5, 108]. Visual loss, trigeminal neuralgia and anosmia are less frequent compressions [5].

Facial distortion due to cranial hyperostosis, with frontal bossing and mandibular overgrowth, occurs in 90%, sometimes with proptosis, hypertelorism or midface hypoplasia, and progresses into adulthood; mandibular hyperostosis causes malocclusion [5]. Intracranial hypertension, due to reduced volume of the cranial cavity from calvarial thickening, often begins at the end of adolescence and was recorded in 71% of patients; impaction of the medulla in the foramen magnum has been described [5, 48]. Bone has increased volume and cortical and trabecular thickness, increased osteoblastic formation and normal or reduced resorption, without altered mineralisation; unlike osteopetrosis, the high density is accompanied by increased biomechanical strength, and the risk of fracture, osteomyelitis and bone marrow failure is not increased [5, 109].

The table compares the frequencies in the series gathered by Beighton (1995) and van Lierop and colleagues (2017), as presented in GeneReviews [5, 110].

Complications progress into adulthood and stabilise in the third decade in most patients [5]. Survival into old age is unusual: the mean age at death was 33 years in the series by Hamersma and colleagues, which followed 63 South African patients for 38 years, and intracranial hypertension was the main cause of death [5, 8, 111]. In the review by van Lierop and colleagues, intracranial hypertension was the cause of death in 12 of 33 deceased Afrikaner patients, and six others died of perioperative complications [5]. GeneReviews accepts that the increasing use of early craniectomy may prolong survival, without published data quantifying this [5].

3.2. Van Buchem disease

Van Buchem disease has normal stature and no syndactyly [5, 48]. Hearing loss, conductive and sensorineural, begins in childhood; facial palsy is the most frequent finding (89%), and the other compressions (visual, trigeminal, auditory) are less common than in sclerosteosis [5]. Cranial hyperostosis manifests mainly as mandibular overgrowth from early adulthood; the teeth are usually unaffected [5]. Intracranial hypertension is rare, and sudden death from brainstem herniation has never been described [5]. Serum alkaline phosphatase is elevated, unlike in Worth-type endosteal hyperostosis [16]. Life expectancy appears normal; the oldest patient studied was 81 years old, with type 2 diabetes, mild heart failure and non-metastatic prostate carcinoma, comorbidities typical of age [5].

The 2025 longitudinal data qualify the idea of stabilisation. Appelman-Dijkstra and colleagues reassessed 11 of 15 Dutch adults with a genetic diagnosis (4 women) after a mean follow-up of 8.9 ± 1.1 years, at a median age of 47 years (20–60): seven developed permanent facial paresis, nine had progression of hearing loss, two required cranial surgery for intracranial hypertension, dental problems were frequent and three developed osteoarthritis; none had a cardiovascular event [106]. BMD did not change: the lumbar Z-score went from 10.2 ± 1.3 to 9.4 ± 2.3 standard deviations (SD) (p = 0.62) and the femoral neck Z-score from 8.9 ± 2.2 to 7.7 ± 2.2 SD (p = 0.15) [106]. BMD stabilises after puberty, but cranial nerve compression continues to progress, which justifies lifelong surveillance [106].

3.3. Craniodiaphyseal dysplasia

Craniodiaphyseal dysplasia manifests in infancy. The first finding is usually a thick bony wedge in the nasal bones and adjacent maxillae, with nasal obstruction and mouth breathing; craniofacial hyperostosis develops in the first year, progresses and invades the foramina, with loss of vision and hearing, intellectual delay, seizures, malocclusion, early tooth loss and intracranial hypertension [13]. The face becomes distorted with a broad nasal bridge, hypertelorism and a prominent mandible (leontiasis ossea); there is macrocephaly and short stature [13]. The ribs and clavicles widen in their middle thirds, and the diaphyses expand with undermodelling and thin cortices; alkaline phosphatase is elevated, with normal calcium and phosphate [13]. Death usually occurs in the second decade [13]. In the two children with a SOST variant, choanal stenosis was a clinically significant complication [5, 11]. The recessive form due to SP7 includes facial dysmorphism, severe hyperostosis of the calvaria, base and mandible, short stature, slender habitus, broad clavicles and ribs, scoliosis and diaphyseal expansion, with recurrent fractures in one of the two patients described [5, 72].

3.4. LRP5-related high bone mass phenotypes and sclerosteosis 2

Worth-type endosteal hyperostosis is autosomal dominant, manifests in adolescence and resembles van Buchem disease clinically and radiologically, with lower severity; it is associated with torus palatinus, height is normal, there is no syndactyly and cranial nerve compression is usually absent [5, 16, 48]. In the family of Boyden and colleagues, the p.(Gly171Val) variant segregated with high bone density, a wide, deep mandible and torus palatinus [62]. The Camurati-Engelmann disease GeneReviews describes LRP5-related osteosclerosis with endosteal diaphyseal sclerosis, cranial nerve involvement in some patients and a wide, deep mandible with an increased gonial angle [23]. OMIM summarises autosomal dominant endosteal hyperostosis as cortical thickening of the long bones without change in external shape and with remarkable resistance to fracture; the skeleton is normal in childhood, and in adolescence the forehead flattens, the mandible lengthens and an enlarging torus palatinus appears that may cause malocclusion or tooth loss [14]. The OMIM description refers to a decreased gonial angle, whereas the Camurati-Engelmann disease GeneReviews refers to an increased gonial angle; the two sources agree on the elongated, wide and deep mandible [14, 23]. There is no published population frequency for any LRP5 phenotype [8]. In the British series by Gregson and colleagues, 406 high bone mass index cases were identified among 219,088 densitometry scans from four centres, after excluding significant osteoarthritis and artefacts; this proportion describes a sample of scans and not a population prevalence [83]. LRP4-related sclerosteosis 2 reproduces the long bone and cranial hyperostosis, facial deformity, nerve compression and tall stature of sclerosteosis 1 [5].

Spranger's atlas groups Worth-type endosteal hyperostosis with LRP5-related autosomal dominant osteopetrosis type I (OPTA1), which it considers impossible to separate, and includes van Buchem disease type 2 (OMIM 607636) in the same entry; heterozygous LRP5 variants cause few symptoms and sclerosis mainly of the cranial vault with near-normal vertebral bodies, unlike CLCN7-related osteopetrosis type II, with fractures, neurological signs and predominant sclerosis of the skull base and vertebral endplates; the disease may be discovered incidentally on a radiograph [112].

3.5. Pyknodysostosis

The clinical description in GeneReviews is based on 159 patients from 59 families with biallelic variants gathered by Xue and colleagues and on 27 patients from 17 families of the French OSCAR network described by Bizaoui and colleagues [18, 113, 114]. The table summarises the frequencies.

Source: GeneReviews [18].

Growth decelerates in early childhood, with disproportionately short limbs (rhizo-, meso- and acromelia); adult height is below 150 cm in men (mean −2.9 SD) and 130–134 cm in women (mean −4.1 SD) [18]. In the French series, mean stature was −3.5 SD and lower in women (p = 0.006) [114]. About half of patients have growth hormone deficiency, almost all have low insulin-like growth factor 1 (IGF-1), and the deficiency is often associated with pituitary hypoplasia, without other hormonal or pubertal abnormalities [18]. The Brazilian textbook of genetic syndromes describes growth deceleration in the first three years with defective growth hormone secretion [115]. Three patients taller than expected have been published, at 153 cm, 150 cm and 137 cm at 11 years [18].

The face — midface retrusion due to a hypoplastic maxilla, a small mandible with an obtuse angle, a convex nasal ridge, frontal and parietal bossing with large anterior and posterior fontanelles and open sutures — is recognisable from infancy and becomes more marked with age, probably because of progressive acro-osteolysis of the facial bones [18]. The palate appears grooved because it is narrow and shallow, with drooping palatine shelves and a prominent median raphe [18]. Osteosclerosis is generalised and progressive, but the medullary canals are preserved, with haematopoiesis [18]. The hands are short and broad, with wrinkled skin over the dorsum of the fingers and flattened, grooved nails; acro-osteolysis of the distal phalanges progresses in some fingers and regresses in others [18, 49, 50]. Coronal craniosynostosis has been described in four patients, and chronic pain affects up to 60% of adults from the third decade [18].

Bone fragility translates into about 0.2 fractures per year, with the first fracture around 10 years; in the French series the rate was 0.21 per year, with a mean of four fractures per patient [18, 114]. Smith's estimates that about two thirds of patients have had fractures, mainly of the mandible, clavicle and lower limbs, including the metatarsals, with poor healing [49]. The earliest fracture occurred at 10 months, in a child with two deceased siblings without molecular study [18]. About 75% of French patients had at least one operation, with a mean of 2.1 procedures [114].

In adults, the European Calcified Tissue Society (ECTS) and ERN BOND review describes fractures as frequent in childhood and rare thereafter, with fragility revealed mainly by fractures at atypical sites, such as the femoral and tibial metaphyses, which may resemble atypical femoral fractures [19]. Bone mineral density measured by dual-energy X-ray absorptiometry has a Z-score above +2 standard deviations; in a Danish cohort, high-resolution peripheral quantitative computed tomography showed increased cortical thickness and area, trabecular volume and trabecular density; and serum procollagen type 1 amino-terminal propeptide and type 1 collagen carboxy-terminal telopeptide are within reference values [19].

The airway is the other axis of morbidity. Stridor and laryngomalacia occur in 20% and may lead to early suspicion; obstructive sleep apnoea, often severe in children, affects more than 60%, and 48% of patients with apnoea required non-invasive ventilation between 5 and 10 years [18]. In the French series, 67% had apnoea and about half required non-invasive ventilation [114]. The ECTS/ERN BOND review, which cites this series and a three-dimensional analysis of the upper airway, gives a frequency of 50% and attributes apnoea to the narrow pharyngeal space and high-arched palate, aggravated by scoliosis and chest deformities [19]. Mild conductive hearing loss affects up to 50% [18]. Intelligence is normal unless there is a brain malformation, but 29% of French patients had psychomotor difficulties and 33% needed educational support, and none had had a psychological assessment [114]. Chiari malformation, cerebral demyelination in three patients, a pyramidal syndrome in one patient, refractive errors, strabismus and one case of visual loss due to intracranial hypertension with papilloedema have been described; 26% of French patients were overweight [18]. According to the ECTS/ERN BOND review, platybasia and Chiari malformation occurred in about 20% of patients in the French series, and mild cognitive changes, not yet characterised, have been inconsistently reported [19]. Dental anomalies include delayed eruption, persistence of deciduous teeth with a double row, hypodontia, malocclusion, enamel hypoplasia and caries; osteomyelitis, particularly mandibular after tooth extraction, is explained by reduced vascularisation and increased density [18, 49]. The ECTS/ERN BOND review, supported by a systematic review, places maxillary osteomyelitis in the context of tooth extractions or mandibular fractures and also mentions a dentine defect [19]. Anaemia due to myelosclerosis with extramedullary haematopoiesis is exceptional, and epidural haematomas after head injury have been described, one of them fatal [50]. Life expectancy is usually normal [18].

3.6. Camurati-Engelmann disease

The mean age at symptom onset in 306 published patients was 13.4 years, ranging from birth to 76 years [23]. The table brings together the frequencies from the two main sources.

Sources: [23, 107].

Bone pain is constant, dull, more intense in the lower limbs, worsens with activity, stress and cold and has intermittent episodes of severe pain and disability; 52% of patients have tenderness on palpation of the thickened diaphyses, sometimes with swelling, erythema and warmth [23]. Muscle weakness and atrophy predominate in the proximal lower limbs, with difficulty rising; there may be delayed walking, contractures (43%), a marfanoid habitus with low body mass index, hyperlordosis, scoliosis, coxa valga, radial head dislocation, genu valgum and flat feet [23]. Hip BMD is increased, but bone strength measured by microindentation in three siblings was below normal, without statistical significance; fracture risk is not increased, and healing may be slow [23]. In a Spanish series of 15 patients, the physical component of the SF-12 questionnaire was 29.8 (7.5), compared with 50.0 (10.0) in the United States reference population (p < 0.0001), with no difference in the mental component; all reported fatigue, 93.3% limb pain and 86.7% muscle pain [116].

Sclerosis of the foramina causes cranial nerve deficits in 38% of patients [23]. Conductive hearing loss results from narrowing of the external auditory canal, invasion of the ossicles or narrowing of the windows; sensorineural loss results from narrowing of the internal auditory canal and may follow attempts at facial nerve decompression; there is tinnitus and vertigo [23, 117]. Orbital involvement causes blurred vision, proptosis, papilloedema, epiphora, glaucoma, globe subluxation and retinal detachment [23]. Calvarial hyperostosis causes intracranial hypertension with severe chronic headaches; one patient developed at 57 years a bone defect with a meningoencephalocele, and hyperostosis recurs after decompression [23]. Hypopituitarism, with short stature, delayed puberty and hypocortisolism, has been attributed to a small sella, pituitary compression due to intracranial hypertension or a direct effect of TGFβ1; hypogonadism and hypothyroidism are rare [23]. Children do not have a recognisable face; severely affected adults develop macrocephaly, frontal bossing, an enlarged mandible and proptosis [23]. Anaemia (due to a narrow medullary canal), hepatosplenomegaly, atrophic skin, palmoplantar hyperhidrosis and delayed tooth eruption are less common [23].

OMIM keeps Ribbing disease in a separate entry (601477): described by Ribbing in 1949 as hereditary multiple diaphyseal sclerosis, it numbered 13 cases in the English-language literature according to Seeger and colleagues (1996), appears after puberty, is unilateral or asymmetric, is limited to the long bones and shows only osteoblastic activity on histology; GeneReviews considers it a phenotypic variation of Camurati-Engelmann disease following the identification of TGFB1 variants in these patients [22, 23]. Intrafamilial variability is wide: in Spranger's atlas, a mother was unaware of the disease at 48 years, while her son and brother were symptomatic; there is a tendency to earlier manifestation in the younger generation and spontaneous improvement during or after adolescence in some patients [51]. Pain may decrease in adulthood [23]. Fracture healing, life expectancy and adult height are normal [51]. The GeneReviews authors know of an adolescent who died of dissection of a dilated ascending aorta; since the disease shares the increased TGFβ signalling of Marfan and Loeys-Dietz syndromes, they recommend reassessing the incidence of aortic disease, with no current recommendation for routine aortic assessment [23]. In a woman treated with corticosteroids, pregnancy reduced pain and increased strength, allowing treatment to be stopped [23]. The TGFB2-related type 2 form described in 2025 began in childhood, with disabling pain and hyperostosis of the whole long bone, more severe in males [24].

3.7. Craniometaphyseal dysplasia

The autosomal dominant form is often detected in the first weeks of life because of respiratory or feeding difficulty caused by choanal stenosis [28]. The face has a thick bony wedge over the nasal bridge and glabella, hypertelorism with increased bizygomatic width, paranasal fullness and a prominent mandible; fronto-occipital hyperostosis produces dolichocephaly [28, 31]. Craniofacial thickening progresses throughout life and narrows the foramina, including the foramen magnum; without treatment, it causes facial palsy, blindness and conductive or sensorineural deafness [28]. Chiari I malformation may cause severe headaches, truncal ataxia responds to posterior fossa decompression, and hyperostosis of the alveolar bone delays or prevents eruption [28, 30]. Nasal obstruction and mandibular hyperostosis affect speech [28]. In the long bones, the diaphyseal sclerosis of infancy disappears, and club-shaped metaphyseal widening develops in childhood, mainly in the distal femur and tibia; transient signs of rickets have been described in infants [28, 31]. In adults with the dominant form, the face becomes less characteristic and sclerosis along the sutures may be the only finding [30]. Life expectancy, intellect and height are normal in uncomplicated forms [28, 31].

The relative severity of the recessive and dominant forms differs between sources. Spranger's atlas and Smith's describe the recessive GJA1 form as rarer, earlier and more severe, with craniofacial progression, severe visual impairment, bilateral hearing loss, facial palsy and, sometimes, intellectual disability; the GeneReviews on the dominant form states that the skeletal phenotype of the GJA1 form may be less severe than that of the typical dominant form [28, 30, 31]. All sources agree that there is wide clinical overlap and that molecular testing is necessary in isolated cases [31]. A 2026 report described a child with persistent macrocephaly and initially normal neuroimaging, whose diagnosis was made only after a head injury revealed progressive cranial sclerosis; up to early adulthood, sensorineural hearing loss did not progress and there were no neurological or visual complications [118].

Rickets is a rare early manifestation of the dominant form. A North American infant girl with the p.(Ser375del) variant had, at 1 month, elevated alkaline phosphatase and low serum phosphate and, at 3 months, radiological signs of rickets; tubular phosphate reabsorption was high and FGF23 was suppressed (< 14 pg/mL), indicating reduced phosphate availability rather than FGF23-mediated renal wasting, and urinary pyrophosphate was undetectable [89]. The same patient underwent facial nerve decompression at 8 months and, at 15 months, CT showed fusion of the coronal sutures and MRI a Chiari I malformation [89]. The review accompanying the case gathers the published patients with elevated alkaline phosphatase or PTH and identifies hypophosphataemia or rickets in only three others [89]. Craniosynostosis was later published as an expansion of the phenotype [119]. In a Turkish cohort of 34 patients with 12 osteosclerotic disorders, followed for between 1 and 22 years, the four patients with craniometaphyseal dysplasia had severe cranial sclerosis with facial dysmorphism; three had hearing loss and one facial palsy, and nasal obstruction, obstructive sleep apnoea and Chiari malformation required surgery [90]. Radiographs in early childhood showed diffuse cranial sclerosis and metaphyseal widening and radiolucency with diaphyseal sclerosis; the Erlenmeyer flask deformity of the distal femur developed later, with the spine and pelvis spared, and variability was intra- and interfamilial [90].

3.8. Osteopathia striata with cranial sclerosis

In women and in men with a mild phenotype, cranial sclerosis and long bone sclerosis are present in all, metaphyseal striations in about 95% (only in women and mosaic men), the characteristic face in about 90%, macrocephaly in about 80%, orofacial clefts and hearing loss in about 50%, mild developmental delay in about 30%, congenital heart disease in about 25% and Wilms tumour in about 5% [26]. Cranial sclerosis may be present at birth and is progressive; the striations usually develop in childhood and do not progress thereafter [26, 53]. Macrocephaly, of postnatal onset, is usually absolute (> +2.5 SD in women); short stature is uncommon in women [26]. Cranial nerve palsies (visual loss due to optic compression, facial palsy) are rare and arise in late adolescence or young adulthood [26]. The most common heart defects are atrial septal defect, ventricular septal defect and patent ductus arteriosus [26]. Moyamoya and cervical instability have been described as rare serious complications [53]. In a 2026 review of 67 patients, orofacial clefts reached 72% and were associated with retention of deciduous teeth and impaction of permanent teeth [120]. Two infants with Robin sequence were treated with mandibular distraction, and the one with the more severe phenotype required tracheostomy [121].

Up to 2023, cancer had been described only in women: four paediatric Wilms tumours, one of them bilateral, one hepatoblastoma, one colorectal cancer and one ovarian cancer in adulthood [26, 97]. An additional case of bilateral Wilms tumour was published in 2022 [122]. A North American multicentre series (2012–2023) gathered four girls with a germline AMER1 variant and Wilms tumour, diagnosed between 5 months and 8 years, at stages I to IV; one had a familial variant, two had nephrogenic rests, three required adjuvant therapy and none relapsed or died of the disease in the published follow-up [123]. Added to the six previously published cases, 2 of 10 tumours (20%) were bilateral and age at diagnosis ranged from 5 months to 12 years; one of the four children had no osteopathia striata phenotype, which calls into question the complete penetrance assumed until then [123]. In 2024 the first neuroblastoma was described, in a boy, and the accompanying review counted nine previously published patients with tumours, with Wilms tumour the most frequent [124]. These numbers are counts of published cases, without a denominator, and do not allow calculation of a lifetime risk [123, 124].

Males have two phenotypes. The mild phenotype, with a constitutional or mosaic variant, has macrocephaly (> +3 SD), clefts in about 66%, hearing loss in about 85%, mild to moderate delay in about 80%, proportionate short stature below −2 SD, progressive scoliosis, contractures, heart disease in about half and brain malformations (ventriculomegaly, partial agenesis of the corpus callosum) [26, 125]. The severe phenotype is a multiple malformation syndrome lethal in mid- or late gestation or in the neonatal period, with recurrent polyhydramnios in some families, macrocephaly and clefts in about half, bilateral absence or hypoplasia of the fibulae in most, polysyndactyly, ventriculomegaly, heart disease in about 40% (including hypoplastic left or right heart), echogenic kidneys with nephrogenic rests and omphalocele or intestinal malrotation; metaphyseal striations have never been observed in these patients [26, 53].

The first Canadian cohort, with 12 patients with an AMER1 variant aged between 5 months and 38 years, documented the common facial dysmorphism and rare extraskeletal features, such as intestinal malrotation in two patients and hypertrophic pyloric stenosis in two others, and included four apparently non-mosaic males (one with a de novo variant and three with a maternal variant) [126]. A series from the United Kingdom and Ireland gathered four women with cerebral vasculopathy, including moyamoya disease, which often presented with stroke and had a variable course; the authors consider that the association is emerging and that screening for vasculopathy may be of value, especially before surgery [127].

3.9. Osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis

Osteopoikilosis produces numerous oval foci of sclerosis, a few millimetres in size, at the ends of the tubular bones, including the epiphyseal centres in children; it is usually an incidental radiological finding, without clinical significance, stationary or with slight growth [34]. In Buschke-Ollendorff syndrome, disseminated connective tissue naevi, elastic (juvenile elastoma) or collagenous (dermatofibrosis lenticularis disseminata), white or yellow papules or plaques, mainly on the lower trunk and limbs, appear before puberty and tend to become less visible [34]. In the systematic review by Pope and colleagues, with 164 published cases and a Toronto cohort, 54% had skin and bone lesions, 24% skin lesions only and 20% bone lesions only, and 92% had a family history; spinal stenosis (about 2%) and short stature (about 7%) were rare [8, 128]. Osteopoikilosis has been described in association with rheumatoid arthritis, synovial chondromatosis and discoid lupus [34].

Melorheostosis is different. Soft tissue contractures, fibrosis and skin changes (tight, shiny skin, induration, oedema, haemangiomas, lymphangiectasias, linear scleroderma) may precede the bone changes by years and be present at birth [73]. The disease begins mainly in late childhood and causes limb length discrepancy, increased girth, bowing or angulation of the limbs, chronic pain, muscle atrophy and intra-articular osteophytes, with considerable disability; contractures and fibrosis recur after surgery [73]. Radiographs show irregular linear densities along the axis of the tubular bones, usually unilateral, in monostotic, monomelic or polyostotic form, continuous across joints according to the sclerotomes, and, in adults, periosteal excrescences with the appearance of «wax dripping down a candle» [73]. Life expectancy and adult height are normal [73]. An observational study of the US National Institutes of Health (NIH) on the natural history of melorheostosis is recruiting up to 350 patients, with completion expected in 2030 [129]. «Mixed sclerosing bone dysplasia» combines lesions of osteopoikilosis, melorheostosis and osteopathia striata [34, 53].

3.10. Pyle disease and Lenz-Majewski dysplasia

Pyle disease usually manifests in childhood with genu valgum; in mild cases it is diagnosed in adults, on a radiograph taken for a fracture or another reason [42]. The clavicles are broad, height is at the upper limit of normal, and there may be joint pain, weakness, mild scoliosis, limited elbow extension, dental anomalies and an increased tendency to fracture [42]. Radiographs show marked metaphyseal widening extending into the diaphysis, with a well-defined transition zone (Erlenmeyer flask), thin cortex, expanded ribs, medial clavicles, pubis and ischium and minimal cranial hyperostosis [42]. GeneGuidance highlights the paradox of a dense-looking, bulky bone with a thin, fragile cortex [8]. Life expectancy, intellect and height are normal [42].

Lenz-Majewski dysplasia manifests from birth with cutis laxa, prominent scalp veins, large late-closing fontanelles, a broad forehead, hypertelorism, large ears, choanal stenosis or atresia, nasolacrimal duct obstruction, cutaneous syndactyly, brachydactyly and proximal symphalangism, with progressive sclerosis of the skull, spine, diaphyses, clavicles and ribs that becomes evident only after six months [44, 52, 130]. Growth failure is severe, and developmental delay is significant, with intelligence quotients of 40–50 in some patients; choanal stenosis causes respiratory failure and pneumonias, and craniovertebral junction stenosis and communicating hydrocephalus have been described [52, 130]. The original patient, reassessed at 30 years, measured 120 cm, spoke a few words and was ambulant [52]. The attenuated form, associated with the p.(Arg95Gln) variant, has slow bone progression, normal stature (164.5 cm at 17 years in one patient), mild to moderate intellectual disability and absence of diaphyseal hyperostosis [44]. A total of 23 patients have been published, 16 with an identified PTDSS1 variant [44].

3.11. Natural history and treated disease

None of the entities has a disease-modifying treatment with demonstrated efficacy, so the cohort data mainly describe natural history with supportive treatment. The partial exceptions are craniectomy in sclerosteosis, which GeneReviews associates with a probable but not yet quantified improvement in survival; somatropin in pyknodysostosis with growth hormone deficiency, effective on linear growth in 40% of French patients; and corticosteroid therapy or losartan in Camurati-Engelmann disease, supported by reports and small series [5, 23, 114].

4. Clinical Recognition and Warning Signs

4.1. When to suspect, by age

The Oxford Desk Reference organises reasoning by age at presentation [16]. From the neonatal period to 2 years, the diagnoses to consider are severe autosomal recessive osteopetrosis, Ghosal haematodiaphyseal dysplasia, pyknodysostosis, severe recessive craniometaphyseal dysplasia, craniodiaphyseal dysplasia and the rare osteosclerotic disorders with extraskeletal signs (Blomstrand dysplasia, Raine dysplasia, Schinzel-Giedion syndrome, Lenz-Majewski dysplasia, Melnick-Needles and otopalatodigital syndromes) [16]. From 2 to 12 years, craniometaphyseal dysplasia, frontometaphyseal dysplasia, Camurati-Engelmann disease, Pyle disease, sclerosteosis, juvenile Paget disease, osteopathia striata with cranial sclerosis, dysosteosclerosis and Kenny-Caffey syndrome [16]. After 12 years, Camurati-Engelmann disease, Pyle disease, van Buchem disease, Worth-type endosteal hyperostosis and mild autosomal dominant osteopetrosis [16]. In the approach to macrocephaly, the same textbook recommends considering the dysplasias with cranial thickening (craniodiaphyseal dysplasia, craniometaphyseal dysplasia and van Buchem disease), confirmed by a radiological skeletal survey [131]; in the presence of a large anterior fontanelle with increased bone density, pyknodysostosis is among the diagnoses to consider [132].

In the Afrikaner population of South Africa, sclerosteosis should be suspected in any newborn with syndactyly and in any child with fluctuating facial palsy; van Buchem disease is found almost exclusively in the Netherlands [5]. Pyknodysostosis should be suspected in the presence of short stature with an anterior fontanelle open beyond the expected age, an obtuse mandibular angle, short distal phalanges and fractures; stridor and laryngomalacia may bring the suspicion forward [18, 50]. Camurati-Engelmann disease should be suspected in a child or adolescent with lower limb pain, proximal weakness, easy fatigability and a waddling gait, especially when the long bone diaphyses are palpable or tender [23]. Craniometaphyseal dysplasia should be considered in a newborn with nasal obstruction or feeding difficulty and a widened nasal root [28]. Osteopathia striata with cranial sclerosis should be considered in a girl with macrocephaly and cleft palate, and the AMER1 gene should be part of any panel for multiple fetal or neonatal malformations in a boy [26]. Melorheostosis should be considered in the presence of contractures of a single limb with skin changes, because a diagnosis of arthrogryposis often precedes it until the bone lesions appear [73].

The clinical history should cover three generations, consanguinity, age at onset, progression, ethnic origin, muscle pain or weakness, vision, hearing and headaches, mandibular osteomyelitis, developmental delay and easy fractures or absence of fractures after major trauma [16]. Examination should include height (short in pyknodysostosis, tall in sclerosteosis), head circumference, overgrowth of the nasal bridge, forehead and face, mandible, eyes and fontanelle, teeth, choanae, cranial nerves, fundus, fingers, sexual development (pituitary compression), liver and spleen and the presence of torus palatinus [16].

4.2. Warning and emergency signs

The signs requiring urgent assessment are those of intracranial hypertension (headaches, vomiting, papilloedema), which is the main cause of death in sclerosteosis and may occur in craniodiaphyseal dysplasia, Camurati-Engelmann disease and pyknodysostosis [5, 13, 18, 23]. Impaction of the medulla in the foramen magnum and Chiari I malformation with truncal ataxia require posterior fossa decompression [28, 30, 48]. Progressive visual loss due to optic compression is a relative emergency in craniometaphyseal dysplasia, because early optic canal decompression may delay or prevent blindness [31]. Neonatal respiratory distress due to choanal stenosis occurs in craniometaphyseal dysplasia, craniodiaphyseal dysplasia and Lenz-Majewski dysplasia [5, 28, 52]. Severe obstructive apnoea is frequent in infantile pyknodysostosis [18, 133]. In pyknodysostosis, head injury may cause an epidural haematoma [50]. In osteopathia striata with cranial sclerosis, an abdominal mass or haematuria in a child requires exclusion of Wilms tumour [26, 97].

4.3. Newborn screening

None of these disorders is included in newborn screening programmes. Prenatal ultrasound may show syndactyly in a fetus at risk of sclerosteosis and, in the dysplasias with increased density, changes that usually become visible only in the second or third trimester [5, 16].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Diagnostic criteria

No formal diagnostic criteria have been published for any of the entities [5, 18, 23, 26, 28]. Diagnosis rests on suggestive clinical-radiological combinations, confirmed by molecular testing. In sclerosteosis and van Buchem disease, typical clinical and radiological features and biallelic pathogenic or likely pathogenic SOST variants or the biallelic 52 kb deletion are required [5]. In pyknodysostosis, the combination of acro-osteolysis, osteosclerosis and loss of the normal mandibular angle is almost pathognomonic, and the diagnosis is established by characteristic clinical and radiological features and/or biallelic CTSK variants [18]. In Camurati-Engelmann disease, the clinical diagnosis is established by the characteristic radiology, and molecular testing is needed when radiology is inconclusive [23]. In craniometaphyseal dysplasia, characteristic craniofacial hyperostosis with metaphyseal widening and undertrabeculation and/or a heterozygous ANKH variant are required [28]. In osteopathia striata with cranial sclerosis, macrocephaly with cranial sclerosis and longitudinal metaphyseal striations is considered pathognomonic in women, and an AMER1 variant confirms the diagnosis [26]. In all of them, identification of variants of uncertain significance neither establishes nor excludes the diagnosis [5, 18].

5.2. Algorithm

The first step in the presence of increased bone density is to exclude acquired causes: fluorosis, beryllium, lead or bismuth poisoning, myelofibrosis, the sclerosing form of Paget disease, lymphoma and osteoblastic metastases [18]. The checklist of the ECTS/ERN BOND review for adults with high bone mineral density follows the same order: exclusion of secondary causes, genetic assessment of the family and, in all cases, bone investigations to measure severity and a search for complications in other organs [19]. The second step is the radiological skeletal survey, interpreted by a radiologist experienced in dysplasias and integrated with the clinical picture and biochemistry [16]. The third is assessment of complications (hearing, vision, cranial nerves, intracranial hypertension, airway). The fourth is phenotype-guided molecular testing: single-gene testing or a multigene panel when the picture points to one entity, and exome or genome sequencing when the phenotype is atypical or indistinguishable from other dysplasias [5, 16, 18, 23]. The table summarises the first-line tests.

5.3. Imaging

In sclerosteosis and van Buchem disease, radiographs show progressive hyperostosis of the calvaria, base, mandible, clavicles and ribs, poorly pneumatised paranasal sinuses, endosteal sclerosis of the diaphyseal cortex without diaphyseal constriction, undermodelling of the metacarpals and phalanges, broad, dense clavicles and ribs and sclerosis of the scapulae and pelvis without enlargement; bony syndactyly is present only in sclerosteosis [5, 48]. Dual-energy X-ray absorptiometry (DXA) shows Z-scores of 7.7 to 14.4 SD at the spine and 7.8 to 11.5 SD at the hip in sclerosteosis, and 5.4 to 12.3 SD at the spine and 5.2 to 12.1 SD at the hip in van Buchem disease; GeneReviews considers a Z-score above 5 SD suggestive [5].

In pyknodysostosis, radiographs show an anterior fontanelle and sutures open into adulthood, a thin, dense calvaria, dense orbital rims, Wormian bones, small facial bones, hypoplastic sinuses, an obtuse mandibular angle (almost 180° in some children), generalised sclerosis with moderate overmodelling, fractures, supra-acetabular constriction, and osteolysis of the distal phalanges and of the acromial ends of the clavicles [50]. In Camurati-Engelmann disease, hyperostosis begins in the diaphyses and may progress to the metaphyses, rarely to the epiphyses; periosteal involvement produces irregular cortical thickening and increased diameter, and endosteal involvement narrows the medullary canal; the skull is involved from the base of the anterior and middle fossae, and there is mild sclerosis of the posterior vertebral arches [23]. Bone scintigraphy and the erythrocyte sedimentation rate help assess disease activity in acute pain, and the use of whole-body magnetic resonance imaging (MRI) to identify the affected areas has been described [23].

In craniometaphyseal dysplasia, sclerosis of the base may begin in infancy; computed tomography (CT) assesses the foramina and the foramen magnum [28]. Also in this disease, club-shaped metaphyseal widening, with a thin cortex, appears in childhood; the spine and pelvis are normal [28, 31]. In osteopathia striata with cranial sclerosis, the fine longitudinal striations are best seen in the pelvis, proximal and distal femur, proximal tibia and humerus, and fan-shaped striations of the ilia are typical [26, 53]. In osteopoikilosis, the foci are oval, symmetrical and well defined; in melorheostosis, the densities are linear, asymmetric and continuous across joints [34, 73].

5.4. Laboratory tests and biomarkers

Bone biochemistry is often normal in these disorders, but some parameters help with classification [16]. The table summarises the findings for parathyroid hormone (PTH), procollagen type 1 amino-terminal propeptide (P1NP) and the carboxy-terminal (CTX) and amino-terminal (NTX) telopeptides of type 1 collagen.

GeneGuidance considers serum sclerostin an informative biochemical test in the SOST dysplasias, but identification of the specific change is molecular, and van Buchem disease requires a test that detects the deletion [8]. In pyknodysostosis there is no cathepsin K enzyme assay used in practice [8]. The ECTS/ERN BOND review recommends serum tartrate-resistant acid phosphatase isoform 5b (TRAP5b) as a marker of osteoclast number in autosomal dominant osteopetrosis, in which it is always above the reference range, unlike in the other sclerosing osteopathies; the value does not correlate with severity [19]. The marker thus helps to separate autosomal dominant osteopetrosis from disorders with increased bone density due to other mechanisms [19]. Bone histology in sclerosteosis shows increased osteoblastic formation, normal or reduced resorption and normal mineralisation [5, 109].

5.5. Limits of testing and interpretation

The van Buchem disease deletion does not overlap the coding region and is not detected by SOST sequencing or by panels; GeneReviews recommends targeted testing in Dutch patients and, in others, only after a negative panel [5]. In sclerosteosis, an apparently homozygous patient may have a deletion of one or more exons not detected by sequencing or uniparental isodisomy; if only one parent is a carrier, a de novo variant or parental mosaicism must be considered [5]. In osteopathia striata with cranial sclerosis, mosaicism in males may require other cell lineages, other technologies or deeper sequencing, and variants in the non-coding exon 1 may escape conventional testing [26]. In melorheostosis, the variant is somatic and absent in blood, so analysis of affected bone or of the skin over the lesion is necessary [38]. In Camurati-Engelmann disease and craniometaphyseal dysplasia, the gain-of-function mechanism makes deletion testing useless [23, 28]. The proportions in table 5.2 refer to variants detected by the method and not to the clinical sensitivity of the test, which depends on patient selection and genetic heterogeneity. When the molecular cause is not found, GeneReviews recommends banking the proband's DNA [18, 23].

In a patient with an osteopathia striata phenotype and negative AMER1 testing (sequencing, deletion/duplication and exon 1), exome sequencing with sufficient depth for low-level mosaicism may identify somatic CTNNB1 variants [99]. In craniometaphyseal dysplasia, a new in-frame variant in the carboxy-terminal region of ANKH that segregates with the disease may remain classified as of uncertain significance while functional data are lacking [90].

The molecular report should state the gene, the transcript with version (for example, NM_025237.3 for SOST), Human Genome Variation Society (HGVS) nomenclature at DNA and protein level, zygosity and classification according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) [5, 78]. Parental testing confirms the phase of variants in recessive disorders and de novo status in dominant ones [5, 28].

5.6. Prenatal and preimplantation diagnosis

Once the familial variants have been identified, prenatal diagnosis and preimplantation genetic testing are possible for all entities [5, 18, 23, 26, 28]. In Camurati-Engelmann disease, incomplete penetrance and variability prevent the result from predicting age at onset, severity or progression [23]. Ultrasound may show syndactyly in a fetus at risk of sclerosteosis, but the absence of syndactyly does not indicate an unaffected fetus [5]. In osteopathia striata with cranial sclerosis, ultrasound of male fetuses may show multiple malformations, clefts, omphalocele or absent fibulae [26, 53].

6. Differential Diagnosis

6.1. Approach to dense bone

The differential begins with exclusion of acquired causes of sclerosis (metal and fluoride poisoning, vitamin D excess, myelofibrosis, Paget disease, neoplasms and osteoblastic metastases) and continues by distinguishing three patterns: osteosclerosis without overgrowth, characteristic of the osteopetroses and pyknodysostosis; hyperostosis with overgrowth and resistance to trauma, characteristic of the SOST, LRP4 and LRP5 dysplasias and Camurati-Engelmann disease; and the craniotubular dysplasias with a modelling defect, such as craniometaphyseal dysplasia and Pyle disease [5, 16, 18]. The location of involvement (vault and base, diaphyses, metaphyses, focal or linear lesions), age at onset, stature, presence of fractures and extraskeletal signs guide the choice of test.

6.2. Comparative table

6.3. Main differentials

The most important distinction for management is that between pyknodysostosis and the osteopetroses. Early haematopoietic cell transplantation may be an option in some osteopetroses and has no benefit in pyknodysostosis, which rarely presents with bone marrow failure [18]. In juvenile osteopetrosis there is no delayed closure of the sutures or fontanelle, the mandibular angle is not widened and there is no clavicular or phalangeal osteolysis; these three features also exclude the other dysplasias with increased density [50]. Dysosteosclerosis was initially diagnosed as osteopetrosis in all cases in early childhood and is distinguished by platyspondyly and radiolucency of the widened submetaphyseal zones [135]. The ECTS/ERN BOND review, which follows the 2023 nosology in including it among the osteoclast disorders, distinguishes three entities (related to TNFRSF11A, CSF1R and SLC29A3) and describes the course into adulthood: constant short-trunk short stature; long bone cortices sclerotic in the child and increasingly thin with age; fractures in all children with SLC29A3 variants and in 25% of children with CSF1R variants, with no fractures described in adults; leukoencephalopathy constant in adults with biallelic CSF1R variants, with seizures, early cognitive decline and parkinsonism; cranial nerve palsies and optic atrophy due to compression, frequent in children and described in adults with CSF1R variants; and oligodontia, delayed eruption and caries that persist into adulthood, with a risk of osteomyelitis and osteonecrosis [19].

Among the craniotubular hyperostoses, sclerosteosis is distinguished by syndactyly, tall stature and severity; van Buchem disease by normal stature and Dutch origin; Worth-type hyperostosis by torus palatinus, normal alkaline phosphatase and the rarity of nerve compression [5, 16]. Craniodiaphyseal dysplasia begins before 5 years and progresses faster than sclerosteosis, and has broad diaphyses with thin cortices instead of endosteal thickening [13, 48]. Camurati-Engelmann disease differs from the endosteal hyperostoses by irregular periosteal thickening and muscular symptoms, and from craniometaphyseal dysplasia by the absence of metaphyseal widening [51]. OMIM maintains an entry for recessive craniodiaphyseal dysplasia (218300), supported by affected siblings of both sexes and parental consanguinity, and notes that the siblings described by de Souza in 1927 probably had van Buchem disease [10]. In craniometaphyseal dysplasia, the diaphyseal sclerosis of infancy may lead to a misdiagnosis of craniodiaphyseal dysplasia [13]. Pyle disease has much less cranial involvement and more marked metaphyseal widening than craniometaphyseal dysplasia; when the Erlenmeyer flask is associated with osteopenia, hepatosplenomegaly and bone infarcts, glucocerebrosidase should be measured to exclude Gaucher disease [42].

Among focal and linear lesions, solitary bone islands are frequent, especially in the pelvis, and are not associated with other changes; osteoblastic metastases, mastocytosis and tuberous sclerosis produce lesions that are less regular, asymmetric and less well defined than those of osteopoikilosis [34]. Melorheostosis is distinguished from osteopoikilosis by size, longitudinal orientation and asymmetry; from fibrous dysplasia by the absence of ground-glass areas and cranial involvement; and from linear scleroderma by bone sclerosis [73]. Osteomesopyknosis was first described in French families and later in a North American family, and axial osteomalacia may correspond to the same disease [140]. The association of axial melorheostosis-like lesions with fibrolipomatous lesions suggests Proteus syndrome [73]. The striations of osteopathia striata are longitudinal, unlike the transverse metaphyseal bands of osteopetrosis [53]. Camurati-Engelmann disease is still confused with rheumatoid arthritis, sarcoidosis, muscular dystrophies and polymyositis, and late congenital syphilis may cause periostitis [23, 51]. Juvenile Paget disease was the first diagnosis in an adult with Camurati-Engelmann disease described in 2025 [150].

7. Treatments and Risk Management Strategies

7.1. Principles and organisation of care

There are no published clinical guidelines for any of the entities in this article; the GeneReviews state this explicitly and base their recommendations on the authors' experience and the published series [5, 18, 23, 26, 28]. The French pyknodysostosis series proposes management axes based on 27 patients, without the status of a formal guideline [114]. The European Calcified Tissue Society (ECTS) and ERN BOND review on osteopetrosis and related osteoclast disorders in adults, which includes pyknodysostosis, stresses that treatment is not standardised and that care requires a multidisciplinary approach, preferably in specialised centres [19]. The review makes no specific recommendations for pyknodysostosis; for autosomal dominant osteopetrosis, it proposes specialised ophthalmological and otorhinolaryngological surveillance to detect early compression of the optic, auditory and facial nerves and plan decompression, with MRI or CT to assess the optic canal, hydrocephalus and vascular anomalies, and notes the absence of orthopaedic guidelines for fractures and arthroplasty in dense bone [19]. None of the dysplasias has an approved disease-modifying treatment. Management combines surveillance of predictable complications (cranial nerve compression, intracranial hypertension, airway, fractures), decompressive or corrective surgery, rehabilitation and, in three situations, pharmacological therapy with some support: glucocorticoids and losartan in Camurati-Engelmann disease and somatropin in pyknodysostosis with growth hormone deficiency [18, 23].

Surgery on sclerotic bone has its own difficulties. In sclerosteosis, the thick, dense bone makes procedures long and difficult, conventional neurosurgical instruments may not suffice (short drills, damaged motors) and bone regrowth causes symptoms to recur [5]. In pyknodysostosis, narrow medullary canals hinder fixation and the sclerotic bone increases the risk of intraoperative iatrogenic fracture [18]. In craniometaphyseal dysplasia, surgical facial contouring is technically difficult, regrowth is common and the serious complications described have led to surgery being reserved for severe compression symptoms [28]. In osteopathia striata with cranial sclerosis, the success of foraminal decompression has not been established [26]. In autosomal dominant osteopetrosis, the ECTS/ERN BOND review advises against intramedullary nails, because of the reduced medullary space, and prefers screws and long plates; it notes the risk of iatrogenic fracture adjacent to hardware, early and late postoperative pseudofractures and fractures, osteomyelitis and the need to limit elective correction of deformities because of slow healing [19]. These indications refer to osteopetrosis; the review does not extend them to the dysplasias with increased bone formation.

7.2. SOST- and LRP4-related dysplasias

GeneReviews recommends, after diagnosis, radiographs of the affected areas, DXA, assessment of the need for syndactyly correction, formal audiology, neurological assessment of the cranial nerves and of signs of intracranial hypertension, ophthalmology (intracranial hypertension and proptosis), dental and orthodontic assessment in children and genetic counselling [5]. Treatment is directed at complications (table) [5].

Glucocorticoids have been used with limited results. In an adult with severe van Buchem disease, they suppressed bone formation and progression, but the patient continued to require repeated surgery; in two children with van Buchem disease, short courses of prednisolone during exacerbations of facial palsy lowered turnover markers without clinical improvement; long-term benefit has not been studied [5]. GeneReviews recommends avoiding antiresorptive drugs (bisphosphonates, denosumab, selective oestrogen receptor modulators) and anabolic agents (teriparatide, abaloparatide, romosozumab) [5]. Romosozumab (Evenity®), an anti-sclerostin monoclonal antibody, was authorised by the FDA (Food and Drug Administration) in 2019 and in the European Union on 9 December 2019 for postmenopausal osteoporosis at high risk of fracture; it pharmacologically reproduces sclerostin deficiency and has no indication in these diseases [8, 151, 152].

7.3. Pyknodysostosis

The initial assessment proposed by GeneReviews includes growth and testing for growth hormone and IGF-1 deficiency as early as possible, radiographs of the whole skeleton with a lateral spine, cranial CT if craniosynostosis is suspected, orthopaedics experienced in dysplasias, otorhinolaryngology (cleft palate and narrow nasal passages) with audiology, polysomnography in all patients as early as possible, dental and ophthalmological assessment, MRI if there are neurological symptoms or suspected Chiari, genetic counselling and family support [18]. The French series proposes systematic brain MRI at diagnosis to screen for Chiari malformation and regular psychological follow-up, given that none of the 27 patients had had a psychological assessment [114]. The Brazilian textbook of genetic syndromes organises management by specialty: otorhinolaryngology for recurrent respiratory infections, adenotonsillar hypertrophy and otitis (ventilation tubes), speech therapy, dentistry with orthodontics, paediatrics, physiotherapy with rehabilitation to reduce fractures, respiratory medicine with polysomnography and bilevel positive airway pressure (BiPAP) ventilation, endocrinology with testing for and treatment of growth hormone deficiency, genetics and orthopaedics [115].

Somatropin. Growth hormone raised IGF-1 and almost normalised adult height and body proportions in the series by Rothenbühler and colleagues; in the French series it was effective on linear growth in 40% of treated patients; Smith's reports a favourable response in three patients [18, 49, 114, 153]. The sources consulted do not give a specific dose for pyknodysostosis. The approved indication covering these patients is growth hormone deficiency, and the applicable dose is the label dose for that indication: the Portuguese summary of product characteristics (SmPC) of Genotropin® recommends, for growth disturbance due to insufficient growth hormone secretion in children, 0.025–0.035 mg/kg body weight per day or 0.7–1.0 mg/m² body surface area per day, subcutaneously, with rotation of injection sites [154]. Without documented deficiency, the use of somatropin in pyknodysostosis is off-label. GeneReviews suggests environmental adaptations and occupational therapy for short stature [18].

Fractures and orthopaedics. At least 35% of patients require orthopaedic intervention (osteosynthesis or immobilisation), and non-union after surgery has been described; scoliosis is treated as advised by the orthopaedic surgeon [18]. There is no effective pharmacological treatment for fragility, and bisphosphonates are contraindicated because of osteoclast dysfunction [18]. The ECTS/ERN BOND review adds that bisphosphonates may induce atypical fractures, that there are no studies of the effect of native vitamin D on the course or on bone mass and that teriparatide, given for 6 months to a 37-year-old woman, did not change microarchitecture, histology, serum markers or the resorptive capacity of osteoclast precursors; in the absence of causal treatment, care focuses on prevention and treatment of complications [19].

Airway and anaesthesia. Obstructive apnoea is managed by respiratory and sleep medicine, with non-invasive ventilation, taking into account nasal obstruction due to narrow airways; before any planned surgery an experienced anaesthetist should be consulted, because of the risk of difficult intubation [18].

Craniofacial and dental. Cleft palate, craniosynostosis and maxillary and mandibular hypoplasia are managed by craniofacial and neurosurgical teams, including distraction osteogenesis; oral hygiene, regular dental care and orthodontics prevent complications, and the risk of osteomyelitis after tooth extraction is increased [18].

7.4. Camurati-Engelmann disease

The initial assessment includes orthopaedics, physical medicine and rehabilitation, physiotherapy and occupational therapy (motor skills, mobility, activities of daily living, assistive devices), radiographs of the whole skeleton, erythrocyte sedimentation rate and bone scintigraphy in acute pain to assess activity, neurological examination, CT of the head and neck if there is sclerosis of the base with symptoms, audiology with brainstem auditory evoked potentials (BAEP) and thin-slice CT of the inner ear if there is hearing loss, ophthalmology, assessment of puberty and hypopituitarism, baseline blood pressure before considering losartan, full blood count and genetic counselling [23]. The disease has no cure [23].

Glucocorticoids. Corticosteroids relieve many symptoms: they reduced pain and weakness, improved gait, exercise tolerance and contractures, corrected anaemia and hepatosplenomegaly and may prevent or delay hyperostosis, including cranial hyperostosis and nerve compression [23]. Spranger's atlas reports considerable clinical, radiological and histological improvement [51]. Histology after treatment showed more resorption and secondary remodelling, but several authors did not observe regression of sclerosis on radiographs or scintigraphy, while others did [23]. The GeneReviews regimen is as follows: in patients with severe symptoms, a bolus of prednisolone 1.0–2.0 mg/kg/day followed by rapid tapering to the lowest tolerated alternate-day dose; in less symptomatic patients, starting with 0.5–1.0 mg/kg on alternate days; discontinuation possible during quiescent periods; higher doses during acute pain crises [23]. After initiation, patients should be seen monthly, with tapering to the lowest tolerated dose to limit osteoporosis and vertebral fractures, and with blood pressure measurement at each visit [23]. BMD should be assessed annually in treated patients, because the disease does not increase spinal density [23]. Prednisolone is used off-label in Camurati-Engelmann disease [8].

Losartan. Losartan, an angiotensin II type 1 receptor antagonist that downregulates TGFβ1 signalling, reduced pain and increased physical activity in several patients [23]. In the first report, by Ayyavoo and colleagues, a prepubertal 9-year-old girl started 0.75 mg/kg/day, gradually increased over 12 weeks to 1.0 mg/kg/day; over 38 months, the severe, disabling pain disappeared, walking capacity and physical activity increased, lean mass and adipose tissue increased, and the full blood count and liver and renal function remained normal [155]. Other favourable reports include a single case with a positive effect, a response in an adult, use as a corticosteroid-sparing agent in a refractory patient and combination with glucocorticoids that allowed puberty to start at 18 years [156–159]. Losartan was not effective in other patients [23, 160]. Its use is off-label: the FDA label of Cozaar® (NDA 020386, original submission in 1995) limits the paediatric indication to hypertension from 6 years, with a starting dose of 0.7 mg/kg once daily up to 50 mg, doses above 1.4 mg/kg or 100 mg per day not studied in children, no recommendation below 6 years or with a glomerular filtration rate (GFR) below 30 mL/min/1.73 m², contraindication with aliskiren in diabetes and a fetal toxicity warning [151, 161]. The Portuguese SmPC of a generic losartan recommends, from 6 to 18 years, 25 mg per day between 20 and 50 kg (exceptionally up to 50 mg) and 50 mg per day above 50 kg (exceptionally up to 100 mg), and makes no recommendation below 6 years [162]. The 1.0 mg/kg/day dose of Ayyavoo lies within the range studied in the paediatric label, but the indication is not the labelled one. GeneReviews recommends adjusting the dose if hypotension occurs and assessing mobility and fall prevention [23].

Other measures. The GeneReviews table includes analgesics, non-pharmacological methods and surgical intramedullary reaming for persistent pain, with success described; intranasal calcitonin relieved pain in one patient and infliximab in a patient unresponsive to corticosteroids [23]. Hearing loss is managed by otorhinolaryngology: bilateral myringotomy improves conductive hearing loss due to serous otitis; a cochlear implant improved one patient with patent internal auditory canals, but narrowing of the canal and absence of a functional cranial nerve VIII, possible in this disease, are contraindications; decompression of the internal auditory canals has mixed results, and compression recurs [23]. Facial palsy was successfully treated by decompression in one patient [23]. Intracranial hypertension and headaches responded to craniectomy, and recurrent hyperostosis was treated with radical craniectomy and titanium mesh cranioplasty [23]. Orbital involvement requires subspecialists and low vision services [23].

Bisphosphonates. GeneReviews includes them among treatments to be considered with caution: pamidronate did not improve four patients, clodronate increased pain in one patient and had no effect in another, zoledronic acid reduced pain and lesions and improved weight and gait in two patients, and a single intravenous dose relieved pain in an adult [23]. In 2025, an adult with a de novo signal peptide variant had almost complete resolution of musculoskeletal symptoms six weeks after starting alendronate [150]. In the TGFB2 form, aminobisphosphonates appeared useful [24]. These are observations of isolated cases, with no established dose for the disease.

Agent to avoid. Cellulose phosphate worsened hypocalcaemia and proximal myopathy in one patient [23].

7.5. Craniometaphyseal dysplasia

The initial assessment includes a craniofacial team with otorhinolaryngology for choanal stenosis in the respiratory and feeding problems of infants, radiographs of the skull, hands and knees, CT of the foramina and foramen magnum, neurological examination, audiology, ophthalmology, serum phosphate and radiological signs of rickets in infancy, alkaline phosphatase, P1NP and CTX, speech therapy in early childhood and a dentist from eruption of the deciduous teeth [28]. Treatment is surgical and supportive: cranial nerve decompression for severe symptoms; foramen magnum surgery for headaches and the risks of Chiari I malformation; early optic canal decompression, which may delay or prevent visual loss but does not always succeed; hearing aids and cochlear implants when possible; visual aids and Braille learning in anticipation of visual loss; speech therapy; surgery for severe malocclusion, taking delayed eruption into account [28, 31]. Calcitonin was ineffective for craniofacial hyperplasia; calcitriol combined with a low-calcium diet, to stimulate osteoclastic resorption, improved facial palsy without effect on the metaphyses; in infants, calcitriol may resolve secondary hyperparathyroidism during treatment of rickets; acetazolamide was used in a patient with a similar phenotype without a confirmed diagnosis [28].

In the infant girl with hypophosphataemic rickets, treatment began at 4 months with oral elemental phosphorus, 15 mg four times daily (11.2 mg/kg/day), increased up to 150 mg/day; calcitriol, 0.06 µg twice daily (21 ng/kg/day), was added when secondary hyperparathyroidism appeared and increased up to 0.25 µg/day [89]. Doses were reduced from 15 months and stopped at 19 months, with normal linear growth, biochemical normalisation and radiological improvement of the metaphyses [89]. These values come from a case report and do not constitute a standardised dose; GeneReviews states that calcitriol may resolve secondary hyperparathyroidism during treatment of rickets, without setting doses [28]. A low-calcium diet combined with calcitriol, used to stimulate osteoclastic resorption, was associated in isolated reports with partial improvement of facial palsy and nasal obstruction and lower cranial density [89].

Otological surgery has published results in isolated cases. A 65-year-old woman with profound, progressive mixed hearing loss received a cochlear implant via subtotal petrosectomy with closure of the external auditory canal, because hyperostosis prevented the conventional mastoidectomy approach; despite extensive stenosis of the internal auditory canal, five weeks after activation thresholds were between 20 and 30 dB HL from 250 to 6000 Hz, and word recognition in quiet rose from 2% to 76% [163]. In a 9-month-old infant girl with bilateral facial palsy and conductive hearing loss, transmastoid decompression of the right facial nerve with ossicular chain reconstruction transiently worsened facial function and then improved it, over 12 months, from House-Brackmann grade IV–V to grade III [164].

In 2024, a French team reported allogeneic bone marrow transplantation in a girl with severe craniometaphyseal dysplasia, assessed at 30 months for optic atrophy, after respiratory difficulty at 20 months, with feeding difficulty, nasal obstruction, reduced mouth opening, progressive macrocephaly from the first months and mixed hearing loss due to ossicular chain fixation and cochlear nerve compression [165]. The rationale is the osteoclast dysfunction described in the murine model and in patient cells [92]. This is an isolated observation, without a published series or comparative follow-up; with the inherent risks of allogeneic transplantation, the procedure is not an established treatment.

7.6. Osteopathia striata with cranial sclerosis

The initial assessment includes radiographs of the long bones and skull, assessment of scoliosis and contractures, otorhinolaryngology (clefts), hearing, ophthalmology (optic compression), growth, development, cardiology with echocardiography in women and surviving men, renal ultrasound (anomalies in men; nephrogenic rests and Wilms tumour in both sexes), brain MRI in surviving men and imaging for malrotation when indicated [26]. Treatment is multidisciplinary: orthopaedics for scoliosis, physiotherapy for contractures, cleft surgery, audiology and speech therapy, ophthalmology, early intervention and special education, cardiology, urology or nephrology and gastrointestinal surgery; foraminal decompression is decided case by case [26]. Cervical stabilisation may be needed in cervical kyphosis and instability [53]. In infants with Robin sequence, mandibular distraction resolved the obstruction in one patient and was followed by tracheostomy in the patient with the more severe phenotype [121]. Wilms tumour and other neoplasms receive standard treatment [26]. Given the proportion of bilateral tumours, the 2025 multicentre series proposes considering nephron-sparing surgery and familial genetic testing in children with a germline AMER1 variant and Wilms tumour [123]. Before surgery, or in the presence of neurological symptoms, assessment for cerebral vasculopathy may be justified [127].

7.7. Osteopoikilosis, melorheostosis, Pyle disease and Lenz-Majewski

Osteopoikilosis and the skin lesions of Buschke-Ollendorff syndrome require no treatment; orthopaedics intervenes in spinal stenosis, short stature and associated melorheostosis, and dermatology for cosmetically troublesome naevi [8, 34]. In melorheostosis, analgesia is often necessary, and contractures may require fasciotomy, capsulotomy, tendon lengthening or excision, with frequent recurrence; limb lengthening and other orthopaedic corrections may be indicated [73]. In Pyle disease, treatment is orthopaedic (correction of genu valgum and other deformities, fractures, physiotherapy) and dental, with advice on fracture prevention because the dense radiological appearance does not reflect strength; no evidence supports bisphosphonates or other antiresorptive or anabolic agents [8, 42]. A trial compared single and double osteotomy for correction of deformity in five patients, with unknown status [129]. In Lenz-Majewski dysplasia, GeneReviews recommends orthopaedics, physiotherapy and occupational therapy, decompression of cervical stenosis, treatment of hydrocephalus, otorhinolaryngology and respiratory medicine for respiratory difficulty and apnoea, careful airway assessment before any surgery, developmental support, a dentist for enamel hypoplasia, standard treatment of genitourinary anomalies, delayed puberty, hernias, vision and hearing, and dermatology [44]. In patients with craniovertebral junction stenosis, extreme cervical extension and flexion should be avoided, and the cervical spine should be imaged before general anaesthesia [44].

7.8. Dosing table

7.9. Regulatory status

No drug has specific authorisation for any sclerosing dysplasia in the United States or the European Union [8, 129].

7.10. Clinical trials

The ClinicalTrials.gov search in October 2026 found no registered therapeutic trials for sclerosteosis, van Buchem disease, pyknodysostosis, Camurati-Engelmann disease, osteopoikilosis, Buschke-Ollendorff syndrome, osteopathia striata with cranial sclerosis or Lenz-Majewski dysplasia [129]. The registered studies are small observational or surgical studies.

Without controlled trials, the therapeutic evidence comes down to small reports and series, without a comparison group, with selection of responding patients and without standardised measurement of pain or function; the favourable losartan reports coexist with published failures, and the results of bisphosphonates in Camurati-Engelmann disease are contradictory [23, 160]. The absence of registered trials does not prove that there are no ongoing studies outside this registry.

7.11. Developments in the last 12 months and therapies under study

The developments between October 2025 and October 2026, and the early 2025 work that remains relevant, are mainly preclinical or descriptive. In sclerosteosis, a preclinical study showed that the porcupine inhibitor LGK974, which blocks acylation of Wnt ligands, reduced in vitro alkaline phosphatase activity and osteoblast mineralisation without affecting osteoclasts and, in Sost-null mice treated for four weeks from six weeks of age, reduced vertebral trabecular number and tibial cortical volume; the response of the Axin2 biomarker differed between sexes (level of evidence: preclinical) [166]. The same group characterised in 2026 the cranial pathology of the Sost-null mouse at 9 months (narrowing of the foramen magnum, otosclerosis with hearing loss, prominent mandible) as a model for assessing drugs (preclinical) [167]. In melorheostosis, palbociclib, a cyclin-dependent kinase 4 (CDK4) inhibitor approved for other indications, reduced the proliferation and mineralisation of cells derived from patients with a MAP2K1 variant (preclinical, in vitro) [39, 168]; MEK1 inhibition had been proposed as a therapeutic route in 2018, without a registered trial [38]. In Pyle disease, anti-sclerostin antibodies and a soluble BMP2 receptor corrected the cortical defect in mice, a result that does not support clinical use of anti-sclerostin drugs (preclinical) [8].

On the clinical side, 2025 saw publication of the longitudinal follow-up of adults with van Buchem disease, the description of a family with TGFB2-related Camurati-Engelmann disease type 2 with an apparent response to aminobisphosphonates, a case of Camurati-Engelmann disease responding to alendronate (case reports), a Spanish series on quality of life and a new SOST variant (p.(Cys109Ter)) with functional study [24, 79, 106, 116, 150]. In 2026 the GeneReviews chapter on Lenz-Majewski dysplasia, a review of 67 patients with osteopathia striata with cranial sclerosis, a series on Robin sequence in this disease and reports of pregnancy and severe apnoea in pyknodysostosis were published [44, 120, 121, 133, 169]. There were no applications, opinions or regulatory authorisations for these diseases in the period [129].

In craniometaphyseal dysplasia, moderate reduction of dietary phosphate (0.3% versus 0.7%) for 13 weeks from birth attenuated mandibular hyperostosis in the mouse with the p.Phe377del deletion, in both sexes, without significantly changing serum phosphate and calcium, and increased osteoclast number and resorption (preclinical) [92]. The recombinant fusion protein ENPP1-Fc IMA2a, given subcutaneously once weekly for 12 weeks from the first week of life, normalised plasma pyrophosphate (1.29 µM) and reduced ectopic calcifications near the foramen magnum and in the joints, but did not correct femoral shape, craniofacial hyperostosis or narrowing of the foramen magnum (preclinical, with sponsor participation) [93]. A murine model of the recessive form, with the Cx43 substitution equivalent to p.(Arg239Gln), became available in 2025 [95]. In osteopathia striata, the developments are the identification of CTNNB1 mosaicism as an alternative cause and the multicentre Wilms tumour series (descriptive) [99, 123].

7.12. Agents and situations to avoid

7.13. Anaesthesia and the perioperative period

In pyknodysostosis, the small mandible, narrow palate and narrow airways make intubation potentially difficult, and GeneReviews recommends consultation with an experienced anaesthetist before any surgery [18]. In sclerosteosis, perioperative complications of surgery for intracranial hypertension caused six of the deaths recorded by van Lierop and colleagues [5]. In Lenz-Majewski dysplasia, the airway should be assessed before surgery, and the cervical spine imaged before general anaesthesia [44]. In all dysplasias with sclerotic bone, drilling and fixation take longer, the risk of iatrogenic fracture increases and healing may be slow [5, 18, 23].

7.14. Pregnancy, lactation and transition

In pyknodysostosis with a small pelvis, caesarean section should be considered, with assessment by an obstetrician and anaesthetist familiar with skeletal dysplasias [18]. A 2026 report described a 28-year-old nulliparous woman, diagnosed during pregnancy, with a multidisciplinary plan (mobilisation, anaesthesia, genetics and obstetrics team), elective caesarean section under regional anaesthesia at 37 weeks and a long bone fracture post partum after a fall at home [169]. In osteopathia striata with cranial sclerosis, there is no specific guidance and following the guidance for pregnant women with skeletal dysplasias is recommended [26]. In Camurati-Engelmann disease, one woman improved during pregnancy to the point of stopping corticosteroids [23]. Losartan should be stopped as soon as pregnancy is detected, because of the risk of fetal toxicity of drugs acting on the renin-angiotensin system [161]. The sources consulted do not address lactation in these diseases.

Transition to adult care is important in diseases in which complications continue after adolescence. In van Buchem disease, BMD stabilises, but facial paresis, hearing loss and intracranial hypertension continue to progress in adulthood [106]. In sclerosteosis, intracranial hypertension often begins at the end of adolescence [5]. In pyknodysostosis, chronic pain begins in the third decade, and the ECTS/ERN BOND review stresses that the complications of adults with osteoclast disorders are often underestimated for lack of specialised knowledge [18, 19].

7.15. Divergences between sources

The sources diverge on five points. First, the inheritance of LRP4-related sclerosteosis 2 is recorded as autosomal dominant and recessive in the SOST GeneReviews and in OMIM and as recessive in GeneGuidance [5, 7, 8]. Second, the relative severity of recessive craniometaphyseal dysplasia is described as greater in Spranger's atlas and in Smith's and as possibly lesser in the GeneReviews on the dominant form [28, 30, 31]. Third, the association between 5' AMER1 truncations and the lethal male phenotype, still mentioned in Spranger's atlas, was refuted in later series [26, 53]. Fourth, bisphosphonates are contraindicated in pyknodysostosis and to be avoided in the SOST dysplasias, but in Camurati-Engelmann disease GeneReviews accepts them with caution, and recent reports describe a response [5, 18, 23, 150]. Fifth, in pyknodysostosis, the frequency of obstructive apnoea is more than 60% in GeneReviews and 67% in the French series, but 50% in the ECTS/ERN BOND review, and prevalence is 1–1.7 per million in GeneReviews and 1–3/100,000 in the same review, which does not cite the source study [18, 19, 114]. In the absence of guidelines, the GeneReviews are the main reference, and divergences are communicated to patients as uncertainty.

8. Reproductive Options and Family Counselling

8.1. Autosomal recessive disorders

In sclerosteosis, van Buchem disease, pyknodysostosis, Pyle disease and GJA1-related craniometaphyseal dysplasia, the parents of a patient are presumed heterozygotes, and molecular testing of the parents is recommended to confirm carrier status and calculate the recurrence risk [5, 18]. Each sibling has, at conception, a 25% probability of being affected, 50% of being a carrier and 25% of inheriting neither variant [5, 18, 115]. The parents' siblings have a 50% probability of being carriers [5]. The offspring of a patient are obligate carriers; if the partner is a carrier, each child has a 50% probability of being affected [5, 18]. The risk increases with consanguinity and in populations with a high carrier frequency, such as the Afrikaner community, where one carrier per 100 people is estimated, and partner testing should be considered especially when both share the same ancestry [5]. SOST carriers have increased bone mass and calvarial widening, without disease; CTSK carriers are asymptomatic; SFRP4 carriers may have mild metaphyseal changes and tibial bowing [5, 18, 42]. Apparent homozygosity may correspond to an undetected deletion or uniparental isodisomy, and pyknodysostosis due to uniparental disomy has been described [5, 49]. De novo variants, although rare, occur in recessive disorders [18].

8.2. Autosomal dominant disorders

In Camurati-Engelmann disease, many patients have an affected parent, and the proportion of de novo cases is unknown; a negative family history may result from unrecognised disease, early death of a parent or reduced penetrance, so radiological study of the parents or molecular testing is recommended [23]. The siblings of a patient with a carrier parent have a 50% risk, with incomplete penetrance and unpredictable severity; if the variant is not detected in the parents, the estimated risk is about 1% due to germline mosaicism; each child of a patient has a 50% risk [23]. Prenatal diagnosis is possible, but does not predict age at onset, severity or progression [23].

In autosomal dominant craniometaphyseal dysplasia, about 30% of cases are de novo, according to unpublished data from the GeneReviews authors; penetrance is 100%, the risk to siblings with an affected parent is 50% and, if the variant is not present in the parents, about 1% [28]. In Lenz-Majewski dysplasia, all cases tested were de novo, with no familial recurrence described, with a risk to siblings of about 1% due to gonadal mosaicism; reproduction of patients has not been described [44]. Osteopoikilosis and Buschke-Ollendorff syndrome are autosomal dominant with a family history in 92% of the cases reviewed, and relatives may have only skin or only bone lesions [8, 34]. In Worth-type hyperostosis and SOST-related craniodiaphyseal dysplasia, transmission is dominant [11, 16]. In the dominant forms, clinical and radiological examination of relatives may be informative [16].

8.3. Osteopathia striata with cranial sclerosis

The disease is X-linked [26]. The father of an affected boy is not a carrier. The mother of an affected boy is an obligate heterozygote when there is more than one affected member in the family; in an isolated case, about 25% of boys have a de novo variant, and a mosaic boy is presumed to result from a post-zygotic change [26]. About 45% of affected girls have a de novo variant, and paternal transmission has been described only from mosaic fathers [26]. A carrier mother transmits the variant in 50% of pregnancies: heterozygous daughters have variable manifestations, and hemizygous sons range from fetal or neonatal lethality to a mild phenotype; about half of published boys died in mid- or late gestation or in the neonatal period, a number probably underestimated because the multiple malformation picture is non-specific [26]. An affected man transmits the variant to all his daughters and to none of his sons [26]. Clarifying the status of asymptomatic relatives allows earlier diagnosis of hearing loss, visual loss and heart defects, cancer surveillance and assessment of malformations in boys [26]. The description of a child with Wilms tumour and a germline AMER1 variant without a skeletal phenotype, and of a familial case, shows that carriers may have minimal expression, which justifies offering cascade testing to women in the maternal family [123].

8.4. Melorheostosis

Isolated melorheostosis results from somatic mosaicism and has no established hereditary transmission; no families with isolated melorheostosis have been documented [38, 73]. The exception is melorheostosis in families with LEMD3-related osteopoikilosis, in which the risk refers to the dominant osteopoikilosis [73].

8.5. Prenatal diagnosis, preimplantation testing and counselling

The ideal time to determine genetic risk and discuss prenatal and preimplantation diagnosis is before pregnancy, and counselling should be offered to affected, carrier or at-risk young adults [5, 18, 26]. With the familial variants identified, prenatal diagnosis and preimplantation genetic testing are possible; opinions on their use vary between professionals and families [5, 23, 28]. Carrier testing and cascade testing require prior identification of the familial variants [5, 18]. Testing of asymptomatic minors is justified when it changes surveillance, as in osteopathia striata with cranial sclerosis (Wilms tumour surveillance) or Camurati-Engelmann disease (early diagnosis of pain), and the Camurati-Engelmann disease GeneReviews recommends assessing at-risk relatives by molecular testing or, if the variant is unknown, by radiographs [23, 26]. In craniometaphyseal dysplasia, at-risk relatives should be assessed clinically and with radiographs of the skull and long bones when the variant is not known [28].

9. Special Considerations: Population Diversity and Epidemiology

9.1. What the available numbers measure

For almost all entities, the available data are counts of published cases and Orphanet prevalence classes, which act as upper limits and not as estimates [1, 170]. The table distinguishes the type of data.

9.2. Founder populations

Sclerosteosis is concentrated in the Afrikaner community, of Dutch ancestry, in South Africa, through a founder effect of the c.70C>T p.(Gln24Ter) variant; of the 94 patients with molecular testing, 66 were homozygous for this variant [5, 56]. The series by Hamersma and colleagues followed 63 South African patients for 38 years [8, 111]. Outside this population, founder variants have been described in Brazil, p.(Trp124Ter), and in Turkey, p.(Cys167Arg), as well as isolated patients of other origins, including a patient of Senegalese origin and Chinese families [5, 56, 79]. Van Buchem disease is almost exclusively Dutch, with two German patients [5]. The common deletion is explained by its origin in a large consanguineous Dutch family [60, 61].

Pyknodysostosis is more frequent where consanguinity is common [8]. In Brazil, Araujo and colleagues found in the state of Ceará a local prevalence of 3 per million, about three times the global estimate, with high parental consanguinity, the c.83dup variant with a single origin in the state and dispersal of Northeastern variants to other regions through internal migration [20]. The Brazilian textbook of genetic syndromes cites this cohort and records, in its epidemiological table, an «incidence of 1:2,000 live births» that is incompatible with the other sources and should not be used; the worldwide prevalence it gives (1.7 per million) coincides with that of GeneReviews [18, 115]. In Europe, the French series of the OSCAR network gathered 27 patients from 17 families [114]. Founder effects have been described in other populations, for example in Egypt, according to the bibliography cited by the Brazilian textbook [115].

9.3. United States, Europe, Portugal and Brazil

The North American data available in the sources are descriptive and do not include prevalence estimates: the bibliography of Spranger's atlas includes the study of an American family with sclerosteosis (1983), and the authors of the Camurati-Engelmann disease GeneReviews gather published series without population data [23, 48]. In Europe, in addition to the Netherlands (van Buchem) and France (pyknodysostosis), there are data from the United Kingdom on high bone mass in densitometry databases and a Spanish series of Camurati-Engelmann disease [83, 116]. In Portugal, the sources record contributions from Portuguese authors: the description of a three-generation family with progressive diaphyseal dysplasia and variable expressivity, and co-authorship of the work that identified PTDSS1 in Lenz-Majewski dysplasia, according to the bibliography of Spranger's atlas and the article metadata [51, 69]. The sources consulted contain no prevalence estimates for Portugal; in Brazil, in addition to Ceará, there is the sclerosteosis founder variant mentioned in GeneReviews [5, 20].

9.4. Special populations and resources

Women with osteopathia striata with cranial sclerosis and boys with the severe phenotype have different needs, and male lethality is probably underestimated [26]. In pyknodysostosis, stature is shorter in women [114]. ERN BOND coordinates the European reference centres for rare bone diseases [45]. In Portugal, ANDO Portugal (Associação Nacional de Displasias Ósseas) supports patients and families [175]. GeneReviews lists, for the United States, the International Skeletal Dysplasia Registry of the University of California, Los Angeles (UCLA ISDR), the Children's Craniofacial Association, deafness associations (American Society for Deaf Children, National Association of the Deaf, Alexander Graham Bell Association) and, for short stature, the Human Growth Foundation and the MAGIC Foundation [18, 26, 28]. The International Skeletal Dysplasia Society maintains the reference nosology [16, 46].

10. Illustrative Clinical Case

Guo and colleagues published in 2025 the case of a Chinese family from Zhejiang province with sclerosteosis 1 [79]. The male proband presented with abnormal facial expression and facial numbness. On examination he had bilateral loss of forehead wrinkles, increased intercanthal distance, bilateral incomplete eyelid closure, flattened nasolabial folds, a low nasal bridge, the corner of the mouth deviated to the left and tenderness on pressure over the maxillary sinuses; stature was normal and there was no syndactyly, but the proband and his sister had deviation of the terminal phalanges, more marked in the sister [79]. Biochemistry showed alkaline phosphatase of 504 U/L (reference < 300 U/L), phosphate of 2.01 mmol/L (reference 0.95–1.95), osteocalcin above 300 µg/L, β-CTX of 4892 ng/L and P1NP above 1200 µg/L [79]. MRI of the facial nerve showed narrow internal auditory canals and thin facial and auditory nerves; brain MRI showed calvarial thickening with loss of the diploic signal, bilateral mastoiditis, adenoid hypertrophy and sinusitis; CT of the temporal bones showed diffuse osteosclerosis of the ossicular chains and internal auditory canals, with bilateral stenosis [79]. Electromyography showed prolonged motor latencies and reduced amplitudes in both facial nerves, and the blink reflex did not evoke the R1 and R2 responses [79]. Whole-body bone scintigraphy showed no evident abnormalities [79].

Trio exome sequencing identified the homozygous variant NM_025237.3(SOST):c.327C>A p.(Cys109Ter), also present in the sister, classified as likely pathogenic according to ACMG criteria; in HEK293T cells, the variant reduced messenger RNA expression and produced a truncated protein of 14 kDa instead of 25 kDa [79]. The authors stress that the phenotype was relatively mild and could confound the initial diagnosis, and that genetic testing confirmed it [79]. Figure 1 of the article (facial photographs, brain MRI, temporal bone CT, hands of the proband and sister and electromyographic recordings) is available at https://pmc.ncbi.nlm.nih.gov/articles/PMC12222177/figure/mgg370109-fig-0001/ [79].

The case illustrates three points of this article. Bilateral facial palsy with hearing loss due to stenosis of the internal auditory canals is the most characteristic presentation of the SOST dysplasias, and elevated alkaline phosphatase and P1NP accompany the increased bone formation [5]. The absence of tall stature and syndactyly does not exclude sclerosteosis when there is a biallelic coding sequence variant, although the combination suggests van Buchem disease first; in this case, the exome identified a coding sequence variant, whereas the van Buchem disease deletion would only be detected by a targeted test [5, 79]. The report describes neither treatment nor follow-up, so it gives no information on management; surveillance of these patients follows GeneReviews (section 11) [5].

11. Prognosis and Long-Term Follow-up

11.1. Prognosis by entity

In sclerosteosis, life expectancy is reduced by sudden death from brainstem herniation and by perioperative complications; the mean age at death was 33 years in the South African series, and intracranial hypertension was the cause of death in 12 of 33 deceased Afrikaner patients, with six additional perioperative deaths [5, 111]. Complications stabilise in the third decade in most patients [5]. In van Buchem disease, life expectancy appears normal, but facial paresis, hearing loss and, in some patients, intracranial hypertension continue to progress in adulthood with stable BMD [5, 106]. In craniodiaphyseal dysplasia, death usually occurs in the second decade [13]. In pyknodysostosis, life expectancy is usually normal, and prognosis is determined by fractures, upper airway obstruction and recurrent respiratory infections [18, 115]. In adults, fractures become rare but occur at atypical sites, and the ECTS/ERN BOND review notes the lack of data on the natural history of fractures in adulthood [19]. In Camurati-Engelmann disease, life expectancy and adult height are normal; the course ranges from spontaneous improvement in adolescence to active disease in adulthood with progressive optic atrophy and hearing loss, and physical quality of life is reduced [51, 116]. In craniometaphyseal dysplasia, life expectancy is normal in uncomplicated forms [28]. In osteopathia striata with cranial sclerosis, women have a normal life expectancy, and about half of published boys died before or shortly after birth [26, 53]. Osteopoikilosis has no clinical significance; melorheostosis causes considerable disability with normal life expectancy [34, 73]. In Lenz-Majewski dysplasia, death may occur in infancy or childhood, and survivors have been followed up to 30 years [130].

11.2. Surveillance table

The following intervals are those proposed in the GeneReviews; in the absence of guidelines, they are at the discretion of the attending physician [5].

Wilms tumour surveillance in osteopathia striata with cranial sclerosis follows, as a precaution, the Beckwith-Wiedemann syndrome protocol, until specific data exist [26, 97]. Published Wilms tumours occurred up to 12 years, beyond the 7-year limit of that protocol, and a neuroblastoma has been described, so attention to abdominal signs continues beyond that age [123, 124]. In van Buchem disease, progression in adulthood justifies maintaining lifelong neurological and auditory surveillance [106]. Relatives at risk of Camurati-Engelmann disease, craniometaphyseal dysplasia and osteopathia striata should be assessed for early diagnosis [23, 26, 28].

12. Summary and Final Considerations

The non-osteopetrotic sclerosing bone dysplasias form a heterogeneous class, united by three main mechanisms: activation of the Wnt pathway in the osteoblast (sclerostin deficiency due to SOST or LRP4, LRP5 gain of function, loss of AMER1 or SFRP4), activation of TGFβ signalling (TGFB1, TGFB2, SMAD3, LEMD3 haploinsufficiency) and resorption defects that do not affect acidification, such as cathepsin K deficiency in pyknodysostosis. Sclerosteosis and van Buchem disease are the paradigm of the craniotubular hyperostoses, with trauma-resistant bone overgrowth and complications resulting from compression of the cranial nerves and brain; sclerosteosis, more severe, has tall stature, syndactyly and early mortality from intracranial hypertension, whereas van Buchem disease, caused by a regulatory deletion that escapes sequencing, has normal life expectancy but neurological progression in adulthood. Pyknodysostosis must be separated from the osteopetroses because it does not benefit from haematopoietic transplantation; its morbidity is concentrated in fractures, the airway and growth, and bisphosphonates are contraindicated. Camurati-Engelmann disease is the only entity with a pharmacological therapy in routine use, glucocorticoids, and with an alternative supported by reports, losartan, both off-label. Craniometaphyseal dysplasia and osteopathia striata with cranial sclerosis require craniofacial, auditory and visual surveillance, and the latter adds the risk of Wilms tumour in girls and male lethality. None of these diseases has clinical guidelines or registered therapeutic trials; the GeneReviews are the main reference, and the recent developments — the longitudinal follow-up of van Buchem disease, TGFB2-related Camurati-Engelmann disease type 2 and the preclinical porcupine and CDK4 targets — have not yet changed practice.

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