Brachycephaly, Deafness, Cataract, Microstomia, and Mental Retardation

What is Brachycephaly, Deafness, Cataract, Microstomia, and Mental Retardation?

Brachycephaly, Deafness, Cataract, Microstomia, and Mental Retardation is a rare disease. It is also known as Fine-lubinsky Syndrome.

DISEASE OVERVIEW:
There are not minimum diagnostic criteria for the Fine-Lubinsky syndrome (FLS). However, Corona-Rivera et al. (2009) identified the following as key signs for diagnosis: non-synostotic brachycephaly or plagiocephaly, structural brain anomalies, abnormal EEG, developmental delay/mental retardation, hearing deficit, ocular abnormalities (cataracts, megacornea or glaucoma), peculiar facies (high/wide forehead, shalloworbits, flat/round face, low-set posteriorly rotated ears, microstomia), and congenital body asymmetry. Autosomal recessive inheritance has been suggested in a family with affected siblings (Schoner et al., 2008), but this is uncertain because most FLS cases have been sporadic. The causative gene or genetic defect remains undetermined.

CLINICAL DESCRIPTION:
All patients with FLS were born from full-term pregnancies and, excluding the reports of Fine and Lubinsky (1983) and Holder et al. [2007] they showed intrauterine growth retardation.
Major neurological abnormalities of the syndrome include large ventricles, cerebral atrophy, hypoplasia or agenesis of the corpus callosum, seizures, abnormal EEG, hypotonia, and developmental delay. Psychomotor retardation was severe in two patients (Fine and Lubinsky, 1983; Corona-Rivera et al., 2009).
Epileptic syndrome can include myoclonic seizures or West syndrome (Preus et al., 1984; Corona-Rivera et al., 2009).
The hearing deficit indicates a sensorineural hearing loss (Preus et al., 1984; Corona-Rivera et al., 2009).
Congenital body asymmetry constitutes an important feature seen in FLS patients, and involving mainly the head, face and trunk (Fine and Lubinsky, 1983; Schoner et al., 2008; Corona-Rivera et al., 2009).
Craniosynostosis is not an excluding feature in this entity because has been reported in at least one FLS patient (Holder et al., 2007).

SYNDROME CHARACTERISTICS:
PENETRANCE: Unknown
PREVALENCE: There are only seven reported patients with clinical diagnosis of FLS and thus, its prevalence is uncertain.
LIFE EXPECTANCY: Life expectancy is unknown. All reported individuals were living at time of publication, excepting for a female fetus reported after an elective termination of pregnancy.
AGE OF ONSET: Age of diagnosis ranges from 24 weeks of gestations to 20 years. 
PRENATAL PESENTATION: Schoner et al. (2008) reported a fetal presentation of FLS in a fetus with polyhydramnios, microbrachycephaly, flat face, cataracts, rocket bottom feet and syndactyly of toes. Termination of pregnancy was performed at 24 weeks and autopsy added brachycephaly without craniosynostosis, microstomia, Robin sequence, bilateral macrocornea and unilateral cataract.

MOLECULAR GENETICS:
RECURRENT MUTATION(S): N/A
TYPE OF MUTATION(S): N/A
GENOTYPE/PHENOTYPE CORRELATION: N/A

KEY CLINICAL FEATURES/PHENOTYPES:
Abnormality of the head and neck
Wormian bones
Brachycephaly/plagiocephaly (Reported in 6/7 patients [86%])
Craniosynostosis (Reported in 1/7 patients [14%])
Large/wide fonatanelles (Reported in 3/3 patients [100%])
High forehead (Reported in 4/6 patients [67%])
Prominent frontal bone (Reported in 5/5 patients [100%])
Flat face (Reported in 6/6 patients [100%])
Asymmetric face (Reported in 3/5 patients [60%])
Low-set ears (Reported in 5/7 patients [71%])
Small ears (Reported in 2/6 patients [33%])
Posteriorly rotated ears (Reported in 4/6 patients [67%])
Stenotic external auditory canals (Reported in 2/3 patients [67%])
Hearing loss/deafness (Reported in 6/6 patients [100%])
Shallow orbits (Reported in 5/6 patients [83%])
Ocular hypertelorism (Reported in 1/4 patients [25%])
Down-slating palpebral fissures (Reported in 3/6 patients [50%])
Long eyelashes (Reported in 2/2 patients [100%])
Megalocornea/glaucoma (Reported in 3/6 patients [50%])
Cataracts (Reported in 3/7 patients [43%])
Sight loss/blindness (Reported in 2/7 patients [29%])
Flat/depressed nasal bridge (Reported in 4/7 patients [57%])
Small nose (Reported in 4/6 patients [67%])
Microstomia/small mouth (Reported in 5/73 patients [71%])
Long philtrum (Reported in 2/4 patients [50%])
Thin upper lip (Reported in 3/5 patients [60%])
Cleft palate (Reported in 3/7 patients [43%])
Abnormality of prenatal development or birth
Low birth weight (Reported in 4/7 patients [57%])
Growth abnormality
Postnatal growth retardation (Reported in 5/6 patients [83%])
Abnormality of the nervous system
Mental retardation/developmental delay (Reported in 6/6 patients [100%])
Hypotonia (Reported in 3/3 patients [100%])
Seizures (Reported in 3/6 patients [50%])
Abnormal EEG (Reported in 3/4 patients [75%])
Hypoplasia of corpus callosum (Reported in 2/5 patients [40%])
Hydrocephaly/large ventricles (Reported in 4/5 patients [80%])
Cerebral atrophy (Reported in 3/4 patients [75%])
Abnormality of the connective tissue
Inguinal hernia
Abnormality of the skeletal system
Scoliosis (Reported in 2/2 patients [100%])
Asymmetric thorax (Reported in 2/3 patients [67%])
Abnormality of limbs
Prominent heels/rockerbottom feet (Reported in 5/6 patients [83%])
Clinodactyly (Reported in 4/6 patients [67%])
Tapered fingers (Reported in 4/4 patients [100%])
Camptodactyly (Reported in 4/4 patients [100%])
Brachydactyly (Reported in 2/2 patients [67%])
Abnormality of the digestive system
Poor feeding
Pyloric stenosis
Abnormality of the genitourinary system
Cryptorchidism (Reported in 2/4 patients [50%])
Abnormality of the skin
Nevus
Verrucous hemangioma (Reported in 1/7 patients [14%])
Abnormal nails (Reported in 3/6 patients [50%])
Prominent fetal finger pads

KEY PUBLICATIONS:
In 1983, Fine and Lubinsky described a severely malformed male infant who had unusually asymmetric shaped head ––flattened in the sagittal plane with a very high forehead creating a round, plate-like appearance, resembling a Kleeblattschädel skull, but without evidence of craniosynostosis on X-rays and cranial CT. He also had ventriculomegaly due to aqueductal stenosis, and absence of the corpus callosum, besides to small and low-set ears, superior helical pits, megacornea and glaucoma on the left eye and cataract on the rigth eye; cleft palate, scoliosis, micropenis, cryptorchidism, hypoplastic scrotum, severe growth and developmental delay, and congenital body asymmetry. Preus et al. (1984) reported a two-year-old male with delayed development, small nose, mouth, and ears; submucous cleft palate, sensorineoural hearing loss, mild hypotonia, and seizures. Suthers et al. (1993), reported a boy with marked brachycephaly without coronal synostosis, deafness, flat face, cataract, microstomia, camptodactyly and mental retardation, and additionally he showed hydrocephaly with raised intracranial pressure required a ventriculo-peritoneal shunt. Aymé and Philip (1996) reported a female patient with brachycephaly, deafness, cataract, microstomia and mental retardation and proposed this phenotype as the same reported by Fine and Lubinsky (1983), Preus et al. (1984), and Suthers et al. (1993), and coined the eponymous term of Fine–Lubinsky syndrome (FLS) to refer to this pattern of defects.

Holder et al. (2007) reported a pair of siblings with FLS and suggested an autosomal recessive inheritance for this entity. Both presented with abnormal calvaria, prominent frontal bones, flat facial profile, small nose, microstomia, developmental delay, permanence of decidual teeth, and abnormal digits –including camptodactyly, short tapered fingers, brachydactyly, fifth finger clinodactyly, and dystrophic nails. Patient 1 had an occipital encephalocele, bicoronal craniosynostosis and normal hearing and the search for telomere FISH study, array-based comparative genome hybridization analysis, and targeted mutations analyses for FGFR2, FGFR3, TWIST1 genes and Fragile X testing yielded normal or negative results. Radiologically, cranial sutures had normal appearance in the patient 2, in which a mild to moderate sensorineural hearing loss was also found. None of them had cataracts. On the patient 1 of Holder et al. (2007). Cole et al. (2010) re-publisehed the patient 1 and review the management of FLS and added the finding of fibrous dysplasia of the lesser sphenoid wing. Schoner et al. (2008) performed the prenatal diagnosis in a female fetus with FLS focusing to those features apparent in early development. These include growth deficiency, brachycephaly, flat asymmetric face with shallow orbits and hypoplasia of facial bones, hypoplastic nose, long philtrum, microstomia, cleft palate, low set dysmorphic ears, brachydactyly, rocker-bottom feet, and even cataract.

Historically, two patients diagnosed as FLS (Aymé and Philip, 1996; Nakane et al., 2002), were later re-classified as having Aymé-Gripp syndrome or congenital cataracts, sensorineural deafness, Down syndrome-like facial appearance, short stature, and mental retardation syndrome (OMIM: #601088). It is now clear that patients with AGS constitute a different entity caused by dominant mutations in MAF gene (Niceta et al., 2015) (OMIM *177075).

Consequently, only the reports of Fine and Lubinsky (1983), Preus et al. (1984), Suthers et al. (1993), Holder et al. (2007), Schoner et al. (2008), and Corona-Rivera et al. (2009) can be included as examples of the FLS. There is no consensus regarding the minimum diagnostic criteria for the FLS, due in part by the variable expressivity on the reduced number of patients and also, because the causative genetic defect remains indeterminate. Corona-Rivera et al. (2009) identified the following as key signs for diagnosis: non-synostotic brachycephaly or plagiocephaly, structural brain anomalies, abnormal EEG, developmental delay/mental retardation, hearing deficit, ocular abnormalities (cataracts, megacornea or glaucoma), dysmorphic features (high/wide forehead, shallow orbits, flat/round face, low-set posteriorly rotated ears, microstomia), and body asymmetry.

SURVEILLANCE:
Cataracts can be an age-dependent manifestation, and besides to glaucoma constitutes important ocular features that can be related to a severe loss of sight (Fine and Lubinsky, 1983; Schoner et al., 2008; Corona-Rivera et al., 2009).

MANAGEMENT AND TREATMENT:
There are no curative treatments for FLS. Management is targeted toward the affected system and can include:
- Evaluation and standard treatment for brain anomalies and exclusion of craniosynostosis by neuroimaging
- Evaluation and standard treatment for hearing deficits
- Ophthalmological evaluation and standard treatment for cataracts and glaucoma.
- Physical and occupational therapy for hypotonia and mental disabilities.

CLINICAL TRIALS:
N/A

PATIENT ORGANIZATIONS:
N/A


DATE OF PUBLISH:
03/21/18

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* This information is courtesy of the L M D.

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What gene changes cause Brachycephaly, Deafness, Cataract, Microstomia, and Mental Retardation?

The syndrome is inherited in the following inheritance pattern/s:

Autosomal Dominant - In the case of autosomal dominant inheritance, just one parent is the carrier of the gene mutation, and they have a 50% chance of passing it onto each of their children. Syndromes inherited in an autosomal dominant inheritance are caused by just one copy of the gene mutation.


Uncertain - The exact mode of inheritance was unknown at the time this entry was recorded.


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 that occurs during the reproductive process.

OMIM Number - 601353 (please check the OMIM page for updated information)

The syndrome can be caused by mutations in the following gene/s location/s:
N/A

What are the main symptoms of Brachycephaly, Deafness, Cataract, Microstomia, and Mental Retardation?

The typical symptoms of the syndrome are:
Malar flattening, Clinodactyly of the 5th finger, Facial asymmetry, Atresia of the external auditory canal, Finger syndactyly, Brachydactyly, Ventriculomegaly, Cryptorchidism, Downslanted palpebral fissures, Thin upper lip vermilion, Camptodactyly of finger, Rocker bottom foot, Sporadic, Scoliosis, Flat face, Camptodactyly, Seizure, Shallow orbits, Sensorineural hearing impairment, Thin vermilion border, Scrotal hypoplasia, Shawl scrotum, Superior pectus carinatum, Pectus excavatum of inferior sternum, Plagiocephaly, Posteriorly rotated ears, Intellectual disability, Intrauterine growth retardation, Narrow mouth, Short nose, Low-set ears, Long eyelashes, Low-set, posteriorly rotated ears, Long philtrum, Tapered finger, Microtia, Pectus excavatum, Megalocornea, Muscular hypotonia, High forehead, Broad forehead, Hypertelorism, Hearing impairment, Short stature, Short toe, Cognitive impairment, Growth delay, Global developmental delay, Depressed nasal bridge, Glaucoma, Visual impairment, Hypoplasia of the corpus

How does someone get tested for Brachycephaly, Deafness, Cataract, Microstomia, and Mental Retardation?

The initial testing for Brachycephaly, Deafness, Cataract, Microstomia, and Mental Retardation can begin with facial genetic analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the type of genetic testing needed. A consultation with a genetic counselor and then a geneticist will follow.

Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.

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