Hypertelorism, Teebi Type

A number sign (#) is used with this entry because of evidence that Teebi hypertelorism syndrome (TBHS) is caused by heterozygous mutation in the SPECC1L gene (614140) on chromosome 22q11.

Clinical Features

Teebi (1987) described a 4-generation Arab family in which many individuals showed striking hypertelorism with some other features suggesting craniofrontonasal syndrome (CFNS; 304110) or Aarskog syndrome (305400). Findings differentiating this disorder from the former condition were a nasal tip that was normal or at the most only slightly broad and no evidence of craniosynostosis or abnormalities of the fingernails. Findings differentiating it from the latter condition were more severe hypertelorism and absence of short stature and joint laxity. It was further distinguished from both CFNS and Aarskog syndrome by the fact that males and females were equally affected and the sex ratio was almost 1:1. In addition to hypertelorism, the disorder described by Teebi (1987) was characterized by prominent forehead, mild antimongoloid slant, long palpebral fissures, heavy and broad eyebrows, widow's peak (194000), broad and depressed nasal bridge, short nose, slightly small, broad hands, mild interdigital webbing, and shawl scrotum. There were several instances of male-to-male transmission.

Morris et al. (1987) described a 4-generation family in which 6 persons had frontonasal dysplasia with variable extracranial abnormalities. All affected persons had hypertelorism, bifid or broad nose, and highly arched palate. Cleft lip and palate were present in 1, Sprengel anomaly in 2, pseudarthrosis of the clavicle in 2, pectus excavatum in 3, diaphragmatic hernia in 2, broad first toe in 4, longitudinal grooves of the nails in 5, shawl scrotum in 2 of 3 males, 1 of whom had first-degree hypospadias, and mild retardation in 1. Morris et al. (1987) concluded that the family had craniofrontonasal syndrome, but McGaughran et al. (2002) suggested that the family may instead have had Teebi syndrome, since the affected males demonstrated additional anomalies not usually observed in CFNS.

Stratton (1991) described a US family with affected persons in 4 generations with instances of male-to-male transmission.

Tsukahara et al. (1995) described Teebi hypertelorism syndrome in a 6-year-old girl who also had ventricular septal defect, lipoma of the occipital area, and hypoplastic left cerebellar hemisphere. The father was thought to have mild manifestations of the condition.

Tsai et al. (2002) reported a family in which the mother and her daughter and son had Teebi hypertelorism syndrome with some previously unrecognized manifestations. The clinical findings included a prominent forehead, arched eyebrows, pronounced hypertelorism, long philtrum, mild interdigital webbing, fifth-finger clinodactyly, umbilical anomalies, and hypotonia. The mother and daughter also had ptosis requiring surgical correction. The mother had an umbilical hernia requiring surgical correction as a child and a history of heart murmur. The daughter had bilateral iridochorioretinal colobomas with high hyperopia and a small umbilical hernia. The son had less striking facial features but was born with a small omphalocele, large atrial septal defect secundum, patent ductus arteriosus (see 607411), bilateral cryptorchidism, right hydronephrosis, and a cystic left kidney.

Koenig (2003) reported a girl with Teebi syndrome, aged 2 years and 5 months, who had a prominent forehead, hypertelorism, mild exophthalmos, long palpebral fissures, depressed nasal bridge, broad nasal tip, long philtrum, and thin upper lip with everted lower lip. She also had a small chin, low-set ears with preauricular fistulas, short neck, and mild pectus excavatum. Clinodactyly of the fifth fingers with mild radial deviation of the distal phalanges of the middle fingers and mild pes adductus were present. Natal teeth and umbilical hernia had been observed. Ultrasound examination detected an ectopic right kidney. Psychomotor development was normal. Her mother and her grandmother had similar features, supporting autosomal dominant inheritance.

Han et al. (2006) reported a 4.5-year-old girl with clinical features of Teebi hypertelorism syndrome who required a pacemaker for third-degree atrioventricular block, a finding not reported in 36 patients previously diagnosed with Teebi hypertelorism syndrome. The authors reviewed data from 18 well-documented cases and noted a characteristic facial appearance with hypertelorism, heavy, broad, and arched eyebrows, a thin upper lip with a long and deep philtrum, and a prominent forehead. Structural cardiac defects were present in 5 patients.

Bhoj et al. (2015) reported 2 unrelated families with clinical features of Teebi hypertelorism syndrome. An affected mother and son in the first family had previously been reported by Hoffman et al. (2007) as having a distinct syndrome resembling Teebi hypertelorism and Aarskog syndromes. Features in the boy included hypertelorism, natal teeth, 2-vessel cord, left preauricular pit, micrognathia, hypersegmented lumbar vertebra, short stature, and a shawl scrotum. He had surgery to repair sagittal and coronal synostosis, bilateral ptosis, and a ventricular septal defect. He was also found to have a dilated aortic root at age 9 years. Although concern was initially raised for developmental delay, his last IQ testing performed at age 10 was in the normal range. His mother had hypertelorism, ptosis, bicornuate uterus, preauricular pit, and short stature. In the second family, the patient was diagnosed with Teebi hypertelorism syndrome at birth after hypertelorism, natal teeth, an atrial septal defect, a ventricular septal defect, and a giant omphalocele were noted. He had short stature. He was diagnosed in childhood with autism and pervasive developmental disorder and had significant behavioral issues with anxiety and panic attacks. His parents were unaffected.

Inheritance

The transmission pattern of Teebi hypertelorism syndrome in several reported families supports autosomal dominant inheritance (e.g., Teebi, 1987; Koenig, 2003; Han et al., 2006).

Molecular Genetics

Using whole-exome sequencing, Bhoj et al. (2015) identified heterozygosity for a deletion (614140.0004) and a missense mutation (E420D; 614140.0005) in the SPECC1L gene in 2 unrelated families with features consistent with Teebi hypertelorism syndrome. Both mutations were confirmed by Sanger sequencing. The family with the missense mutation, in which a mother and son were affected, had previously been reported by Hoffman et al. (2007) as having a distinct syndrome resembling Teebi hypertelorism and Aarskog syndromes. The deletion mutation occurred de novo.