Opitz Gbbb Syndrome, Type Ii

A number sign (#) is used with this entry because of evidence that autosomal dominant Opitz GBBB syndrome (GBBB2) is caused by heterozygous mutation in the SPECC1L gene (614140) on chromosome 22q11.2.

The phenotype can also result from heterozygous deletion at chromosome 22q11.2. Deletion in the same region may also result in DiGeorge syndrome (188400) and velocardiofacial syndrome (192430).

Heterozygous mutation in the SPECC1L gene can also cause isolated oblique facial clefting-1 (OBLFC1; 600251).

Description

Features of the Opitz GBBB syndrome include hypertelorism or telecanthus; laryngotracheoesophageal cleft; clefts of lip, palate, and uvula; swallowing difficulty and hoarse cry; genitourinary defects, especially hypospadias in males and splayed labia majora in females; mental retardation; developmental delay; and congenital heart defects.

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 as recently as the seventh edition of MIM (1986).

The Opitz GBBB syndrome is genetically heterogeneous, with both autosomal dominant and X-linked (300000) forms. Robin et al. (1996) compared the phenotypic features of the X-linked and autosomal forms. They found that anteverted nares and posterior pharyngeal cleft were seen only in the X-linked form. However, all other manifestations of the syndrome, such as hypertelorism, swallowing difficulties, hypospadias, and developmental delay, were seen in both forms.

Nomenclature

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.

It is proposed that the X-linked form of Opitz BBBG syndrome be referred to as type I and the chromosome 22 form as type II.

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.

Clinical Features

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 in a male infant. Michaelis and Mortier (1972) described a case.

Van Biervliet and Van Hemel (1975) observed 3 affected brothers whose mother had similar facies and mild mental retardation and had dysphagia with aspiration in infancy.

Funderburk and Stewart (1978) described a case in which the father of the proband 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 case. The mother had a similar facies.

Cote et al. (1981) described 2 families; 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 2 affected males who showed hypertelorism and hypospadias and 3 affected females who showed only hypertelorism.

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 have 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.

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 case 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.

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 subjects 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.

Allanson (1988) reported a family in which the proband had 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. Further, there was no evidence of dysplasia, respiratory abnormality, or hoarse voice in any relative other than the proposita. This supported the notion that the BBB and G syndromes are in fact the same disorder. The family of Allanson (1988) was shown by Robin et al. (1995) to have the autosomal dominant, chromosome 22 form of Opitz BBBG syndrome. Kruszka et al. (2015) noted that the proband in the family reported by Allanson (1988) had sagittal craniosynostosis and that none of the affected males had hypospadias.

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 BBBG syndrome. In 48 of the patients, at least 1 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.

Kruszka et al. (2015) reported a mother and her 2 sons with GBBB2. Typical features included cleft lip and palate, micrognathia, prominent forehead, hypertelorism, 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 had similar features.

Inheritance

Kasner et al. (1974) described a lethally affected female born into the family originally reported by Opitz's group. They suggested that this indicates autosomal dominant inheritance. Frias and Rosenbloom (1975) described a full-blown case 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.

Arya et al. (1980) reported the second lethal case in a female, the niece of the original G brothers. An updated pedigree was presented. The authors stated: 'Autosomal dominant inheritance of the G syndrome seems well established....'

Farndon and Donnai (1983) suggested autosomal dominant inheritance 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.

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.' Opitz (1987), however, cited work of Stevens and Wilroy (1986, 1988) suggesting that the BBB syndrome is an X-linked dominant. 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.'

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. It later turned out, as indicated by the information given in Robin et al. (1995), that both McKusick and Opitz were correct: an X-linked form that maps to Xp (300000) and an autosomal form that maps to proximal 22q are well established.

Mapping

Robin et al. (1995) presented evidence that Opitz syndrome is genetically heterogeneous, with both an X-linked and an autosomal form. In 3 families, they found linkage to DXS987 in Xp22, with a lod score of 3.53 at zero recombination. On the other hand, 5 families were linked to D22S345 from 22q11.2, with a lod score of 3.53 at zero recombination.

Cytogenetics

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.

Molecular Genetics

In 4 members of a 3-generation family with GBBB2, Kruszka et al. (2015) identified a heterozygous missense mutation in the SPECC1L gene (T397P; 614140.0002). The mutation was found by whole-exome sequencing and segregated with the disorder in the family. 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 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.

History

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.