Short Stature, Facial Dysmorphism, And Skeletal Anomalies With Or Without Cardiac Anomalies

A number sign (#) is used with this entry because of evidence that short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies (SSFSC) is caused by heterozygous mutation in the BMP2 gene (112261) on chromosome 20p12.

Description

Patients with SSFSC have short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies. Distinctive facial features include midface retrusion, short upturned nose, long philtrum, high-arched or cleft palate, and variable degrees of micrognathia and dental crowding. Skeletal anomalies include patterning defects of the axial skeleton, characterized by 11 pairs of ribs and brachydactyly of the fifth ray. Congenital heart defects are variably observed and appear to involve primarily the cardiac outflow tract (Tan et al., 2017).

Clinical Features

Tan et al. (2017) studied 12 affected individuals from 8 families with short stature and facial dysmorphism as well as skeletal and cardiac anomalies. Affected individuals shared similar distinctive craniofacial features such as broad forehead with temporal narrowing, flat midface, short nose with anteverted nares, long philtrum, thin upper lip, crowded dentition, and high-arched or cleft palate. Skeletal anomalies included proportionate short stature, short fifth-digit proximal phalanges or clinodactyly, 11 pairs of ribs, and sandal gap. Cardiac malformations were reported in 4 patients and included transposition of the great arteries, pulmonary valve stenosis, Ebstein anomaly, and ventricular septal defect. In addition, 3 patients had cardiac arrhythmias, including Wolff-Parkinson-White syndrome, paroxysmal supraventricular tachycardia, and nonspecific palpitations. Less common features were synophrys, low-set posteriorly rotated ears, conductive hearing impairment, sternal deformity, delayed bone age in early childhood, and L5/S1 spondylolisthesis. Pierre Robin sequence and a cleft palate were observed in 3 patients, and 2 of them required mandibular distraction osteogenesis. Obstructive sleep apnea was diagnosed in 4 patients, in childhood or adulthood. All 12 patients had normal cognitive development, although hypotonia in infancy was observed in 3. Bone densitometry was normal for height in the 5 affected children who were tested; however, 1 adult patient had generalized osteopenia at age 54 years without a history of fracture, and the other 2 affected adults had not undergone bone densitometry studies.

Molecular Genetics

In 8 patients from 6 unrelated families with short stature and facial dysmorphism as well as skeletal and cardiac anomalies, Tan et al. (2017) identified heterozygosity for 6 different variants in the BMP2 gene (see, e.g., 112261.0003-112261.0006) that were all predicted to be truncating and to result in haploinsufficiency. In the 3 sporadic patients for whom parental DNA was available, the mutations were shown to have arisen de novo; in 1 family, 2 sisters inherited their mutation from an unaffected father who was mosaic for the variant. In addition, overlapping 2.5- to 2.6-Mb microdeletions, involving BMP2 as well as surrounding genes, were detected in 4 similarly affected patients from 2 families. None of the BMP2 mutations were found in public variant databases. Functional studies were not performed.