Frias Syndrome

A number sign (#) is used with this entry because of evidence that it represents a contiguous gene deletion syndrome on chromosome 14q22.1-q22.3 (chr14:52.1-56.2 Mb). The deleted region contains at least 20 genes, including the BMP4 gene (112262).

Description

Frias syndrome is characterized by mild exophthalmia, palpebral ptosis, hypertelorism, short square hands with minimal proximal syndactyly between the second and third fingers, small broad great toes, and short stature. Some patients may exhibit bilateral pedunculated postminimi (summary by Martinez-Fernandez et al., 2014).

Clinical Features

Frias et al. (1975) reported a 6-year-old boy with a peculiar facies, characterized by downslanting palpebral fissures, epicanthic folds, hypertelorism, and ptosis. He was noted to have slightly slower psychomotor development than his unaffected sister and was reported to have 'low average intelligence.' His ears were cup-shaped and posteriorly rotated. Both hands were square in shape, with short stubby fingers, clinodactyly of the fifth fingers, and ulnar deviation of the index fingers. His toes were also short, and moderate hallux valgus was present. Radiographic studies revealed shortened middle phalanges of digits 2 to 5 of the hands and feet, and bone age was retarded. The patient's mother was similarly affected, with downslanting palpebral fissures, hypertelorism, ptosis, and poorly differentiated ears. Her hands were small and square, with evident brachydactyly and radial deviation of the fourth finger; her toes were small, and a moderate hallux valgus was present. X-ray showed shortened middle phalanges of digits 2 to 5 of her hands, and the middle phalanx of the second toe was short and wide. She was of average intelligence. Frias et al. (1975) suggested that this condition constituted a previously unrecognized autosomal dominant dysmorphic syndrome.

Martinez-Frias et al. (2005) reported a 3-year-old girl with bilateral ptosis requiring surgical repair, mild exophthalmia, downslanting palpebral fissures, micrognathia, cup-shaped posteriorly rotated ears, bilateral pedunculated postminimi, and small, broad big toes. She had slow psychomotor development and delayed bone age. The patient's mother and maternal uncle had a similar facial appearance with bilateral ptosis requiring surgical repair, hypertelorism, mild exophthalmos, and downslanting palpebral fissures. The mother had short stature and short, square hands with small proximal syndactyly between fingers 2 and 3, and the uncle had very short hands with bowed fifth metacarpals. The proband's maternal grandmother had a similar facial appearance and hand anomalies, with ulnar deviation of the index fingers. Martinez-Frias et al. (2005) concluded that this family had the same condition as that described by Frias et al. (1975), with apparent complete penetrance and variable expressivity. Martinez-Frias et al. (2005) noted that X-linked inheritance could not be excluded.

Martinez-Fernandez et al. (2014) provided follow-up on the family originally reported by Martinez-Frias et al. (2005), including a report of a newborn affected member of the family. The infant had mild exophthalmia, bilateral ptosis, downslanting palpebral fissures, and apparent hypertelorism. In addition, she had right diaphragmatic hernia, through which the liver had entered the thoracic cavity. She died of refractory hypoxemia 2 days after surgical repair of the diaphragmatic hernia; postmortem examination did not show any malformation of the brain or other organs. At 10 years of age, her older half sister, who was the proband reported by Martinez-Frias et al. (2005), had moderate psychomotor delay and mild right-sided hearing loss. Brain MRI showed segmental hypoplasia of the corpus callosum and mild increase in ventricular size. She also exhibited altered eruption of dentition, with absence of the upper and lower lateral incisors and a large upper right central incisor overlapping the left one. Martinez-Fernandez et al. (2014) noted that this anomaly appeared to be present in other affected family members, as suggested by clinical photographs.

Molecular Genetics

In 3 affected members of a family with Frias syndrome, originally reported by Martinez-Frias et al. (2005), Martinez-Fernandez et al. (2014) performed high resolution G-banded chromosome analysis, which was normal, and array-CGH, which revealed an identical 4.06-Mb interstitial deletion on chromosome 14q22.1-q22.3 (chr14:52,183,541-56,239,131, Genome Browser, 2009) in all 3 patients. The deleted area included at least 20 genes, including BMP4 (112262). Martinez-Fernandez et al. (2014) noted that the clinical manifestations in this family correlated with defects observed in patients with 14q22-q23 deletions or mutations of BMP4, although this family showed a milder phenotype; they concluded that haploinsufficiency of BMP4 was likely to be responsible for the clinical expression of Frias syndrome.