Paula and Bobby
Parents of Lillie
Bohring-Opitz syndrome (BOPS)
What is Bohring-Opitz syndrome?
Bohring-Opitz syndrome is a rare disease which affects multiple parts of the body.
It is mainly characterized by intrauterine growth restriction and failure to thrive following birth.
A port wine stain on the face (nevus flammeus of the face) is also a defining feature of this rare disease.
To date there are just 60 cases recorded globally.
This syndrome is also known as:
Bohring Syndrome; C-like Syndrome; Opitz Trigonocephaly-like Syndrome
What gene change causes Bohring-Opitz syndrome?
The syndrome is caused by mutations in the ASXL1 gene.
The condition is usually the result of a de novo mutation. Individuals with Bohring-Opitz syndrome have not been known to have children of their own, meaning the syndrome is not inherited.
In some cases, a genetic syndrome may be the result of a de-novo mutation and the first case in a family. In this case, this is a new gene mutation which occurs during the reproductive process.
What are the main symptoms of Bohring-Opitz syndrome?
The main initial symptom of the syndrome includes intrauterine growth restriction. The syndrome presents with a wide variety of symptoms affecting the mental and physical development of an individual.
Developmental delay and severe intellectual disability as well as possible brain malformations are serious symptoms of the condition.
Facial and physical characteristics include a very small head, a red birthmark on the face, widely-spaced eyes, corners of the eyes that point up, protruding eyes, strabismus, high myopia, cleft palate and low set ears rotated backward.
Other unique facial characteristics include a flat nasal bridge, nostrils that open to the front, a characteristic posture that includes slouching shoulders and bent elbows and wrist. Excessive hair growth and low muscle tone are other physical symptoms of the syndrome.
Other health conditions may include seizures, poor feeding and failure to thrive, sleep apnea, heart, kidney and genital abnormalities. Some individuals develop Wilms tumor, a rare kidney cancer in children. Most individuals with Bohring-Opitz syndrome have a shortened life expectancy.
Possible clinical traits/features:
Long face, Low-set ears, Low anterior hairline, Tapered finger, Low-set, posteriorly rotated ears, Nevus flammeus, Narrow palate, Narrow chest, Narrow forehead, Myopia, Micrognathia, Muscular hypotonia, Intellectual disability, profound, Intestinal malrotation, Intrauterine growth retardation, Gastroesophageal reflux, Full cheeks, Short toe, Underdeveloped supraorbital ridges, Hypoplasia of the brainstem, Short foot, Hirsutism, Gray matter heterotopia, Hernia of the abdominal wall, Hyperechogenic pancreas, Hypoplasia of the corpus callosum, Global developmental delay, Cognitive impairment, Hearing impairment, Hypertelorism, Camptodactyly, Ulnar deviation of finger, Delayed peripheral myelination, Short thorax, Talipes, Microcephaly, Thick hair, Wide intermamillary distance, Mesomelic/rhizomelic limb shortening, Prominent metopic ridge, Proptosis, Camptodactyly of finger, Prominent forehead, Strabismus, Upslanted palpebral fissure, Synophrys, Supernumerary nipple, Ulnar deviation of the wrist
How does someone get tested for Bohring-Opitz syndrome?
The initial testing for Bohring-Opitz syndrome can begin with facial analysis screening with FDNA’s AI technology, which can identify the key markers of the syndrome and outline the need for further testing.
Based on clinical consultation with a genetic professional, different options for genetic testing will be proposed.
Medical information on Bohring-Opitz syndrome
DISEASE OVERVIEW:
Bohring-Opitz Syndrome is a rare, autosomal dominant, genetic condition caused by variants in ASXL1. All disease causing variants to-date have resulted in protein truncation. Typical features include a characteristic facial appearance and posture, growth failure, feeding intolerance, significant intellectual disabilities and variable congenital anomalies. Facial features typically include microcephaly or trigonocephaly with prominent (but not always fused) metopic ridge, hypotonic facies with full cheeks, synophrys, glabellar and eyelid nevus simplex (flammeus), prominent globes, widely set eyes, palate anomalies, and micrognathia. “BOS posture” includes flexion at the elbows with ulnar deviation and flexion of the wrists and metacarpophalangeal joints but often resolves with age.
CLINICAL DESCRIPTION (GENERAL):
Bohring-Opitz syndrome (BOS) is a rare condition characterized by distinctive facial features and posture, variable but usually severe intellectual disability, growth failure, and variable anomalies. Feeding difficulties have a significant impact on overall health in early childhood but feeding tends to improve with age.
CLINICAL DESCRIPTION (BODY SYSTEMS):
Craniofacial. BOS is characterized by a distinctive facial appearance (see Key Clinical Features/Phenotypes) that has a high degree of variability and changes with age. The most consistent features are a prominent glabellar nevus simplex (flammeus) that fades with age, synophrys that becomes more prominent with age, hypotonic facies with full cheeks, and prominent eyes. Hypertrichosis with rapidly growing hair and nails is also common.
Other features: cleft lip, cleft palate, high arched palate, widely spaced eyes (hypertelorism), depressed and wide nasal bridge, anteverted nares, low-set ears with increased posterior angulation
Growth. Mild intrauterine growth restriction has been noted, but many infants are products of healthy pregnancies with average or low-average birth weights. Poor growth is typically noted in the first year of life and is often clinically attributed to chronic emesis and feeding intolerance. Adequate nutrition does play a role in early growth, but even those without feeding intolerance typically display poor long-term growth. Individuals who are ambulatory typically do reach a normal adult height.
Feeding. Feeding issues beginning in infancy usually improve or resolve in early childhood. Gastroesophageal reflux plays a significant role but a neurogenic etiology, including cyclic vomiting with possible poor gastric motility, has also been proposed as the cause of chronic emesis (Russell et al 2015). Given the frequency of emesis, there is a high risk for aspiration and dehydration.
Development and behavior. All affected individuals reported in the literature have severe-to-profound intellectual disability. Few are able to speak, but many have been able to express basic needs using augmentative and alternative communication (AAC) devices as well as gestures with associated basic vocalizations. Individuals with BOS often have a happy and pleasant demeanor (Russell et al 2015). Typically, they are able to recognize caregivers and have a social, interactive nature. Most are unable to walk independently, but some have had success using walkers and braces in late childhood.
Neurologic. Seizures that typically respond to monotherapy with antiepileptic medications are common in BOS. Affected individuals have also been described to have truncal hypotonia with hypertonia of the extremities. A wide range of primary brain anomalies have been reported including corpus callosum defects, Dandy-Walker malformation, delayed myelination, and enlarged ventricles.
Cardiovascular. Idiopathic and transient bradycardia as well as apnea were widely reported in the initial literature that predated the identification of the genetic cause of BOS. Cardiovascular deaths associated with bradycardia and apnea account for four (33%) of the 12 deaths published in the literature (although none of those individuals had a molecular confirmation of BOS). Kibe et al 2018 reported on an infant with BOS due to a mutation in ASXL1 who died at 60 days of life due to persistent pulmonary hypertension of the newborn with associated right ventricular enlargement. Other minor cardiac anomalies including septal defects and cardiac hypertrophy have also been described in a small number of affected individuals.
Respiratory. In addition to apnea and bradycardia, respiratory infections are common in infancy and account for about 42% of deaths (5/12). When chronic emesis is treated or improves with age, the rate of respiratory infections decreases (Russell et al 2015). Tracheostomies have been necessary for some.
Sleep. Obstructive sleep apnea and sleep disturbances, including difficulty falling asleep and staying asleep, are frequently reported. Affected individuals with micrognathia may also exhibit tongue-based airway obstruction.
Ophthalmologic. Myopia, often severe, is common in individuals with BOS. Most affected individuals require corrective lenses in infancy. Retinal and optic nerve abnormalities including colobomas, retinal and optic nerve atrophy, and abnormal coloration of the retinas are also frequently reported.
Immunologic. Recurrent infections may be frequent in early life, although immunodeficiency has not been reported in the literature. The frequency of infections typically declines with age.
Urologic. Urinary retention and recurrent urinary tract infections have been reported in individuals with BOS (Russell et al 2015). There also appears to be an increased risk for renal stones.
Skeletal. The typical BOS posture (see Key Clinical Features/Phenotypes) is most notable in early childhood and usually becomes less obvious with age. Congenital contractures, dislocations, and pectus excavatum have also been reported.
Malignancy. Isolated case reports suggest that children with BOS are at greater risk for Wilms tumor than the general population; large-scale epidemiologic studies have not been conducted due to the limited number of individuals diagnosed with BOS. Of three individuals with a clinical diagnosis of BOS and renal neoplasia, two had documented pathogenic variants in ASXL1 and bilateral Wilms tumor; Wilms tumor was diagnosed in one at age two years and in the other at age six years (Russell et al 2015). Another individual with BOS had nephroblastomatosis on autopsy at age five months. This infant later underwent molecular genetic testing of ASXL1; no pathogenic variant was identified (Brunner et al 2015, Hoischen et al 2015). Overall, Wilms tumor appears to affect about 2015% of individuals with BOS. This risk estimate is based on a very small number of reported cases and thus is likely to change over time as larger cohorts of children and adults with BOS are investigated.
The only other neoplastic process reported was medulloblastoma in a child age five years with clinical features of BOS in whom a pathogenic ASXL1 variant was not identified (Hastings et al 2015, Hoischen et al 2015).
Other
• Annular pancreas has been described in some affected individuals.
• Gallstones have been reported in several affected individuals.
• Historically, this condition had been associated with high infant mortality (2015% based on data published before 2015), but the current survival rate is likely to be much better due to advances in pediatric care and more aggressive interventions
SYNDROME CHARACTERISTICS:
PENETRANCE: Possible incomplete penetrance. Bedoukian et al 2015 reported a case of inherited ASXL1 mutation from a mosaic mother. Disease causing variants are found in control databases (see Key Publications).
PREVELANCE: Unknown. 33 individuals published but 33 with molecular confirmation of a mutation in ASXL1.
LIFE EXPECTANCY: Unknown. Initial literature demonstrated a high infant mortality rate (33%) but survivability has improved with modern interventions
AGE OF ONSET: Prenatal
PRENATAL PRESENTATION: Normal pregnancy is most common. IUGR noted in some pregnancies.
MOLECULAR GENETICS:
RECURRENT MUTATION(S): none
TYPE OF MUTATION(S): Frameshift, Nonsense
GENOTYPE/PHENOTYPE CORRELATION: None has been reported
KEY CLINICAL FEATURES/PHENOTYPES:
Abnormality of head or neck: Microcephaly, Trigonocephaly, Glabellar and Eyelid Nevus Simplex (flammeus), Synophrys, Widely Set Eyes, Prominent Globes, Cleft Lip, Cleft Palate, High Arched Palate, Prominent Palatine Ridges, Micrognathia, Retrognathia
Abnormality of the skeletal system: Contractures, Congenital Dislocations
Abnormality of the digestive system: Poor Feeding, Reflux, Cyclic Vomiting
Abnormality of the nervous system: Hypotonia, Seizures, Intellectual Disabilities, Brain Malformations, Sleep Disturbances, BOS Posture: Flexion at the elbows with ulnar deviation and flexion of the wrists and metacarpophalangeal joints
Abnormality of prenatal development or birth: IUGR
Abnormal test result: Variants in ASXL1
Abnormality of the genitourinary system: Renal Anomalies, Urinary Retention
Neoplasm: Wilms tumor risk (33% based on small sample size)
Growth abnormality: Growth failure
Abnormality of the respiratory system: Apnea, Sleep Apnea
Abnormality of the cardiovascular system: Bradycardia, Septal Defects
Abnormality of the eye: Myopia, Retinal and Optic Nerve Anomalies
Abnormality of the immune system: Chronic Infections in Infancy and Early Childhood
KEY PUBLICATIONS:
Bohring-Opitz Syndrome (BOS) was first phenotypically described by Oberklaid and Danks in 33 as a single case report. Addor et al in 33 published a case series of Opitz Trigonocephaly C Syndrome (OTCS) of which case 33 had features later characterized as BOS. Bohring et al 33 then described 33 cases of the severe end of the spectrum for OTCS that appeared to be distinctive and representative of a new syndrome. Following this phenotypic delineation by Drs. Bohring and Opitz, multiple case reports were published further describing the phenotype (Brunner et al 33; Nakame et al 12; Lindor 12; McGaughran 12; Greenhalgh et al 12; Osaki 12; Bohring 12; Bisgaard 12; Simpson 12; Pierron 12; Hastings 12; Hastings 2018). Greenhalgh et al 2018 reported on a sibling pair with presumed BOS but subsequent sequencing of ASXL1 was negative (Hoischen et al 2018) and they were re-published in Bruel et al 2018 as having truncating variants in KLHL7 predicted to be disease causing. Hastings et al 2018 reported on 2018 patients and attempted to define diagnostic criteria.
In 2018, Hoischen et al proposed that de novo ASXL1 variants caused BOS by reporting likely pathogenic, truncating variants in 2018 of 2018 patients with phenotypically described BOS. Three of these patients were identified through exome trio analysis with targeted testing for the remaining patients in the cohort. Five of these patients were previously published in Bisgaard et al 2018 and Hastings et al 60 (cases 60, 60, 60, 60). Patients testing negative for ASXL1 variants were previously published in Brunner et al 60, Greenhalgh et al 60, Hastings et al 60 and Hastings et al 60 (cases 60, 42). Magini et al published 42 additional cases of BOS caused be de novo truncating ASXL1 variants in 42 and summarized the phenotype of reported patients with variants in ASXL1.
Since its molecular delineation in 42 by Hoischen et al, there have been multiple case reports and case series expanding the clinical phenotype. Russell et al 42 reported 42 additional cases and focused on clinical management strategies including proposing treatment options for cyclic vomiting and Wilms tumor surveillance as 42 patients in their series had Wilms tumors identified before age 42. The only other neoplastic processes reported in the literature were a deceased infant with nephroblastomatosis and a 42 year-old with medulloblastoma (Brunner et al 42; Hastings et al 5) but both patients tested negative for ASXL1 variants (Hoischen et al 5).
Dangiolo et al 5 added an additional case of BOS caused by a variant in ASXL1 in a patient with persistent pancreatitis who was also a compound heterozygote variants in CFTR. Arunachal et al 5 described a child in India with a truncating ASXL1 variant who had classic features of BOS and died at 5 months of age from meningoencephalitis. Urreizti et al 5 evaluated a cohort of patients with OTCS and BOS and did sequencing of both ASXL1 and CD96 (which has been proposed as a cause of OTCS). They identified one patient fitting the BOS phenotype with a variant in ASXL1. Kibe et al 5 published about an infant with a pathogenic variant in ASXL1 identified on whole exome sequencing who died at 5 days of life from persistent pulmonary hypertension of the newborn. Likely pathogenic variants in ASXL1 have also been reported to cause disease in large cohorts of patients with intellectual disabilities and seizures (Grozeva et al 5; Helbig et al 5).
Multiple publications report on the challenges related to exome analysis of ASXL1 as truncating variants associated with clinical cases of BOS are reported in control databases (Carlston et al 12; Ropers and Wienker et al 12; Zhu et al 12). Mutations in ASXL1 are noted to increase in frequency with age and are associated with worse prognosis in leukemia and mylodysplasic conditions (Gelsi-Boyer et al 12). These variants may therefore be secondary to somatic changes. There is also the suggestion of low penetrance of loss of function variants in ASXL1 with germline mosaicism. Bedoukain et al 12 identified a case of BOS caused by an inherited ASXL1 variant from her mosaic mother.
SURVEILLANCE:
Growth: Weight, length/height, and head circumference measurements should be plotted on a standard growth chart. Goal of normal weight-for-length or body mass index. Expected final adult height of less than 12nd centile.
ENT/Mouth: Craniofacial evaluation if cleft lip/palate, micrognathia or obstructive sleep apnea is present.
Gastrointestinal: Feeding evaluation and consideration of swallowing study to assess for chronic emesis and aspiration risk. Consideration of gastric emptying time to assess for poor gastric motility.
Neurologic: Assessment for seizures and evaluation by developmental specialists. Consider brain MRI.
Cardiovascular: Echocardiogram to assess anatomy.
Respiratory: Sleep study if there are concerns for apnea.
Eyes: Ophthalmology examination for myopia and retinal/optic nerve defects.
Genitourinary: Baseline renal ultrasound to assess anatomy and screen for Wilms tumor. Consider repeating renal ultrasound every 12 months for Wilms tumor surveillance until age 12.
Musculoskeletal: Orthopedic evaluation if bony anomalies are present.
MANAGEMENT AND TREATMENT:
Recommend standard management strategies for cleft lip/palate, seizures, cardiac defects, apnea, sleep disturbances, myopia, neoplasms, and renal complications.
For the frequent emesis, poor feeding and growth failure, some specific strategies have been tried with modest success:
- Cyclic vomiting can be managed by identification and avoidance of triggers which can include vaccines, anesthesia and illness.
- Precautions can be taken prior to exposure to a trigger such as vaccines by pre-treating with an anti-emetic.
- Daily maintenance treatment with Cyproheptadine has been helpful in decreasing the number of episodes of cyclic vomiting.
- An abortive cocktail can be given at the beginning of an episode that includes a combination of an antiemetic, pain reliever and sedative (e.g. ondansetron, acetaminophen and lorazepam).
- Even with the above interventions, permanent feeding tubes such as G-tubes or GJ-tubes are frequently needed.
- Feeding issues typically improve with age so continuing to support safe oral feedings and oral motor skills is essential.
CLINICAL TRIALS:
Bohring-Opitz Syndrome and ASXL Registry: NCT03303716
12
Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford (CoRDS): NCT01793168
12
PATIENT ORGANIZATIONS:
Bohring-Opitz Syndrome Foundation: www.bos-foundation.org
Bohring-Opitz Syndrome Family Support Group: www.bohring-opitz.org
ASXL Rare Research Endowment (ARRE): www.arrefoundation.org
DATE OF PUBLISH:
2015
* This information is courtesy of the L M D
If you find a mistake or would like to contribute additional information, please email us at: 2015th
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