An Autosomal Dominant High Bone Mass Phenotype in Association With Craniosynostosis in an Extended Family Is Caused by an LRP5 Missense Mutation


  • The authors have no conflict of interest.


Gain-of-function mutations in LRP5 have been shown to cause high BMD disorders showing variable expression of some clinical symptoms, including torus palatinus and neurological complications. In an extended family, we were able to add craniosynostosis and developmental delay to the clinical spectrum associated with LRP5 mutations.

We report on an extended four-generation family with 13 affected individuals (7 men and 6 women) in which an autosomal dominant type of osteosclerosis segregates. Osteosclerosis was most pronounced in the cranial base and calvarium, starting in early childhood with variable expression and a progressive character. Craniosynostosis at an early age was reported in four affected family members (two males and two females). The patients also presented with dysmorphic features (macrocephaly, brachycephaly, wide and high forehead, hypertelorism, prominent cheekbones, prominent jaw). They have normal height and proportions. Neurological complications like entrapment of cranial nerves resulting in optical nerve atrophy, hearing loss, and facial palsy were reported in two individuals. A mild developmental delay was reported in three affected individuals. None of the patients have torus palatinus, increased rate of fractures, osteomyelitis, hepatosplenomegaly, or pancytopenia. A missense mutation 640G→A (A214T) in the low-density lipoprotein receptor-related protein 5 (LRP5) gene was found in all affected individuals analyzed, including cases in whom craniosynostosis, a mild developmental delay, and/or macrocephaly is observed. To our knowledge, this is the first report in the literature of patients presenting with autosomal dominant osteosclerosis in whom a variable expression of craniosynostosis, macrocephaly, and mild developmental delay is observed, which is most likely associated with a mutation in the LRP5 gene. These phenotypes can therefore be added to the clinical spectrum of LRP5-associated bone disorders.


LOSS- AND GAIN-of-function mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene have been associated with, respectively, low and high bone mass phenotypes. The autosomal recessive osteoporosis pseudoglioma (OPPG) syndrome is caused by loss of function of LRP5. To date, 11 different nonsense, missense, and frameshift mutations have been reported in OPPG patients.(1) These patients have very low bone mass resulting in increased fractures, deformation of the bones, and ocular pathology.(2) The opposite gain of function effect of LRP5 is associated with a number of different conditions with increased BMD. Little et al.(3) were the first to report an LRP5 gene mutation (G171V), resulting in the autosomal dominant high bone mass (HBM) trait without other obvious clinical symptoms. This G171V mutation was afterward also reported in three other apparently unrelated kindreds with autosomal dominant high BMD associated with other clinical features, such as torus palatinus and neurological complications including deafness and sensorimotor neuropathy.(4,5) Seven additional missense mutations in LRP5 (D111Y, G171R, N198S, A214T, A214V, A242T, and T253I) were subsequently found in families and isolated cases from the United States, Sardinia, England, Belgium, France, Argentina, and Denmark diagnosed with a sclerosing bone dysplasia.(5,6) All cases share an increased thickness of the skull and of the cortices of the long bones.

LRP5 is a transmembrane protein acting as a co-receptor together with Frizzled to which Wnt proteins bind, resulting in an activation of the intracellular signaling cascade of the canonical Wnt pathway.(7,8) Phenotypic characterization of transgenic mice overexpressing wildtype LRP5 or LRP5G171V and LRP5-null mice showed a clear role for the protein in normal proliferation and function of osteoblasts.(9,10) The “high BMD” mutations identified thus far are all located in the first propeller domain of LRP5. Functional studies have already been initiated to elucidate the mechanism of action of the different mutations. Results indicate that the mutations might cause a Dkk1-dependent increase in Wnt signaling.(4,11,12)

In this study, we describe an extended family with an autosomal dominant type of osteosclerosis. In a number of patients, craniosynostosis is an additional presenting feature. The association of craniosynostosis with autosomal dominant osteosclerosis has never been published before. Craniosynostosis is defined as a premature fusion of one or more of the cranial sutures and occurs as an isolated defect or as part of a syndrome. Syndromic craniosynostosis is less common, even though to date over 150 syndromes with craniosynostosis have been identified, most of which have an autosomal dominant mode of inheritance. Genetic studies have shown the involvement of a number of genes, such as TWIST, FGFR1/2/3, MSX2, and FBN1 in the pathogenesis of craniosynostosis, with a high mutation frequency found in the TWIST and FGFR2/3 genes.(13,14)

We were able to show the presence of a heterozygous LRP5 mutation (640G→A; A214T) in five affected individuals from the family, two of them also developed craniosynostosis. Absence of TWIST and FGFR2/3 mutations in one patient with osteosclerosis and craniosynostosis and clear co-segregation of both phenotypes in the family indicate that the A214T mutation in LRP5 can be associated with increased bone formation associated with craniosynostosis; however, the presence of the latter occurs with reduced penetrance.


Radiological, clinical, and biochemical findings

The pedigree of the family reported here is shown in Fig. 1. Generations I-III were described earlier by Brouwer,(15) who included a detailed description of 10 affected individuals (4 adults and 6 children). Radiological and clinical data of these patients are summarized in Table 1. Three patients (III-3, III-9, and III-11) were restudied after >30 years in this study, and we were able to evaluate two additional affected family members (IV-2 and IV-3; Fig. 1; Table 1). Unfortunately the original radiographs of the patients are not available for reinvestigation.

Table Table 1.. Clinical Data of Affected Members of the Reported Family With Autosomal Dominant Osteosclerosis Associated With a LRP5 mutation
original image
Figure FIG. 1..

Pedigree of the family. Symbols provided with a plus sign represent individuals from whom blood samples were collected and genomic DNA was isolated. Different symbol fillings were applied to show family members with osteosclerosis, craniosynostosis, and/or developmental delay.

All studied affected individuals were diagnosed with an increased thickness of the skull, and all adult patients displayed an increased cortical thickness of all bones analyzed. None of them showed a sandwich vertebra or bone-within-bone appearance. Neither did they show an increased fracture rate, increased height, hepatosplenomegaly, osteomyelitis, or pancytopenia. Biochemically normal levels of serum calcium, phosphor, and alkaline phosphatase were found.

The index case of the study of Brouwer(15) was individual III-3. He presented in 1959 at the age of 2 years and 4 months with progressively declining of his vision in both eyes. There was craniosynostosis of all the cranial suturae, high intracranial pressure, and secondary optic nerve atrophy. There was apparent osteosclerosis of the cranial base and os occipitalis, there was no pneumatization of mastoid and sphenoid, and he had diffuse sclerosis of the skeleton. Craniotomy was done immediately in 1960, but unfortunately his visual defects were irreversible. He went to a school for the blind. Radiographs at the age of 6(15) and 40 years showed progressive thickening of the skull (Figs. 2A and 2B). At 47 years, he has poor vision but no further complaints.

Figure FIG. 2..

(A and B) Radiographs of the skull of individual III-3 at the age of 40 years. Note severe sclerosis of the skull. No pneumatization of mastoid and sphenoid. Craniectomy was done in 1959 and 1960.


Shortly after birth, she showed diffuse sclerosis of the skeleton without craniosynostosis.(15) At the age of 31 years, she complained of headaches without vomiting or dizziness. There were no visual or hearing problems. She showed macrocephaly, a broad and prominent forehead, hypertelorism, and a prominent mandible and cheekbones, but no torus palatinus. There were slightly ulnar deviations of the third finger and radial deviations of the fourth finger. Radiographs showed diffuse sclerosis of the skull and long tubular bones (data not shown).

IV-2, the son of III-9

He was born by caesarean section because of bradycardia after 33 weeks of gestation. His birth weight was 2000 g. At birth, he showed trigonocephaly and a prominent sutura metopica. On the second day, an open ductus Botalli and ventricle septal defect (VSD) were diagnosed. At the age of 3 months, his head circumference was 35 cm (below the second percentile).

At the age of 5 months, he underwent closure of the ductus and VSD. Radiograph of the skull showed craniosynostosis of sutura metopica and a progressive sclerosis of the cranial base and vault (Figs. 3A-3C). Craniotomy was done at the age of 11 months. The radiographs of the vertebrae, ribs, and tubular bones were normal at the age of 3 months. Cytogenetic study showed a normal male karyotype.

Figure FIG. 3..

Cranial radiographs of individual IV-2 (A, at the age of 1 year and 10 months; B and C, at the age of 3 years and 5 months). Note progressive sclerosis of cranial base and vault. Craniotomy was done at the age of 11 months.


IV-3 was born by caesarean section after 33 weeks of pregnancy, which was complicated by maternal hemolysis elevated liver enzymes low platelet (HELLP) syndrome.

His birth weight was 1840 g (20th percentile), length was 42.5 cm (10th percentile), and head circumference was 33 cm (>95th percentile). Apgar scores were 6 and 9 after 1 and 5 minutes, respectively. He had macrocephaly, a broad and prominent forehead, hypertelorism, and epicanthus (Fig. 4). Ophthalmological investigation was normal. At the age of 6 weeks, his head circumference was 37 cm, and at the age of 3 years and 4 months, it was 56.5 cm (3.5 cm >98th percentile). He walked within 2 years, and spoke several words at the age of 2.5 years.

Figure FIG. 4..

Picture of individuals IV-3 and his mother III-11 (at the age of 3 and 40 years, respectively). Note both showed macrocephaly, broad and prominent forehead, hypertelorism, prominent cheekbones, and prominent jaw. The mother also had mild facial nerve palsy on the left side.

Radiographs of the skull at the age of 6 months showed a big neurocranium, the sutura coronaria and sutura sagittalis were nearly closed, and there was diffuse osteosclerosis. The vertebrae were normal.

III-11, the mother of IV-3

She presented in 1995 at the age of 30 years with periods of headaches, ringing in the ears (tinnitus), and periods of dizziness since childhood. She had a hearing loss of 15 dB and hypertension. Examination at the age of 37 years revealed macrocephaly (head circumference was 61 cm, >98th percentile), a broad and prominent forehead, an asymmetrical face because of facial palsy on the left side, prominent cheekbones, and a prominent jaw (Fig. 4), but no torus palatinus. Radiographs showed an increased density of the calvarium, mandible, pelvis, spine, and endosteal surface of the long bones (Figs. 5A-5D). The cranial sutures were closed.

Figure FIG. 5..

(A-C) Radiographs of the arm, leg, and pelvis of individual III-11 at the age of 31 years. There is cortical sclerosis of the long tubular bones and short tubular bones. Sclerosis is seen of the vertebral and pelvic bones, the sacrum, and proximal femora. (D) Radiographs of the spine of individual III-11 at the age of 31 years. There is a mild degree of increased density of the end plates of the bodies and the posterior elements of the spine because of osteosclerosis.

Craniosynostosis was also found in individuals II-8 (of sutura lambdoidea) and III-1 (at the age of 2 years, synostosis of suturae coronaria and sagittalis), and a mild developmental delay was also reported in patient III-1. The osteosclerosis showed variable expression in the family, with individuals II-6, II-8, III-4, and III-5 being only mildly affected. Complaints were mostly periods of headaches without vomiting, some low back pain, and ringing in the ears and dizziness (Table 1).

Mutation analysis of the TWIST, FGFR2, FGFR3, and LRP5 genes

Genomic DNA from five patients of the family (III-3, III-9, III-11, IV-2, and IV-3) was isolated from peripheral blood leukocytes by standard procedures. Mutation analysis on four genes—TWIST, FGFR2, FGFR3, and LRP5—has been carried out by sequencing. Extensive mutation analysis on genomic DNA of patient IV-2 for the FGFR2, FGFR3, and TWIST genes revealed no disease-causing mutations.

Sequencing analysis of exons 2-4 of the LRP5 gene from the extended family revealed, in all five patients studied (III-3, III-9, III-11, IV-2, and IV-3), the presence of a heterozygous missense mutation in exon 3 with the substitution of the G at position 640 by an A (640G→A; Fig. 6). This mutation results in an amino acid substitution at position 214 of the LRP5 protein (A214T). The mutation is located in the fifth YWTD repeat of the first YWTD/epidermal growth factor (EGF) domain of LRP5. The presence of this mutation has previously been reported in one family from Portland (United States), in which an autosomal dominant endosteal hyperostosis segregates.(6)

Figure FIG. 6..

Sequencing analysis of exons 2-4 of the LRP5 gene in five affected individuals (II-3, III-9, III-11, IV-2, and IV-3) from the family revealed the presence of a heterozygous missense mutation in exon 3 with the substitution of the G at position 640 by an A (640G→A).


The family described in this study presented with progressive osteosclerosis and was originally diagnosed with autosomal dominant type II osteopetrosis (Albers-Schönberg).(15) However, detailed radiological and clinical evaluation of the patients showed the absence of the typical features for this type of osteopetrosis, such as the sandwich vertebra appearance in the spine, the classical bone-within-bone in the pelvis, fractures, osteomyelitis, and osteoarthritis.(16) The predominant characteristic of the patients described in this study is a progressive osteosclerosis already manifesting in early childhood, which is most pronounced in the cranial base and calvarium. They have dysmorphic features with macrocephaly, brachycephaly, a wide and high forehead, hypertelorism, and prominent cheekbones and mandible, but no torus palatinus. Interestingly, craniosynostosis and a mild developmental delay were additionally diagnosed in four and three patients, respectively (Fig. 1; Table 1).

To find the disease-causing gene in the extended family described here, we performed a mutation analysis on four candidate genes. Three genes, FGFR2, FGFG3, and TWIST, were chosen for their involvement in inherited forms of craniosynostosis.(13) Extensive mutation analysis did not result in the identification of a disease-causing mutation in any of these genes. The fourth gene we investigated was LRP5. This gene was recently identified as one of the regulators of peak bone mass in vertebrates, and gain-of-function mutations in LRP5 have been shown to cause “high BMD syndromes.”(3,4,5,6,17) LRP5 acts as a co- receptor for Wnt proteins and is expressed in osteoblasts, where it is required for osteoblast proliferation.(9) The LRP5 signaling pathway plays an important role in the regulation of bone mass in vertebrates. In this study, we were able to identify a 640G→A missense mutation resulting in the A214T amino acid substitution in LRP5. This mutation, located in the first propeller domain of the LRP5 protein is considered to be a gain-of-function mutation(12) and was previously reported by Van Wesenbeeck et al.(6) in a family from Portland (United States). Patients from this family present with cortical thickening of the long bones with no alteration in external shape, no fractures, elongated mandible, torus palatinus, and increased BMD of the calvarium, mandible, and endosteal surface of the long bones.(18) Craniosynostosis and developmental delay were not reported in this family. The family in our study had the same form of osteosclerosis as the family reported by Beals but without torus palatinus and with craniosynostosis and mild developmental delay.

An association of an autosomal dominant type of osteosclerosis with craniosynostosis and/or developmental delay has not previously been reported in the literature. The incidence of craniosynostosis in the general population is relatively low (1:3000), making a coincidental association between osteosclerosis and craniosynostosis in these four members of the family unlikely. In the literature, two cases have been reported of autosomal recessive malignant osteopetrosis with the development of secondary craniosynostosis caused by bony overgrowth of the sutures, which inhibited their separation, and outward displacement of the cranial bones.(19,20) In the family presented in this study, we propose a similar mechanism of increased appositional growth at the sutures caused by increased bone formation associated with the 640G→A mutation in LRP5.

The prevalence of developmental delay is higher, with estimates of 1-3% in children,(21) therefore increasing the chance of coincidental co-occurrence of osteosclerosis and developmental delay. However, developmental delay in two patients (III-1 and III-3) might be related to craniosynostosis, because an increased risk for developmental delay in patients with craniosynostosis has already been shown in several studies.(22-24)

In conclusion, both in this family and previous cases(6) with a gain-of-function mutation in the LRP5 gene, the radiologically observed osteosclerosis is the only consistent characteristic. In some cases, this bone phenotype is the only symptom present,(3) but variable expression of additional clinical symptoms has been reported, including torus palatinus,(4,5,6,17) jaw enlargement,(4,6) and neurological complications caused by overgrowth of the facial bones and calvarium.(5,17) This study provides evidence that craniosynostosis and mild developmental delay are additional clinical features that can also be observed in patients with an LRP5 mutation.


The authors thank the members of this family for participation in this study. This study was supported by the Fund for Scientific Research Flanders, with a research project grant (G.0404.00), the Interuniversity Attraction Poles program P5/19 of the Belgian Federal Science Policy Office, and the EV FP6 project ANABONOS (LSHM-CT-2003-503020) to WVH.