Gracile Bone Dysplasia
A number sign (#) is used with this entry because of evidence that gracile bone dysplasia (GCLEB) is caused by heterozygous mutation in the FAM111A gene (615292) on chromosome 11q12.
Autosomal dominant Kenny-Caffey syndrome (KCS2; 127000) is also caused by mutation in the FAM11A gene.
DescriptionGracile bone dysplasia is a perinatally lethal condition characterized by gracile bones with thin diaphyses, premature closure of basal cranial sutures, and microphthalmia (summary by Unger et al., 2013).
Clinical FeaturesMaroteaux et al. (1988) reported a condition characterized by thin, brittle bones and perinatal death. Verloes et al. (1994) described a similar entity on the basis of 3 unrelated fetuses and a reevaluation of some patients in the report of Maroteaux et al. (1988). The 3 affected fetuses showed exceedingly thin, dense, fishbone-like diaphyses, flared metaphyses, mild micromelic dwarfism, brachydactyly, facial dysmorphism, ocular malformations (microphthalmia, aniridia), cloverleaf skull deformity, and splenic hypoplasia. Histopathologic investigations showed abnormalities of the metaphyseal cartilage and adjacent diaphyseal ossification, excessive modeling of the metaphyses, and, in 1 case, dysplasia of the epiphyseal cartilage. Verloes et al. (1994) referred to the condition as 'osteocraniostenosis.'
Thomas et al. (1998) reported a lethal skeletal dysplasia in male and female sibs. The parents were nonconsanguineous and of Asian-Indian background. The male infant, stillborn at 35 weeks of gestation, had microphthalmia, ankyloglossia, and abdominal ascites. The thorax was small with severe pulmonary hypoplasia. A subsequent pregnancy was terminated at 24 weeks of gestation because of suspected recurrence on ultrasound images. The female fetus had prominent forehead, flat nasal bridge, upturned nasal tip, and markedly distended abdomen. The limbs showed marked micromelic shortness with redundant skin folds, fifth finger hypoplasia and clinodactyly, and markedly short halluces. Chondroosseous morphology was strikingly abnormal. Autosomal recessive inheritance was considered likely. Thomas et al. (1998) noted that a major mechanical factor in fetal bone modeling is muscle strength; thus, fetal hypokinesia results in bones that are slender and have reduced mass. Accordingly, any condition that results in fetal hypokinesia can result in gracile bones; however, in fetal hypokinesia, the chondroosseous structure is normal.
Costa et al. (1998) described affected brothers; the mother had a dwarfing condition with asymmetry, suggesting that she may have had somatic/germline mosaicism for a dominant lethal gene. The male stillborn sibs died in utero in the third trimester. Both were found by ultrasound to have short limbs and probable long bone fractures late in the second trimester. At autopsy, one fetus had no spleen and the other a hypoplastic spleen. Radiographically, the 2 male sibs and another sporadic case had very thin diaphyses, diaphyseal fracture, and thin ribs and clavicles. The sibs had grossly deficient calvarial mineralization. Microscopically, endochondral ossification was qualitatively normal but quantitatively deficient in all 3 cases.
Brennan and Hall (2002) reported a case of this rare skeletal dysplasia in a 31-week stillborn male fetus with ambiguous external genitalia and asymmetry in whom a 46,XX/46,XY karyotype was demonstrated in both cartilage and skin.
Korniszewski et al. (2003) described 2 sisters with what they considered to be a unique form of lethal skeletal dysplasia with gracile bones. Born to nonconsanguineous Polish parents with 1 healthy daughter, both had severe intrauterine growth retardation (birth weights of 1300 grams and 1000 grams at 42 weeks of gestation, length and head circumference also below 3rd centile) and a history of decreased intrauterine activity with normal amniotic fluid volume on ultrasound. The sisters had coarse facies with prominent foreheads, relatively large noses, and mild hypertelorism. Despite tube and/or parental feeding, both infants did not gain weight. Radiographic studies demonstrated that the L5 vertebral body was rectangular, the L3 and L4 bodies were oval-shaped, and the thoracic bodies were pear-shaped. The ribs, clavicles, and long bones were thin with slightly flared metaphyses. The younger sister had a normal karyotype. The sisters died from pneumonia at 3 and 5 months of age. Autopsies revealed no congenital malformations. Pathologic examination of the ribs showed fairly normal resting cartilage but growth plate disorganization with short, sparse trabecular formation, poor columnization, decreased cellularity, and poor hypertrophy of the chondrocytes. Both sibs had hematopoietic marrow extending to the growth plate, a finding consistent with arrested growth.
Verloes et al. (2005) described 2 brothers of Algerian ancestry with a distinctive disorder overlapping Melnick-Needles osteodysplasia (309350), Yunis-Varon syndrome (216340), and osteocraniostenosis that they suggested could represent a new syndrome. The brothers demonstrated ossification anomalies of membranous and cranial bones, remodeling defect of long bones leading to dense, overtubulated, narrow diaphyses, metaphyseal flare, periosteal hyperostosis that increased during the first months of life, thoracic dystrophy, and severe hypotonia. One boy had hypospadias and cleft palate. Follow-up of the surviving boy at age 3 documented progressive osteopenia, slow healing of the periosteal anomalies, liver angiomatosis, mental and motor delay, thoracic deformity, delay in tooth eruption, and progressive microcephaly with enlargement of the cerebral ventricles. The disorder shared some characteristics with osteocraniostenosis but lacked the cranial deformity and some other features. Verloes et al. (2005) suggested naming this entity 'habrodysplasia,' from the Greek root for 'gracile.'
Elliott et al. (2006) reported 4 infants, 2 unrelated and 2 sibs, with osteocraniostenosis. Common features included a cloverleaf-shaped skull with hypoplastic cranial bones, overtubulated long bones with metaphyseal rounding, dysmorphic facies, and splenic hypoplasia. Histologic examination of bone in all cases showed an abnormal growth plate with short irregular columns. The resting cartilage showed pleomorphic chondrocytes with increased cellularity and unique pseudocolumn formation. Radiographic studies also showed that the abnormal skulls were due to hypoplastic cranial bones rather than true craniosynostosis. Elliott et al. (2006) noted some radiographic and histologic similarities to Hallermann-Streiff syndrome (HSS; 234100). The authors concluded that the term 'osteocraniostenosis' is an inaccurate term to describe this syndrome and suggested 'osteocraniosplenic syndrome' (see NOMENCLATURE below). Spear (2006) reported further clinical details of an affected Korean boy reported by Elliott et al. (2006) who died of cardiac arrest at 9 hours of age. Postmortem examination showed absence of the parietal bones of the skull, hypomineralization of the calvaria, polymicrogyria, Kleeblattschaedel (cloverleaf skull anomaly), thin clavicles and ribs, overtubulated, gracile, bowed long bones, micromelia, fractures, dysmorphic facies, malformations of the eyes, and splenic hypoplasia. Spear (2006) speculated that homeobox genes (see, e.g., MSX2; 123101) may be involved in the pathogenesis of the disorder.
Smith et al. (2007) reported antenatal findings of gracile bone dysplasia in a female born to healthy, unrelated parents. The infant was noted at birth to have hypoplastic genitalia with some fusion of the labia, which had not previously been described in this disorder.
Nyholm et al. (2008) described a liveborn infant with slender bone dysplasia (gracile) with early fatal outcome and suggested that the prenatal diagnosis of the disorder should be suspected when shortened limbs, acrocephalic skull, bowed radii or ulna, and fractures are seen on ultrasound.
Molecular GeneticsIn 5 patients with gracile bone dysplasia and 5 patients with autosomal dominant Kenny-Caffey syndrome (KCS2; 127000), Unger et al. (2013) identified heterozygosity for 6 mutations in the FAM111A gene (615292.0001-615292.0006, respectively). In the 7 families in which DNA was available from both parents, the mutations were confirmed to have arisen de novo. None of the mutations was found in the 1000 Genomes Project or NHLBI Exome Variant Server databases. The authors concluded that KCS2 and gracile bone dysplasia represent allelic disorders of differing severity.
NomenclatureSpear (2006) noted that the term 'craniostenosis,' or premature fusion of cranial sutures, has been replaced by 'craniosynostosis.' In a detailed review of the literature concerning clinical reports of gracile bone dysplasia, Spear (2006) found that craniostenosis was clearly recorded in only 2 patients (Verloes et al., 1994; Kozlowski et al., 2002), 1 of whom had fusion limited to a 1- to 2-cm segment. Indeed, most patients reportedly had widened sutures. Spear (2006) concurred with Elliott et al. (2006), who suggested the term 'osteocraniosplenic syndrome.'