Dental Anomalies And Short Stature

A number sign (#) is used with this entry because of evidence that dental anomalies and short stature (DASS) is caused by homozygous or compound heterozygous mutation in the LTBP3 gene (602090) on chromosome 11q13.

Description

Dental anomalies and short stature (DASS) is characterized by significant short stature with brachyolmia as well as hypoplastic amelogenesis imperfecta with almost absent enamel (Huckert et al., 2015). Some patients exhibit valvular and/or vascular defects, including mitral valve prolapse, aortic root dilation, and aortic as well as other arterial aneurysms (Dugan et al., 2015; Guo et al., 2018). Inter- and intrafamilial variability has been reported.

Clinical Features

Verloes et al. (1996) described an apparently 'new' form of skeletal dysplasia with amelogenesis imperfecta and platyspondyly in a brother and sister born of consanguineous parents. Hallmarks were amelogenesis imperfecta (absence of the enamel cap) associated with short trunk and brachyolmia-like anomalies (platyspondyly with short pedicles, narrow intervertebral and interpedicular distances, rectangular-shaped vertebrae with posterior scalloping, herniation of the nuclei, and broad femoral necks). Inheritance appeared to be autosomal recessive. The girl was 141 cm tall at age 16, with an arm span of 142 cm, a sitting height of 72 cm, and short hands. She was completely edentulous, all teeth having to be removed within a year of eruption. At the age of 12 years, the brother was 133 cm tall with sitting height of 63 cm and arm span of 134 cm. The permanent teeth were yellowish and almost completely lacking in enamel cap.

Bertola et al. (2009) described 3 affected patients (2 sibs and 1 unrelated patient), from consanguineous matings, presenting with brachyolmia with enamel defects. In the first family, the older brother had oligodontia and enamel hypoplasia; the younger brother had widely spaced permanent teeth, enamel hypoplasia, agenesis of both inferior second premolars and retention of their deciduous. In the second family, the patient had retarded eruption of permanent teeth, amelogenesis imperfecta, and taurodontic pulp chambers.

Noor et al. (2009) reported a consanguineous Pakistani family in which 5 sibs had selective tooth agenesis characterized by absence of many of the permanent teeth. Two affected males were examined in detail. Radiographs showed apparent congenital oligodontia, with absence of 23 permanent teeth in the more severely affected brother, and absence of 18 permanent teeth in the other affected brother. Fully formed impacted upper third molars were identified bilaterally, and fully formed unerupted unilateral lower second and third molars were seen; no completely or incompletely formed impacted nonmolar teeth were noted. Alveolar bone was absent where the teeth were missing, an area encompassing most of the mandible. Radiographic studies and dual-energy x-ray absorptiometry (DEXA) suggested that affected individuals had a higher bone mineral density in the spine, as well as an increase in bone density at the base of the skull, compared to unaffected individuals. There was apparent prognathism on lateral skull film (Figure 1). Affected individuals also had short stature with varying degrees of scoliosis, although the relationship of this finding to the genotype was unclear.

Dugan et al. (2015) reported 2 sisters of Emirati origin who had 'small and decayed' deciduous teeth, over which crowns were placed when neither had eruption of permanent teeth. Both girls had short stature, and neither responded to growth hormone (GH1; 139250) administration. Both were diagnosed with mitral valve prolapse (MVP) in childhood, and follow-up echocardiography in the teenage years showed MVP with mild insufficiency in both. Other features included hypertrichosis, especially on the back, and short first metatarsals; the older sister exhibited arachnodactyly and swan-neck deformity of the fingers on extension, whereas the younger sister had the swan-neck deformity without arachnodactyly.

Huckert et al. (2015) studied 2 sisters, born of consanguineous Turkish parents, who presented with amelogenesis imperfecta and short stature. Examination revealed facial dysmorphism, including large forehead, thick eyebrows, and almond-shaped eyes, as well as myopia and learning difficulties. Skeletal x-rays showed platyspondyly with indentations of both upper and lower vertebral endplates (brachyolmia), but there were no signs of a generalized skeletal dysplasia, and bone age was normal. Orodental evaluation revealed nearly complete absence of enamel in both primary and permanent dentitions. Teeth were yellow, small, and widely spaced, and several teeth had been extracted due to recurrent infection. On orthopantomogram, no enamel was seen, pulp chambers were large, and molars were taurodontic. Lateral skull x-rays showed somewhat thickened cortical plates of the frontal bone with absence of pneumatization of the frontal and sphenoid sinuses, as well as class III mandibular prognathism, due to maxillary underdevelopment. Huckert et al. (2015) also studied patients from 3 more families with amelogenesis imperfecta, short stature, and variable platyspondyly, including a patient originally reported by Bertola et al. (2009). Delayed tooth eruption and missing teeth were each noted in 1 family, respectively, and patients in 1 family also exhibited osteopenia and scoliosis. Huckert et al. (2015) noted that the published skull x-ray of 1 of the Pakistani family members with selective tooth agenesis studied by Noor et al. (2009) clearly showed absent enamel and short roots in the remaining teeth, suggesting a diagnosis of amelogenesis imperfecta.

Clinical Variability

Guo et al. (2018) reported 2 unrelated families with DASS and mutations in the LTBP3 gene (see MOLECULAR GENETICS), in which affected individuals also exhibited thoracic and abdominal aortic aneurysms. In the first family (family TAA909), the proband was a 54-year-old man with DASS and aortic root dilation, abdominal aortic aneurysm, and multiple visceral and peripheral arterial aneurysms. His 2 affected sisters had DASS with mild mitral valve prolapse, and 1 also showed mild aortic root dilation. In the second family (family TAA376), a brother and sister had DASS and aneurysm of the ascending aorta with dissection in the fourth decade of life, as well as involvement of the descending aorta. In the sister, aneurysmal disease extended to the abdominal aorta, and she also had cervical artery tortuosity, pulmonary artery dilation, other arterial aneurysms, and mitral valve disease. Their parents were unaffected, but 2 paternal aunts and 1 uncle had thoracic aortic aneurysm or dissection in the eighth and ninth decades of life, and 2 of the 3 were also known to have dental anomalies. Three other paternal relatives of that generation died suddenly of unknown cause in the sixth and seventh decades of life, one of whom had dental abnormalities.

Pathogenesis

In a Turkish girl with amelogenesis imperfecta and short stature, Huckert et al. (2015) performed scanning electron microscopic analysis of the enamel structure of an affected permanent tooth, which showed very thin or absent enamel with normal dentin. The initial aprismatic enamel layer was absent, and a very thin shell of irregular prismatic enamel covered the dentin scaffold. A Hunter-Schreger band pattern of enamel prisms was present in this layer, without deposition of an aprismatic outer layer. In some areas, however, amelogenesis continued, and 'bubbling' of nonprismatic enamel occurred on top of the basal enamel layer, with alternating waves of aprismatic and prismatic enamel; the outermost layer was always aprismatic in areas where enamel formation continued.

Inheritance

Bertola et al. (2009) suggested autosomal recessive inheritance of this disorder because of consanguinity and a negative family history for any bone or dental abnormalities in their families.

Mapping

In a consanguineous Pakistani family segregating autosomal recessive selective tooth agenesis and short stature, in which mutation in the MSX1 (142983) and PAX9 (167416) genes had been excluded, Noor et al. (2009) performed genomewide linkage analysis and microsatellite marker genotyping. The authors identified a 28-Mb autozygous region spanning the centromere of chromosome 11 that was shared among the 4 affected sibs but not among unaffected members of the family.

Molecular Genetics

In a consanguineous Pakistani family with selective tooth agenesis and short stature mapping to chromosome 11, Noor et al. (2009) performed candidate gene sequencing and identified a homozygous nonsense mutation in the LTBP3 gene (Y744X; 602090.0001). The mutation, which segregated with disease in the family, was not found in 240 Pakistani controls.

In 2 Emirati sisters with complete agenesis of permanent dentition and short stature, Dugan et al. (2015) sequenced the LTBP3 gene and identified homozygosity for a 1-bp insertion (602090.0002), which was present in heterozygosity in their unaffected father. Their unaffected mother and brothers were unavailable for screening. Dugan et al. (2015) suggested that mitral valve prolapse, present in both sisters, might be an important clinical feature of this disorder, and noted that the Pakistani sibs studied by Noor et al. (2009) did not undergo cardiac evaluation.

In patients from 4 families with amelogenesis imperfecta, short stature, and variable degrees of platyspondyly, including a patient originally reported by Bertola et al. (2009), Huckert et al. (2015) performed whole-exome sequencing (WES) and identified biallelic mutations in the LTBP3 gene in all affected individuals (602090.0003-602090.0007). None of the mutations, which segregated with disease in the respective families, were found in the Exome Variant Server or 1000 Genomes Project databases.

By WES in a cohort of 271 unrelated families with aneurysms of the thoracic aorta, Guo et al. (2018) identified homozygous or compound heterozygous mutations in the LTBP3 gene (see, e.g., 602090.0011-602090.0012) in 2 families with DASS and aortic aneurysm with or without dissection. The mutations segregated fully with disease in 1 family (family TAA909), whereas in the other family (TAA376), some heterozygous relatives exhibited aneurysmal disease at older ages, with dental anomalies reported in some of them. Evaluation of WES data in 338 sporadic patients with thoracic aortic dissections before 56 years of age, who were negative for syndromic features or mutation in known dissection-associated genes, revealed heterozygous LTBP3 rare variants in 9 patients. The authors concluded that biallelic mutations in LTBP3 are associated with risk for thoracic aortic aneurysms and dissections and other arterial aneurysms, in addition to the previously reported skeletal and dental defects, whereas heterozygous LTBP3 mutations might be associated with increased risk for later-onset thoracic aortic disease.