Bohring-Opitz Syndrome

A number sign (#) is used with this entry because Bohring-Opitz syndrome, also known as C-like syndrome, is caused by de novo heterozygous mutation in the ASXL1 gene (612990) on chromosome 20q11.

Description

Bohring-Opitz syndrome is a malformation syndrome characterized by severe intrauterine growth retardation, poor feeding, profound mental retardation, trigonocephaly, prominent metopic suture, exophthalmos, nevus flammeus of the face, upslanting palpebral fissures, hirsutism, and flexion of the elbows and wrists with deviation of the wrists and metacarpophalangeal joints (summary by Hoischen et al., 2011).

See also the C syndrome (211750), a disorder with a similar phenotype caused by heterozygous mutation in the CD96 gene (606037) on chromosome 3q13.

Clinical Features

Bohring et al. (1999) presented 4 unrelated cases of a syndrome resembling Opitz trigonocephaly (C) syndrome (211750). However, these cases differed from C syndrome on the basis of intrauterine growth retardation, cleft lip/palate, exophthalmos, retinal involvement, flexion deformities of the upper limbs, dislocation of radial heads, and forehead hirsutism. The authors also identified 2 cases in the literature, formerly reported as having C syndrome (Addor et al., 1995; Oberklaid and Danks, 1975), with a similar phenotype to that in their cases. All 6 cases were sporadic. The authors suggested that these infants may represent the most severe form of the C syndrome or a new entity.

Addor et al. (1995) reported a 6-year-old girl with C-trigonocephaly syndrome and diaphragmatic hernia. Two other examples of this complication of the syndrome were included in their report. Their first patient showed retrognathia, high-arched palate, broad alveolar ridges, and abnormal oral frenula. Their other 2 cases showed similar orofacial findings.

Bohring et al. (2006) reported 4 additional unrelated cases of Bohring-Opitz syndrome with the highly characteristic phenotype of facial anomalies including bulging forehead, frontal nevus flammeus, retrognathia, exophthalmos, hypertelorism, upslanting palpebral fissures, and cleft/lip palate. All showed severe failure to thrive, lack of development, brain abnormalities, and flexion deformities of upper limbs. Other features included hirsutism and possible hearing loss. Bohring et al. (2006) provided a review of previously reported patients.

Pierron et al. (2009) reported a patient with Bohring-Opitz syndrome. At birth, she had a low weight, bitemporal narrowing, bulging forehead, facial hemangiomas, hypertelorism, broad nasal bridge, puffy cheeks, thick ear lobes, and high-arched palate. She also had articular instability of the elbows and left knee, flexion deformity of the wrists, camptodactyly, and dislocation of the radial head. Brain MRI showed hypoplasia of the corpus callosum and narrowed upper cervical canal due to malformation of the atlas. She had very poor feeding and failure to thrive. Later features included hirsutism, seizures, and an episode of prolonged apnea. At age 5 years 9 months, she had significant psychomotor retardation, but had gained weight. No mutation was found in the coding region of the CD96 gene.

Hoischen et al. (2011) reported 7 unrelated patients with Bohring-Opitz syndrome due to de novo heterozygous mutations in the ASXL1 gene (see MOLECULAR GENETICS). All patients fulfilled the main criteria proposed by Bohring et al. (2006). There were 6 females and 1 male, ranging in age from 2.5 to 24 years, although 2 died at ages 6 years and 23 hours after birth, respectively. The most common clinical features included intrauterine growth retardation, poor feeding, profound mental retardation, hypertrichosis, fixed contracture with flexion of the elbows and wrists, ulnar deviation of the wrists and metacarpophalangeal joints, hypotonia, dislocations, and brain anomalies. Craniofacial dysmorphisms were also characteristic and included trigonocephaly, microcephaly, micro/retrognathia, facial hemangioma, prominent eyes, broad alveolar ridges, low-set or posteriorly rotated ears, and myopia. Three had seizures, 3 had retinal or optic nerve abnormalities, 3 had a sacral dimple, 4 had recurrent infections, and 4 had deep palmar creases. Examination of 2 older patients, who were 14 and 24 years, suggested that the facial appearance and prominent eyes become less striking with age; the facial nevus may also fade. None had tumors.

Magini et al. (2012) reported 2 unrelated patients with Bohring-Opitz syndrome confirmed by molecular analysis. An affected girl was born with microcephaly and hypotonia. She had a typical facial appearance, including prominent forehead, facial nevus flammeus, exophthalmos, hypertelorism, low-set and posteriorly angulated ears, long philtrum, high and narrow palate, and everted lower lip. She also had elbow contractures, abnormal posture, and mild hirsutism. She later developed seizures, severe myopia, and showed failure to thrive. Brain MRI showed dilatation of lateral ventricles, mildly thin corpus callosum, and apparent moderate atrophy of the spinal cord. At age 3 years, she had mild hepatomegaly, thoracolumbar scoliosis, and severe psychomotor retardation with no language. A unrelated boy had trigonocephaly with partially fused metopic suture, facial capillary hemangioma, upslanting palpebral fissures, prominent eyes with hypoplastic supraorbital ridges, high and narrow palate, low-set ears, short neck, truncal hypotonia, scoliosis, marked hirsutism, cryptorchidism, and the typical BOS posture with contractures of the hips, knees, and ankles, as well as talovalgus deformity of the feet. He had feeding difficulties with failure to thrive, and myopia. Brain MRI showed enlarged cerebral ventricles, hypomyelination of the periventricular white matter, and a hypoplastic corpus callosum. At age 7 years, he had severely delayed global development with no speech. Hower, he had learned to communicate through images, letters, and signs, and seemed to enjoy social contacts.

Clinical Variability

Osaki et al. (2006) reported a newborn male infant, one of dizygotic twins whose brother was phenotypically normal, who had many clinical manifestations similar to the C-like syndrome, including intrauterine growth retardation with failure to thrive, trigonocephaly involving the metopic suture, narrow forehead, optic nerve atrophy, high-arched palate, flexion deformity of the limbs, and hemangiomata. However, he lacked exophthalmos, which has been regarded as a hallmark of C-like syndrome. Osaki et al. (2006) suggested that the manifestations in this patient are an indication of overlap between C-like syndrome and C syndrome. In the patient reported by Osaki et al. (2006), Kaname et al. (2007) identified a heterozygous mutation in the CD96 gene (606037.0002), which is disrupted in C syndrome (211750). Kaname et al. (2007) noted that this patient had relatively severe features for C syndrome, but also stated that it was uncertain whether there is (1) a gradient of spectrum in the C syndrome, from the mild form (C syndrome) to the severe form (C-like syndrome), or (2) genetic heterogeneity among the patients with the C syndrome. Kaname et al. (2007) also found disruption of the CD96 gene in a patient with classic C syndrome and a balanced translocation (606037.0001), suggesting that CD96 mutations are associated with variable severity of that disorder.

Diagnosis

The observation of a common phenotype in Bohring-Opitz syndrome has led to the development of diagnostic criteria, including microcephaly, trigonocephaly, palatal abnormalities, prominent eyes and hypoplastic supraorbital ridges, upslanting palpebral fissures, depressed nasal bridge and anteverted nares, facial nevus flammeus, low-set, posteriorly angulated ears, failure to thrive, and severe developmental delay. In addition, patients have an unusual and characteristic limb posture, with external rotation and/or adduction of shoulders, flexion at elbows and wrists, and ulnar deviation of wrists and/or fingers at the metacarpophalangeal (MCP) joint (summary by Magini et al., 2012).

Inheritance

With few exceptions, Bohring-Opitz syndrome occurs as a sporadic disorder (Hoischen et al., 2011). Nakane et al. (2000), Lindor et al. (2000), and Brunner et al. (2000) reported further cases of Bohring-Opitz cases, all of which were sporadic.

Greenhalgh et al. (2003) described a brother and sister with Bohring-Opitz syndrome, suggesting the possibility of autosomal recessive inheritance.

Molecular Genetics

By exome sequencing in combination with direct sequencing, Hoischen et al. (2011) identified 7 different de novo heterozygous nonsense or truncating mutations in the ASXL1 gene (see, e.g., 612990.0001-612990.0005) in 7 of 13 unrelated patients with Bohring-Opitz syndrome. Six patients with the phenotype did not carry mutations, suggesting genetic heterogeneity. Hoischen et al. (2011) postulated a loss-of-function mechanism. The ASXL1 gene is involved in the maintenance of both activation and silencing of the HOX genes, which are involved in body patterning, as well as in chromatin remodeling, although the patients did not have any specific homeotic transformations.

In 2 unrelated patients with classic features of Bohring-Opitz syndrome, Magini et al. (2012) identified 2 different de novo heterozygous truncating mutations in the ASXL1 gene (612990.0006 and 612990.0007).