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Opitz-Frias syndrome(GBBB1)

MedGen UID:
104493
Concept ID:
C0175696
Disease or Syndrome
Synonyms: GBBB1; HYPERTELORISM WITH ESOPHAGEAL ABNORMALITY AND HYPOSPADIAS; HYPERTELORISM-HYPOSPADIAS SYNDROME; OPITZ BBBG SYNDROME, TYPE I; Opitz G/BBB Syndrome, X-Linked; OPITZ GBBB SYNDROME, TYPE I; OPITZ SYNDROME; OPITZ SYNDROME, X-LINKED; OPITZ-G SYNDROME, TYPE I; TELECANTHUS-HYPOSPADIAS SYNDROME
Modes of inheritance:
Heterogeneous
MedGen UID:
67020
Concept ID:
C0242960
Organism Attribute
Source: HPO
The presence of apparently similar characters for which the genetic evidence indicates that different genes or different genetic mechanisms are involved in different pedigrees. In clinical settings genetic heterogeneity refers to the presence of a variety of genetic defects which cause the same disease, often due to mutations at different loci on the same gene, a finding common to many human diseases including ALZHEIMER DISEASE; CYSTIC FIBROSIS; LIPOPROTEIN LIPASE DEFICIENCY, FAMILIAL; and POLYCYSTIC KIDNEY DISEASES. (Rieger, et al., Glossary of Genetics: Classical and Molecular, 5th ed; Segen, Dictionary of Modern Medicine, 1992)
X-linked recessive inheritance
MedGen UID:
375779
Concept ID:
C1845977
Finding
Sources: HPO, OMIM, Orphanet
A mode of inheritance that is observed for recessive traits related to a gene encoded on the X chromosome. In the context of medical genetics, X-linked recessive disorders manifest in males (who have one copy of the X chromosome and are thus hemizygotes), but generally not in female heterozygotes who have one mutant and one normal allele.
X-linked recessive inheritance (HPO, OMIM, Orphanet)
SNOMED CT: Congenital cleft larynx and Opitz-Frias syndrome (81771002)
 
Gene (location): MID1 (Xp22.2)
OMIM®: 300000

Definition

X-linked Opitz G/BBB syndrome (XLOS) is a multiple congenital anomaly disorder characterized by facial anomalies (ocular hypertelorism, prominent forehead, widow's peak, broad nasal bridge, anteverted nares), laryngotracheoesophageal defects, and genitourinary abnormalities (hypospadias, cryptorchidism, and hypoplastic/bifid scrotum). Developmental delay and intellectual disability are observed in about 50% of affected males. Cleft lip and/or palate are present in approximately 50% of affected individuals. Other malformations present in fewer than 50% of individuals include congenital heart defects, imperforate or ectopic anus, and midline brain defects (Dandy-Walker malformation and agenesis or hypoplasia of the corpus callosum and/or cerebellar vermis). Wide clinical variability occurs even among members of the same family. Female carriers usually manifest only ocular hypertelorism. [from GTR]

Additional descriptions

From GeneReviews
X-linked Opitz G/BBB syndrome (XLOS) is a multiple congenital anomaly disorder characterized by facial anomalies (ocular hypertelorism, prominent forehead, widow's peak, broad nasal bridge, anteverted nares), laryngotracheoesophageal defects, and genitourinary abnormalities (hypospadias, cryptorchidism, and hypoplastic/bifid scrotum). Developmental delay and intellectual disability are observed in about 50% of affected males. Cleft lip and/or palate are present in approximately 50% of affected individuals. Other malformations present in fewer than 50% of individuals include congenital heart defects, imperforate or ectopic anus, and midline brain defects (Dandy-Walker malformation and agenesis or hypoplasia of the corpus callosum and/or cerebellar vermis). Wide clinical variability occurs even among members of the same family. Female carriers usually manifest only ocular hypertelorism.  https://www.ncbi.nlm.nih.gov/books/NBK1327
From OMIM
The Opitz GBBB syndrome is a congenital midline malformation syndrome characterized by hypertelorism, hypospadias, cleft lip/palate, laryngotracheoesophageal abnormalities, imperforate anus, developmental delay, and cardiac defects (So et al., 2005). This disorder was first reported as 2 separate entities, BBB syndrome and G syndrome; subsequent reports of families in which the BBB and G syndromes segregated within a single kindred suggested that they represent a single entity. Genetic Heterogeneity See also GBBB2 (145410), caused by mutation in the SPECC1L gene (614140) on chromosome 22q11.  http://www.omim.org/entry/300000
From GHR
Opitz G/BBB syndrome is a genetic condition that causes several abnormalities along the midline of the body. "G/BBB" represents the first letters of the last names of the families first diagnosed with this disorder and "Opitz" is the last name of the doctor who first described the signs and symptoms. There are two forms of Opitz G/BBB syndrome, X-linked Opitz G/BBB syndrome and autosomal dominant Opitz G/BBB syndrome. The two forms are distinguished by their genetic causes and patterns of inheritance. The signs and symptoms of the two forms are generally the same.Nearly everyone with Opitz G/BBB syndrome has wide-spaced eyes (ocular hypertelorism). Affected individuals commonly have defects of the voice box (larynx), windpipe (trachea), or esophagus. These throat abnormalities can cause difficulty swallowing or breathing, in some cases resulting in recurrent pneumonia or life-threatening breathing problems. A common defect is a gap between the trachea and esophagus (laryngeal cleft) that allows food or fluids to enter the airway. The cleft can vary in size, and infants may struggle to breathe when feeding. Most males with Opitz G/BBB syndrome have genital abnormalities such as the urethra opening on the underside of the penis (hypospadias), undescended testes (cryptorchidism), an underdeveloped scrotum, or a scrotum divided into two lobes (bifid scrotum). These genital abnormalities can lead to problems in the urinary tract.Mild intellectual disability and developmental delay occur in about 50 percent of people with Opitz G/BBB syndrome. Affected individuals have delayed motor skills, such as walking, speech delay, and learning difficulties. Some people with Opitz G/BBB syndrome have features of autistic spectrum disorders, which are characterized by impaired communication and socialization skills. About half of affected individuals also have an opening in the lip (cleft lip) with or without an opening in the roof of the mouth (cleft palate). Some have cleft palate without cleft lip. Less common features of Opitz G/BBB syndrome, affecting less than half of people with this disorder, include minor heart defects, an obstruction of the anal opening (imperforate anus), and brain defects such as a small or absent connection between the left and right halves of the brain (corpus callosum). Distinct facial features that may be seen in this disorder include a prominent forehead, widow's peak hairline, flat nasal bridge, thin upper lip, and low-set ears. These features vary among affected individuals, even within the same family.  https://ghr.nlm.nih.gov/condition/opitz-g-bbb-syndrome

Clinical features

Hypertelorism
MedGen UID:
9373
Concept ID:
C0020534
Finding
Although hypertelorism means an excessive distance between any paired organs (e.g., the nipples), the use of the word has come to be confined to ocular hypertelorism. Hypertelorism occurs as an isolated feature and is also a feature of many syndromes, e.g., Opitz G syndrome (145410), Greig cephalopolysyndactyly (175700), and Noonan syndrome (163950) (summary by Cohen et al., 1995).
Cryptorchidism, unilateral or bilateral
MedGen UID:
8192
Concept ID:
C0010417
Congenital Abnormality
Cryptorchidism, or failure of testicular descent, is a common human congenital abnormality with a multifactorial etiology that likely reflects the involvement of endocrine, environmental, and hereditary factors. Cryptorchidism can result in infertility and increases risk for testicular tumors. Testicular descent from abdomen to scrotum occurs in 2 distinct phases: the transabdominal phase and the inguinoscrotal phase (summary by Gorlov et al., 2002).
Hypospadias
MedGen UID:
305577
Concept ID:
C1691215
Congenital Abnormality
Displacement of the urethral opening on the ventral (inferior) surface of the penis.
Heart, malformation of
MedGen UID:
6748
Concept ID:
C0018798
Congenital Abnormality
An anatomical defect of a gross structure of the heart.
Imperforate anus
MedGen UID:
1997
Concept ID:
C0003466
Congenital Abnormality
A congenital abnormality characterized by the persistence of the anal membrane, resulting in a thin membrane covering the normal ANAL CANAL. Imperforation is not always complete and is treated by surgery in infancy. This defect is often associated with NEURAL TUBE DEFECTS; MENTAL RETARDATION; and DOWN SYNDROME.
Dysphagia
MedGen UID:
41440
Concept ID:
C0011168
Disease or Syndrome
A symptom referring to difficulty in swallowing. It may be observed in patients with stroke, motor neuron disorders, cancer of the throat or mouth, head and neck injuries, Parkinson disease, and multiple sclerosis.
Gastroesophageal reflux disease
MedGen UID:
6553
Concept ID:
C0017168
Disease or Syndrome
Gastroesophageal reflux (GER) is characterized by the retrograde movement of stomach contents into the esophagus. In its most severe form, GER results in extensive tissue damage caused by acid reflux. In adolescents and adults, and even infrequently in children, chronic GER is associated with the risk of developing Barrett metaplasia (614266), a premalignant lesion of the esophageal mucosa (Hu et al., 2000). In turn, Barrett metaplasia is correlated with the development of adenocarcinoma of the esophagus (see 614266), estimated as the fifth most prevalent neoplasia in the Western world (Lagergren et al., 1999).
Dysphagia
MedGen UID:
41440
Concept ID:
C0011168
Disease or Syndrome
A symptom referring to difficulty in swallowing. It may be observed in patients with stroke, motor neuron disorders, cancer of the throat or mouth, head and neck injuries, Parkinson disease, and multiple sclerosis.
Corpus callosum agenesis
MedGen UID:
104498
Concept ID:
C0175754
Congenital Abnormality
The corpus callosum is the largest fiber tract in the central nervous system and the major interhemispheric fiber bundle in the brain. Formation of the corpus callosum begins as early as 6 weeks' gestation, with the first fibers crossing the midline at 11 to 12 weeks' gestation, and completion of the basic shape by age 18 to 20 weeks (Schell-Apacik et al., 2008). Agenesis of the corpus callosum (ACC) is one of the most frequent malformations in brain with a reported incidence ranging between 0.5 and 70 in 10,000 births. ACC is a clinically and genetically heterogeneous condition, which can be observed either as an isolated condition or as a manifestation in the context of a congenital syndrome (see MOLECULAR GENETICS and Dobyns, 1996). Also see mirror movements-1 and/or agenesis of the corpus callosum (MRMV1; 157600). Schell-Apacik et al. (2008) noted that there is confusion in the literature regarding radiologic terminology concerning partial absence of the corpus callosum, where various designations have been used, including hypogenesis, hypoplasia, partial agenesis, or dysgenesis.
Cognitive delay
MedGen UID:
351243
Concept ID:
C1864897
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Aspiration
MedGen UID:
751786
Concept ID:
C2712334
Finding
Inspiration of a foreign object into the airway.
Cryptorchidism, unilateral or bilateral
MedGen UID:
8192
Concept ID:
C0010417
Congenital Abnormality
Cryptorchidism, or failure of testicular descent, is a common human congenital abnormality with a multifactorial etiology that likely reflects the involvement of endocrine, environmental, and hereditary factors. Cryptorchidism can result in infertility and increases risk for testicular tumors. Testicular descent from abdomen to scrotum occurs in 2 distinct phases: the transabdominal phase and the inguinoscrotal phase (summary by Gorlov et al., 2002).
Hypospadias
MedGen UID:
305577
Concept ID:
C1691215
Congenital Abnormality
Displacement of the urethral opening on the ventral (inferior) surface of the penis.
Frontal bossing
MedGen UID:
67453
Concept ID:
C0221354
Congenital Abnormality
A skeletal deformity characterized by an unusually prominent forehead. Causes include acromegaly, Hurler syndrome, Silver-Russell syndrome, and thalassemia major.
Hypertelorism
MedGen UID:
9373
Concept ID:
C0020534
Finding
Although hypertelorism means an excessive distance between any paired organs (e.g., the nipples), the use of the word has come to be confined to ocular hypertelorism. Hypertelorism occurs as an isolated feature and is also a feature of many syndromes, e.g., Opitz G syndrome (145410), Greig cephalopolysyndactyly (175700), and Noonan syndrome (163950) (summary by Cohen et al., 1995).
Frontal bossing
MedGen UID:
67453
Concept ID:
C0221354
Congenital Abnormality
A skeletal deformity characterized by an unusually prominent forehead. Causes include acromegaly, Hurler syndrome, Silver-Russell syndrome, and thalassemia major.
High palate
MedGen UID:
66814
Concept ID:
C0240635
Congenital Abnormality
Height of the palate more than 2 SD above the mean (objective) or palatal height at the level of the first permanent molar more than twice the height of the teeth (subjective).
Telecanthus
MedGen UID:
140836
Concept ID:
C0423113
Finding
Distance between the inner canthi more than two standard deviations above the mean (objective); or, apparently increased distance between the inner canthi.
Flat philtrum
MedGen UID:
222980
Concept ID:
C1142533
Finding
Flat skin surface, with no ridge formation in the central region of the upper lip between the nasal base and upper vermilion border.
Anteverted nares
MedGen UID:
326648
Concept ID:
C1840077
Finding
Anteriorly-facing nostrils viewed with the head in the Frankfurt horizontal and the eyes of the observer level with the eyes of the subject. This gives the appearance of an upturned nose (upturned nasal tip).
Posterior pharyngeal cleft
MedGen UID:
336332
Concept ID:
C1848389
Finding
Wide nasal bridge
MedGen UID:
341441
Concept ID:
C1849367
Finding
Increased breadth of the nasal bridge (and with it, the nasal root).
Widow peak
MedGen UID:
342891
Concept ID:
C1853486
Congenital Abnormality
Frontal hairline with bilateral arcs to a low point in the midline of the forehead.
Thin upper lip vermilion
MedGen UID:
355352
Concept ID:
C1865017
Finding
Height of the vermilion of the upper lip in the midline more than 2 SD below the mean. Alternatively, an apparently reduced height of the vermilion of the upper lip in the frontal view (subjective).
Prominent forehead
MedGen UID:
401234
Concept ID:
C1867446
Finding
Forward prominence of the entire forehead, due to protrusion of the frontal bone.
Cleft secondary palate
MedGen UID:
756015
Concept ID:
C2981150
Congenital Abnormality
Cleft palate is a developmental defect of the palate resulting from a failure of fusion of the palatine processes and manifesting as a separation of the roof of the mouth (soft and hard palate).
Cleft upper lip
MedGen UID:
892653
Concept ID:
C4020893
A gap in the upper lip. This is a congenital defect resulting from nonfusion of tissues of the lip during embryonal development.
Abnormality of the nasopharynx
MedGen UID:
425069
Concept ID:
CN001583
Finding
Widow peak
MedGen UID:
342891
Concept ID:
C1853486
Congenital Abnormality
Frontal hairline with bilateral arcs to a low point in the midline of the forehead.

Recent clinical studies

Diagnosis

Antao B, Soccorso G, Bateman N, Shawis R
Eur Arch Otorhinolaryngol 2007 Nov;264(11):1373-6. Epub 2007 Jun 9 doi: 10.1007/s00405-007-0356-3. PMID: 17558506
Conlon BJ, O'Dwyer T
J Laryngol Otol 1995 Mar;109(3):244-6. PMID: 7745346

Clinical prediction guides

Bershof JF, Guyuron B, Olsen MM
J Craniomaxillofac Surg 1992 Jan;20(1):24-7. PMID: 1564117
Wilson GN, Oliver WJ
J Med Genet 1988 Mar;25(3):157-63. PMID: 3351901Free PMC Article

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