Alternative titles; symbols
SNOMEDCT: 724284005; ORPHA: 1519; DO: 0080698; MONDO: 0800025;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 22q11.23 | Teebi hypertelorism syndrome 1 | 145420 | Autosomal dominant | 3 | SPECC1L | 614140 |
A number sign (#) is used with this entry because of evidence that Teebi hypertelorism syndrome-1 (TBHS1) is caused by heterozygous mutation in the SPECC1L gene (614140) on chromosome 22q11.
Teebi hypertelorism syndrome-1 (TBHS1) is an autosomal dominant disorder characterized by hypertelorism with upslanting palpebral fissures, prominent forehead, broad and depressed nasal bridge with short nose, thick eyebrows, and widow's peak. Additional features include small broad hands with mild interdigital webbing and shawl scrotum. Umbilical malformations, cardiac defects, natal teeth, cleft lip/palate, congenital diaphragmatic hernia, and malformations of the central nervous system (ventriculomegaly, abnormal corpus callosum) have also been reported. Development is typically normal, although some patients with developmental delays have been reported (summary by Bhoj et al., 2015).
Genetic Heterogeneity of Teebi Hypertelorism Syndrome
Teebi hypertelorism syndrome-2 (TBHS2; 619736) is caused by mutation in the CDH11 gene (600023) on chromosome 16q21.
Based on similarity of clinical features and the identification of heterozygous mutations in the SPECC1L gene in patients diagnosed with Teebi hypertelorism syndrome-1 (TBHS1) and Opitz GBBB syndrome type II (GBBB2), these disorders are considered to be the same. Because differences between GBBB2 and Opitz GBBB syndrome type I (GBBB1; 300000) have been described (see, e.g., Bhoj et al., 2019 and Zhang et al., 2020), the preferred designation used here for the disorder is 'Teebi hypertelorism syndrome-1.'
See HISTORY for a discussion of early reports of autosomal dominant G syndrome, BBB syndrome, and GBBB syndrome. The mutation in these families is not known and the inheritance pattern in some of these families is in doubt.
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. Wild et al. (2020) reported a personal communication with the authors of the article by Morris et al. (1987), who agreed that the clinical diagnosis was consistent with a 'SPECC1L-related' syndrome. The 2 affected males from the originally described family had affected daughters.
Allanson (1988) reported a family with what they designated as an 'unusual' form of GBBB syndrome; affected individuals were later found by Kruszka et al. (2015) to have a mutation in the SPECC1L gene. The female proband had hypertelorism as well as the typical laryngotracheoesophageal manifestations of the G syndrome, whereas her father and all 4 of the father's sibs had megalencephaly, hypertelorism, and a broad prominent nasal root and bridge, reminiscent of the facial appearance in the BBB syndrome. There was no evidence of dysplasia, respiratory abnormality, or hoarse voice in any relative other than the proposita. Allanson (1988) concluded that this family supported the notion that the BBB and G syndromes were in fact the same disorder. Kruszka et al. (2015) noted that, unlike typical GBBB, the proband in the family reported by Allanson (1988) had sagittal craniosynostosis, and that none of the affected males had hypospadias, a classic feature of Opitz GBBB syndrome. Bhoj et al. (2019) concluded that the pattern of developmental anomalies caused by mutation in SPECC1L was distinct enough from that of Opitz GBBB that the phenotype should be referred to as Teebi syndrome.
Stratton (1991) described a US family with Teebi syndrome 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. Bhoj et al. (2019) suggested that the phenotype in this family likely represented the Baraitser-Winter cerebrofrontofacial syndrome (see 243310).
Koenig (2003) reported a 2-year-old girl with Teebi syndrome 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 and mutation in the SPECC1L gene. 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.
Kruszka et al. (2015) studied a mother and 2 sons (family A) with ocular hypertelorism and mutation in the SPECC1L gene. Common features included cleft lip and palate, micrognathia, prominent forehead, broad nasal bridge, downslanting palpebral fissures, and inguinal and umbilical hernias. One boy had metopic craniosynostosis and aortic stenosis; neither had hypospadias. The mother had similar features as well as a bicornuate uterus. She reported that her mother, sister, and her sister's 2 children were also affected. The authors also studied the family originally reported by Allanson (1988) (family B), and noted that although affected individuals in both families exhibited many of the classic features associated with Opitz GBBB syndrome, they also showed unusual features, including craniosynostosis in the brother of the proband in family A and in the original proband in family B. In addition, none of the affected males in either family had hypospadias, which is a common feature of Opitz GBBB syndrome.
Bhoj et al. (2019) studied 16 new patients from 8 families with Teebi hypertelorism syndrome and mutation in the SPECC1L gene. Consistent features included hypertelorism, prominent forehead, high and/or broad nasal bridge with anteverted nares, and long philtrum. Short stature was present in 7 of the 12 patients for whom stature was reported; other notable features included arched eyebrows, ptosis, and micrognathia. None of the male patients exhibited hypospadias, and bicornuate uterus was present in all 5 female patients in whom it was sought.
Zhang et al. (2020) reported a 4-year-old Chinese girl with marked hypertelorism, giant omphalocele, and congenital heart defects. Atrial and ventricular septal defects were repaired at age 10 months. Developmental milestones were delayed, and she experienced a wide variety of infections, including pneumonia, septicemia, and omphalitis. She was reported to have had several febrile seizures. Her anterior fontanel was widely open and closed late at age 4 years. Examination at age 4 years showed a peculiar facial appearance including prominent forehead with widow's peak, noticeably wide-set eyes, arched eyebrows, and wide bridge of the nose with slightly broad nasal tip. The omphalocele was still present. The authors stated that this was the first reported Chinese patient with Teebi hypertelorism syndrome.
Wild et al. (2020) described a 2-week-old Hispanic boy (subject 1) with congenital diaphragmatic hernia (CDH) and mutation in the SPECC1L gene. He was born with respiratory distress requiring intubation; chest x-ray revealed a right-sided CDH displacing the heart to the left. In addition, he had a large anterior fontanel, widely open metopic suture, and prominent glabella. Ophthalmologic evaluation showed large pale excavated optic nerves with possible foveal hypoplasia. Despite respiratory support, oxygenation and mean arterial pressure deteriorated and he died on day 14 of life. Autopsy showed craniosynostosis of bilateral lambdoidal and coronal sutures with widening of frontal suture. The neck was short, and there were 13 ribs bilaterally. Right-sided posterior CDH was confirmed, with secondary hypoplasia of the right lung. The right lobe of the liver, distal ileum, loops of jejunum, the cecum, the appendix and ascending colon were in the right hemithorax, and there was intestinal malrotation. A persistent left superior vena cava connected to a dilated coronary sinus. Both kidneys appeared hypoplastic, and both testes were found in the abdomen. Dysmorphic facial features included a slightly inferiorly displaced left ear, a broad and flat nasal bridge with slightly anteverted nostrils, an elongated philtrum, and a thin upper lip. The authors noted that 5 previously reported patients with mutation in SPECC1L had left-sided diaphragmatic hernia, including the proband from family A of Kruszka et al. (2015) as well as the family 1 proband, 2 fetuses from family 4, and the family 6 proband studied by Bhoj et al. (2019). Other unifying features included prominent foreheads, ocular hypertelorism, high and broad nasal bridge, anteverted nares, long philtrum, micrognathia, and umbilical or inguinal hernia. Wild et al. (2020) concluded that CDH is a prominent feature in patients with mutation in the SPECC1L gene.
Reviews
Bhoj et al. (2019) reviewed 31 reported patients with SPECC1L mutations, noting that high and/or broad nasal bridge was present in all, ocular hypertelorism in 97%, long philtrum in 95%, prominent forehead in 86%, anteverted nares in 83%, ptosis in 71%, and short stature in 64%. Laryngeal cleft and anorectal malformation were not reported in these patients, and none of the 14 male patients showed hypospadias. All 9 female patients examined had bicornuate uterus. Brain anomalies were reported in 5 patients, including 3 with ventriculomegaly and 2 with a short or thin corpus callosum. In patients for whom information was available, developmental delay or learning disability was reported in 11 patients and intellectual disability in 3. Bhoj et al. (2019) stated that the pattern of developmental anomalies caused by mutation in SPECC1L was different enough from the pattern associated with variants in MID1 (300552; see GBBB, 300000), that rather than being termed 'GBBB2,' the phenotype should be designated 'Teebi syndrome.'
Zhang et al. (2020) reviewed 33 patients from 14 families with mutations in the SPECC1L gene. The most characteristic manifestation was dysmorphic facial features, including hypertelorism (31/33; 94%), broad nasal bridge (25/33; 75%), downslanting palpebral fissures (14/33; 42.4%), long or deep philtrum (12/33; 36.3%), arched or thick eyebrows (11/33; 33.3%), ear abnormalities (11/33; 33.3%), and prominent forehead (10/33; 30.3%). Bicornuate uterus (9/17; 53%), umbilical defect (14/33; 42.4%) and congenital heart defect (9/33; 27.2%) were also recurrent. Developmental delays were variable and occurred in 8 (24.2%) of 33 patients; some with delays developed to a normal level during childhood. Zhang et al. (2020) agreed with the proposal of Bhoj et al. (2019) that patients with a SPECC1L-associated phenotype who did not have Tessier IV cleft (see OBLFC1, 600251) should be considered to have Teebi syndrome. The authors noted that congenital diaphragmatic hernia (7/33; 21.2%), cleft lip/palate (6/33; 18.2%), and central nervous system defects (6/33; 18.2%) were not rare in Teebi syndrome caused by mutation in the SPECC1L gene.
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).
In a study of multiple families diagnosed with Opitz BBBG syndrome, Robin et al. (1995) found linkage in 3 families to DXS987 on Xp22, with a lod score of 3.53 at zero recombination, and in 5 families they found linkage to D22S345 on 22q11.2, with a lod score of 3.53 at zero recombination. They saw no phenotypic differences between the families and designated the disorder mapped to Xp22 as Opitz BBBG syndrome type I and that mapped to 22q11 as Opitz BBBG syndrome type II. One of the families mapped to 22q11 was the family reported by Allanson (1988); this family was later found to have a mutation in the SPECC1L gene. Autosomal dominant Opitz BBBG syndrome is now considered to be the same as Teebi hypertelorism syndrome-1.
Deletion on chromosome 22q11.2, in the same region resulting in DiGeorge syndrome (188400) and velocardiofacial syndrome (192430), has been reported in patients with an Opitz syndrome phenotype.
A candidate chromosome for the site of the BBBG mutation was indicated by Christodoulou et al. (1990), who found a ring 22 chromosome in 2 male patients with this disorder.
McDonald-McGinn et al. (1995) reported 2 cases of what they referred to as the GBBB syndrome in which a vascular ring was the mode of clinical presentation. Since a vascular ring is found in cases of 22q11.2 deletion (Zackai et al., 1996), fluorescence in situ hybridization studies were performed which demonstrated 22q11.2 deletion in the 2 cases and in the father of 1 of them who also showed changes considered consistent with mild BBB syndrome. In a note added in proof, McDonald-McGinn et al. (1995) described a fourth patient with clinical findings consistent with Opitz GBBB syndrome in association with 22q11.2 deletion. Based on a comparison of Opitz-GBBB syndrome with the chromosome 22 microdeletion syndrome, McDonald-McGinn et al. (1995) suggested that autosomal dominant Opitz-GBBB syndrome may be the result of a 22q11.2 deletion in some cases.
Fryburg et al. (1996) reported the fifth instance of the Opitz oculogenitolaryngeal syndrome associated with a 22q11.2 microdeletion demonstrated on the basis of a fluorescence in situ hybridization analysis using the DiGeorge probe. Lacassie and Arriaza (1996) found a microdeletion of 22q11.2 in a newborn boy by fluorescence in situ hybridization.
Erickson et al. (2007) reported a child with an Opitz syndrome-like phenotype who was found to have a chromosome 22q11.2 deletion with the same breakpoints as found in a patient with classic velocardiofacial syndrome. The child had been diagnosed with Opitz syndrome based on feeding difficulties, hypospadias, and asymmetry of the skull, despite a lack of significant hypertelorism; he did not have velar problems, cardiac defects, or a pear-shaped nose to suggest VCFS. Erickson et al. (2007) speculated that genetic background and/or environmental factors might explain the different phenotypes.
By whole-exome sequencing in 4 members of a 3-generation family (family A) with hypertelorism and other congenital anomalies, Kruszka et al. (2015) identified a heterozygous missense mutation in the SPECC1L gene (T397P; 614140.0002) that segregated with disease. Direct screening of the SPECC1L gene in 19 patients with a similar phenotype identified a heterozygous missense mutation (G1083; 614140.0003) in affected members of a family (family B) that was originally reported by Allanson (1988). In vitro functional expression studies showed that both mutant proteins had abnormal punctate expression patterns and a drastically reduced ability to stabilize microtubules. Although both families had originally been reported as having autosomal dominant Opitz GBBB syndrome, Bhoj et al. (2019) concluded that the pattern of developmental anomalies caused by mutation in SPECC1L was distinct enough from that of classic Opitz GBBB (see 300000) that the phenotype should be referred to as Teebi syndrome.
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.
By exome sequencing or targeted Sanger sequencing, Bhoj et al. (2019) identified 16 patients from 8 families with syndromic hypertelorism and heterozygous mutation in the SPECC1L gene (see, e.g., 614140.0002 and 614140.0006-614140.0008).
By whole-exome and Sanger sequencing in a 4-year-old Chinese girl with marked hypertelorism, congenital heart defects, and omphalocele, Zhang et al. (2020) identified heterozygosity for a de novo missense mutation in the SPECC1L gene (T417P; 614140.0009).
In a Hispanic male infant who died at 2 weeks of life from respiratory failure due to congenital diaphragmatic hernia, Wild et al. (2020) identified heterozygosity for a missense mutation in the SPECC1L gene (R399G; 614140.0010). Autopsy revealed craniosynostosis and dysmorphic features including broad nasal bridge with anteverted nostrils and long philtrum, as well as hypoplastic kidneys and cryptorchidism.
The Opitz GBBB syndrome was earlier thought to be 2 separate X-linked syndromes called the G syndrome and the BBB syndrome; both were listed in the X-linked catalog in the seventh edition of MIM (1986). Once it was known that the G syndrome and the BBB syndrome were in fact the same, Sedano and Gorlin (1988) suggested that the condition be called the Opitz oculogenitolaryngeal syndrome. They suggested that 'oculo' is more appropriate than either 'telecanthus' or 'hypertelorism'; that cryptorchidism in males and splayed labia majora in females represent additional genital abnormalities; and that laryngeal abnormalities occur which are part of a laryngotracheoesophageal combination of defects. Neri and Cappa (1988) found the suggested designation 'rather burdensome' and suggested that it be left as simply 'Opitz syndrome.' Verloes et al. (1989) proposed the designation BBBG syndrome.
Ocular hypertelorism is often incorrectly diagnosed when a flat nasal bridge, epicanthal folds, external strabismus, widely spaced eyebrows, blepharophimosis, or some combination of these is present. Telecanthus is a preferable term when increased distance separates the inner canthi. Dystopia canthorum is a synonym for telecanthus.
Opitz et al. (1969) described 4 brothers with hypertelorism, a neuromuscular defect of the esophagus and swallowing mechanism, hoarse cry, hypospadias, cryptorchidism, bifid scrotum, and, in one, imperforate anus. Two other brothers had died of aspiration. The parents were not related. The mother, who was thought to have minor stigmata such as hypertelorism, had difficulty swallowing fluids until age 11 months when a lingual frenulum (also present in at least 1 of the affected sons) was resected. Four living sisters were well except for one with Usher syndrome (congenital deafness and retinitis pigmentosa) and one with swallowing difficulties like the mother. As was his practice, Opitz et al. (1969) designated the condition 'G syndrome' after the family in which he observed it.
Under the designation of BBB syndrome (from the surnames of the families), Christian et al. (1969) and Opitz et al. (1969) reported, in all, 4 families in which telecanthus with or without hypertelorism was associated in males with hypospadias, cryptorchidism, cleft lip and palate, urinary malformations, and sometimes mental retardation. Female carriers had less severe telecanthus and escaped congenital malformation. Except for one alleged and unconfirmed instance in a remote branch of one of the families of Opitz et al. (1969), no male-to-male transmission was observed. Thus, X-linked inheritance was possible.
Coburn (1970) described an isolated case of G syndrome in a male infant.
Michaelis and Mortier (1972) described a patient with BBB syndrome.
Frias and Rosenbloom (1975) described a full-blown case of G syndrome whose maternal grandfather showed partial expression. Pedersen et al. (1976) favored autosomal dominant inheritance. Cordero and Holmes (1978) also favored autosomal dominant inheritance with males more severely affected than females. The mother of their proband showed not only telecanthus and hypertelorism, but also anosmia, a feature not previously noted in this disorder.
Van Biervliet and Van Hemel (1975) observed 3 affected brothers with G syndrome whose mother had similar facies and mild mental retardation and had dysphagia with aspiration in infancy.
Funderburk and Stewart (1978) described a patient with features consistent with G syndrome whose father had mild hypertelorism and first-degree hypospadias. Parisian and Toomey (1978) suggested that the G syndrome and the BBB syndrome are identical.
Greenberg and Schraufnagel (1979) reported a patient with G syndrome whose mother had a similar facies.
Cote et al. (1981) described 2 families with G syndrome; one had a lethal case with a laryngotracheoesophageal cleft, and the other showed only relatively mild expression in both sexes.
Da Silva (1983) reported a family with hypertelorism-hypospadias syndrome in which 2 affected males showed hypertelorism and hypospadias and 3 affected females showed only hypertelorism.
Farndon and Donnai (1983) suggested autosomal dominant inheritance of G syndrome on the basis of male-to-male transmission. Furthermore, Chemke et al. (1984) presented evidence of sex-limited autosomal dominant inheritance; their pedigree had affected males in 3 generations. Since the affected male in the first generation was related to his wife, the disorder in their 2 sons could have been inherited from the mother. One of the sons, however, had an affected son by a presumably unrelated woman.
Peeden et al. (1983) reported on a series of 16 families with BBB syndrome. They stated that a quarter of their patients have congenital heart disease, most often coarctation of the aorta and atrial septal defect. Fifteen percent had upper urinary tract anomalies. Twinning occurred in a third of the families. Cleft palate, lip, and uvula and cryptorchidism were present in a third. Mental retardation had a high frequency in males. There was no instance of male-to-male transmission. One affected was the father of 3 unaffected sons, 2 of whom were identical twins.
Stoll et al. (1985) reported father-to-son transmission of the BBB syndrome. Although the findings, especially in the son, seemed typical, the authors were compelled to conclude: '...as no marker of the BBB syndrome is now available it is possible that this father and son do not have the BBB syndrome. Further data on the offspring of affected males are needed.'
Tolmie et al. (1987) identified congenital anal anomalies as a feature of the Opitz-G syndrome. Their observations related to 5 children from 2 families. Two half sibs of the proband's mother in 1 family were reported to have died in the newborn period after undergoing surgery for imperforate anus. The proband had imperforate anus. A first cousin had congenital anal stenosis. This family included an apparent instance of male-to-male transmission. Tolmie et al. (1987) listed 21 syndromes that may include an anal malformation.
Neri et al. (1987) described a female patient with the G syndrome. The clinical expression was relatively severe and included 2 features not previously reported, i.e., agenesis of the corpus callosum and umbilical hernia. The new findings supported the notion that there is a developmental defect of the midline as the basis of the G syndrome.
Sudden death at 8 years of age, probably due to aspiration, was reported in a patient with G syndrome by Einfeld et al. (1987). Williams and Frias (1987) concluded that the G syndrome was present in a 3-month-old boy who presented with severe gastroesophageal reflux because of neck and upper limb dystonia. The infant was the product of a reportedly incestuous relationship.
Opitz (1987) gave a follow-up on his original family and presented information on a large number of unpublished cases. In conclusion, he wrote as follows: 'We would petition again that the G syndrome be moved from its present entry in the X-linked catalog (in Mendelian Inheritance in Man) into the autosomal dominant section since there is now good evidence of male-to-male transmission with female involvement almost as common (but generally less severe) than male involvement in newly referred proposita.' He cited numbers of 11 females to 17 males and an unpublished 3-generation family.
Stevens and Wilroy (1988) reported findings in 12 families with the BBB syndrome, with a total of 18 affected males, and summarized findings in 21 patients from 7 previous publications. Wilson and Oliver (1988) described 5 patients in 3 families and reviewed 23 published cases of G syndrome. The constellation of midline defects included hypertelorism or telecanthus (89%), esophageal dysmotility (69%), laryngotracheal clefts (44%), cleft palate or bifid uvula (34%), heart defects (29%), hypospadias (100% of males), renal or ureteral anomalies (42%), and mental retardation (38%). Affected relatives, often identified by hypertelorism, dysphagia or hypospadias, had a much lower frequency of associated defects and of mental retardation. Wilson and Oliver (1988) concluded that the disorder is compatible with normal intelligence and life span. Five cases of male-to-male transmission were observed. Wilson and Oliver (1988) counseled vigilance for the morphologic characteristics of G syndrome in patients with dysphagia.
Young et al. (1988) observed a strikingly different degree of severity of the G syndrome in twins shown to be monozygotic by DNA minisatellite 'fingerprint' analysis. They concluded that this indicates that the expression of the G syndrome can be strongly influenced by the prenatal developmental environment.
On the basis of 2 new cases and scrutiny of the literature, Cappa et al. (1987) concluded that there are no qualitative differences that permit discrimination between the G syndrome and the BBB syndrome. They concluded that both are 'most likely autosomal dominant.'
Howell and Smith (1989) reported 2 additional cases of G syndrome with laryngotracheoesophageal clefts. Robinson and Hilger (1989) presented the case of a 19-year-old woman with G syndrome whom they had seen for cosmetic rhinoplasty. Agenesis of nasal cartilages was a striking feature but, in addition, the cartilage of the pinnae was underdeveloped and the larynx and the trachea were described as 'infantile.' She had had recurrent bouts of croup until she was 15 years old and exercise limitation because of stridor. The mother had the same saddle nose and widely spaced eyes. Gorlin, who saw the patient in consultation, suggested the diagnosis of Opitz-BBB/G compound syndrome. Verloes et al. (1989) likewise reported a family in which the propositus had G syndrome, including laryngeal cleft, and another relative had the facial anomalies typical of the BBB syndrome. They concluded that the 2 syndromes represent a single entity.
Fryns et al. (1992) pointed to posterior scalp defects as another feature of Opitz syndrome that represents a midline defect. MacDonald et al. (1993) used brain magnetic resonance imaging in 4 patients with this disorder to extend the description of the midline anomalies to include a wide cavum septum pellucidum.
Brooks et al. (1992) reviewed the dental findings in a 12-year-old boy and in 139 published cases of GBBB syndrome. In 48 of the patients, at least one oral abnormality was described. These included clefting, micrognathia, ankyloglossia, and high-arched palate. Guion-Almeida and Richieri-Costa (1992) reported the cases of 12 Brazilian boys with the Opitz G/BBB syndrome associated with CNS midline anomalies, namely, Dandy-Walker anomaly (in 2), enlarged cisterna magna (in 4), enlarged fourth ventricle (in 4), and callosal aplasia or hypoplasia (in 2). They emphasized that the experience demonstrates the involvement of the CNS midline in this disorder.
Schrander et al. (1995) reported a Dutch family in which Opitz BBBG syndrome occurred in a male and in 2 maternal uncles, with minor manifestations in his mother and maternal grandmother. The proband developed late-onset symptoms of a structural laryngeal abnormality. He was born with bilateral cleft lip and palate, hypertelorism, marked epicanthal folds, and a prominent metopic suture. There was grade II hypospadias, a short penis, and bifid scrotum. He had anal and partial rectal atresia with a rectovesical fistula. Continuous monitoring of esophageal pH showed gastroesophageal reflux which was symptomatic in his first year. He also had bilateral ureteric reflux grade III, hydronephrosis necessitating reimplantation of the ureters, and intestinal malrotation. He suffered from many urinary tract infections and developed severe constipation. At the age of 2 years, he developed recurrent episodes of inspiratory stridor and hoarseness with upper respiratory tract infections. At age 5 years, he presented with very serious inspiratory stridor, became cyanotic, and required intubation. Laryngoscopy showed subglottic narrowing and small larynx. Although no cleft of the cricoid cartilage and no signs of tracheoesophageal cleft could be documented, the larynx was strikingly narrowed. One of the affected maternal uncles died 2 days after birth with bilateral cleft lip and palate and hypospadias; the other maternal uncle, a mentally subnormal male living at age 36 years, had been born with bilateral cleft lip/palate, tetralogy of Fallot, low anal atresia with a rectourethral fistula, and hypospadias. The mother and grandmother had hypertelorism.
Opitz (1996) suggested that monozygotic twinning is one expression of the defect in this syndrome.
Leichtman et al. (1991) described an infant with features consistent with Opitz BBBG syndrome who was found to have partial duplication of 5p. This led Leichtman et al. (1991) to suggest that the gene for the BBBG syndrome may be located in the duplicated region 5p13-p12.
Urioste et al. (1995) described a patient with clinical features consistent with Opitz GBBB syndrome and a terminal deletion of chromosome 13 with a breakpoint at 13q32.3. Coagulation factors VII (F7; 613878) and X (F10; 613872), which are encoded by genes in 13q34, were markedly reduced in the patient.
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