Cohen Syndrome

Clinical characteristics.

Cohen syndrome is characterized by failure to thrive in infancy and childhood; truncal obesity in the teen years; early-onset hypotonia and developmental delays; microcephaly developing during the first year of life; moderate to profound psychomotor retardation; progressive retinochoroidal dystrophy and high myopia; neutropenia in many with recurrent infections and aphthous ulcers in some; a cheerful disposition; joint hypermobility; and characteristic facial features.

Diagnosis/testing.

The diagnosis of Cohen syndrome is based on clinical findings, but no consensus diagnostic criteria exist. Identification of biallelic pathogenic variants in VPS13B (also known as COH1) on molecular genetic testing establishes the diagnosis if clinical features are inconclusive.

Management.

Treatment of manifestations: Spectacle correction of refractive errors, low-vision training for the visually impaired, and psychosocial support. Early intervention and physical, occupational, and speech therapy help address developmental delay, hypotonia, joint hyperextensibility, and motor clumsiness. Recurrent infections are treated per standard therapy; consideration should be given to use of granulocyte-colony stimulating factor (G-CSF) for the treatment of neutropenia.

Surveillance: Annual ophthalmologic and hematologic evaluations; monitor growth and weight gain.

Agents/circumstances to avoid: Caution should be used regarding medications with the potential to decrease the neutrophil count.

Genetic counseling.

Cohen syndrome is inherited in an autosomal recessive manner. Each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Offspring of an individual with Cohen syndrome are obligate heterozygotes (carriers). Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible if the pathogenic variants have been identified in an affected family member.

Suggestive Findings

Cohen syndrome should be suspected in individuals with the following findings [Chandler et al 2003a, Falk et al 2004, Kolehmainen et al 2004, Seifert et al 2006, El Chehadeh-Djebbar et al 2013]:

• Retinal dystrophy appearing by mid-childhood
• Progressive high myopia
• Acquired microcephaly
• Non-progressive intellectual disability and global developmental delay
• Hypotonia
• Joint hypermobility
• Typical Cohen syndrome facial gestalt: thick hair and eyebrows, long eyelashes, wave-shaped palpebral fissures, broad nasal tip, smooth or short philtrum, and hypotonic appearance
• Short stature
• Small or narrow hands and feet
• Truncal obesity appearing in or after mid-childhood
• Friendly disposition
• Neutropenia

Establishing the Diagnosis

The diagnosis of Cohen syndrome is established in a proband with at least six of the following eight cardinal features [Kolehmainen et al 2004] and/or by identification of biallelic pathogenic variants in VPS13B (COH1) on molecular genetic testing (see Table 1).

Cardinal features

• Retinal dystrophy and high myopia
• Microcephaly
• Developmental delay
• Joint hypermobility
• Typical Cohen syndrome facial gestalt
• Truncal obesity with slender extremities
• Overly sociable behavior
• Neutropenia

Molecular testing approaches can include the following:

• Single-gene testing begins with sequence analysis of VPS13B (COH1), followed by deletion/duplication analysis if only one or no pathogenic variant is found (see Table 1). Because of the high proportion of deletion and/or duplication alleles [Parri et al 2010, El Chehadeh-Djebbar et al 2011], it may be appropriate to perform sequence analysis and deletion/duplication analysis concurrently.
• Targeted analysis for pathogenic variants can be performed first in Old Order Amish or individuals of Finnish ancestry. Two founder pathogenic variants, c.8459T>C in exon 46 and 9258_9259insT in exon 51 have been identified in Old Order Amish. These variants are found in cis and segregate together, so either may be used for targeted variant testing. A 2-bp deletion (c.3348_3349delCT) accounts for 75% of pathogenic alleles in Finland [Kolehmainen et al 2003]. Some individuals of Finnish ancestry heterozygous for this 2-bp deletion were found to have a multiexon deletion on the other VPS13B allele [Balikova et al 2009]; thus, deletion/duplication analysis may be appropriate for affected individuals with only a single detectable VPS13B pathogenic variant.
• A multigene panel that includes VPS13B and other genes of interest (see Differential Diagnosis) may also be used. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Description

Phenotypic features of Cohen syndrome among the more than 200 affected individuals reported to date are variable and include progressive retinochoroidal dystrophy and myopia, acquired microcephaly, developmental delay, hypotonia, joint laxity, characteristic facial features, truncal obesity, cheerful disposition, and neutropenia.

Note: Certain statistics presented here are from National Cohen Syndrome Database (NCSD) in which approximately 50% of individuals are Old Order Amish; the diagnosis of Cohen syndrome has been confirmed by molecular genetic testing in the vast majority of individuals.

Ophthalmologic. Individuals with Cohen syndrome had a first ophthalmologic visit and were prescribed their first pair of glasses at an average age of 4.5 years. Defective dark adaptation/night blindness (nyctalopia) was typically noticed after age seven years. However, studies of younger individuals with Cohen syndrome demonstrate that abnormal retinal findings and ERG changes are present much earlier in life [Kivitie-Kallio et al 2000, Chandler et al 2002]. The studies further show that the two most prominent ophthalmologic findings, myopia and retinal dystrophy, markedly progress in severity over time with many individuals developing a bull’s eye maculopathy.

The progressive myopia and late-onset lens subluxation that occur in some individuals result from progressive laxity of zonules and progressive rounding up of the lens (spherophakia). Older individuals can have tremulousness of the iris (iridodonesis) because of lens subluxation and/or microspherophakia.

More than 70% of individuals in the NCSD fall often or trip easily, most likely because of constriction of peripheral visual fields secondary to retinal degeneration. Among ten individuals from nine families of Italian heritage with Cohen syndrome, 90% had retinal dystrophy and 80% had high myopia [Katzaki et al 2007]. Twenty percent of individuals in the Greek cohort developed blindness [Douzgou & Petersen 2011, Douzgou et al 2011], although progression to complete blindness has not been reported in other ethnic groups to the authors’ knowledge.

Other reported ophthalmic features include astigmatism, strabismus, microcornea, microphthalmia, sluggish pupillary reaction, iris atrophy and oval pupil, cataracts, optic atrophy, bull’s-eye maculopathy, coloboma of the retina or lids, congenital ptosis, and exophthalmos [Taban et al 2007]. Corneal changes and early-onset cataracts are frequently observed in individuals of Greek ancestry, but not in other ethnic groups [Douzgou & Petersen 2011, Douzgou et al 2011]. A few individuals have developed retinal detachments [E Traboulsi, personal observation].

Microcephaly develops during the first year of life and continues into adulthood. Although 80% of mothers providing data to the NCSD reported that their infants had a small head size at birth, the average birth head circumference (35 cm) was in fact in the 50^th centile. Earlier studies also reported normal head circumference at birth [Kivitie-Kallio & Norio 2001, Chandler et al 2003a, Hennies et al 2004].

Developmental. All children with Cohen syndrome have delayed developmental milestones in the first year of life. Analysis of individuals in the NCSD showed fairly consistent findings on certain developmental milestones compared with other cohorts with Cohen syndrome (Table 2) [Kivitie-Kallio & Norio 2001, Chandler et al 2003a, Nye et al 2005]. Overall, children with Cohen syndrome attain developmental milestones at a rate slower than average (Table 2), and once achieved, psychomotor skills do not regress. All but one of the individuals in the NCSD is able to walk without assistance, but at least 20% are unable to communicate verbally. The degree of developmental delay varies considerably, even among sibs [Horn et al 2000].

Hypotonia. Half of mothers whose children are included in the NCSD recalled reduced fetal movement during an otherwise normal pregnancy. Infants with Cohen syndrome frequently have feeding and breathing difficulties during the first days of life, likely related to hypotonia. The majority of newborns with Cohen syndrome are hypotonic. Hypotonia is present in all infants by age one year [Kivitie-Kallio & Norio 2001] and appears to improve over time regardless of intervention. The mechanism of hypotonia is unknown but speculated to be of central nervous system origin [Kivitie-Kallio et al 1998].

Joint laxity and additional musculoskeletal features including kyphosis, scoliosis, and pes planovalgus are most likely the consequence of hypotonia. The relatively disease-specific motor clumsiness appears to be quite common [Kivitie-Kallio et al 2000, Chandler et al 2003a].

Distinctive facial features have been described in different ethnic populations. Features include hypotonic facies, thick hair, low hairline, high-arched and wave-shaped eyelids, long and thick eyelashes, thick eyebrows, prominent nasal root, high and narrow palate, smooth or short philtrum, and prominent upper central incisors; the latter two together result in an open-mouth appearance. Lack of the frontonasal angle, together with a short philtrum, made the nose appear "overly long" in a cohort from Greece [Bugiani et al 2008]. Horn et al [2000] and Falk et al [2004] also found that although quite consistent among affected individuals within a particular ethnic group, facial gestalt appears to be inconsistent across ethnic populations. However, taking into consideration that reported individuals with Cohen syndrome are evaluated by different clinicians, the distinctive facial features that are shared by individuals from different ethnic backgrounds are fairly impressive. In fact, a significant number of parents in the NCSD noted distinct facial features in their children and discussed them with clinicians as the first clues leading to the late diagnosis of Cohen syndrome.

Systematic anthropometric and cephalometric analysis of 14 individuals confirmed microcephaly, short philtrum, forward-inclined upper incisors, and maxillary prognathia [Hurmerinta et al 2002]. Long-term evaluation of six individuals with Cohen syndrome from three consanguineous families showed that the clinical features are stable over time [Peeters et al 2008].

Endocrine and obesity. Children with Cohen syndrome tend to manifest failure to thrive in infancy and early childhood, but subsequently become significantly overweight in their teenage years. More than 80% of individuals in the NCSD were reported to be underweight during early childhood, but overweight afterward. The obesity tends to be truncal in nature. The average age of the onset of obesity is 11.3 years (14.6 years in individuals of Amish descent and 8.4 years in individuals of non-Amish ancestry). The authors have noted that this change usually occurs very rapidly, with a weight gain of 10-15 kg seen over a period of four to six months. In contrast to Prader-Willi syndrome, appetite and food intake are not increased during this time period and activity is not noticeably decreased.

Among individuals in the NCSD, the prevalence of short stature is approximately 65% and delayed puberty 74%; clinical endocrinologic evaluations did not identify explanations for these findings. Adult height in six affected individuals from three families was at or below the 3^rd centile, with body mass index (BMI) ranging from 20.1 to 30.8 [Peeters et al 2008]. A study of ten affected individuals from nine families ranging in age from five to 52 years found short stature in seven and truncal obesity in eight; BMI ranged from 21.8 to 32.2 [Katzaki et al 2007]. Extensive endocrine evaluations of pituitary, adrenal, and thyroid function in the cohort of Finnish descent showed no significant abnormalities [Kivitie-Kallio et al 1999a].

Growth hormone deficiency was reported in a girl who was clinically diagnosed with Cohen syndrome [Massa et al 1991] but whose phenotype differed considerably from that seen in individuals with genetically confirmed Cohen syndrome. Three other individuals with Cohen syndrome who had growth hormone deficiency displayed catch-up growth following initiation of growth hormone replacement therapy [Author, personal observation]. The prevalence of growth hormone deficiency in Cohen syndrome is unknown.

Psychological and behavioral. Individuals with Cohen syndrome are typically described as having a "cheerful and friendly disposition."

While cognitive ability varies, the majority of affected individuals fall into the moderate-to-profound range of intellectual disability [Kivitie-Kallio et al 1999b, Chandler et al 2003b, Karpf et al 2004]. Independence levels are generally poor but socialization skills are relatively less impaired; indeed, sociability is characteristic of individuals with Cohen syndrome. In contrast, psychological evaluations performed in previous studies have identified maladaptive and autistic-type behavior in some individuals [Kivitie-Kallio et al 1999b, Chandler et al 2003b, Karpf et al 2004]. Detailed psychometric and behavioral analyses did not identify any severe behavioral problems in six affected adults but confirmed a wide range of dysfunction related to individual degree of intellectual and visual disability [Peeters et al 2008].

Hematologic. Neutropenia, defined as an absolute neutrophil count (ANC) lower than 1,500/mm³ is mild to moderate, non-cyclic, and usually not fatal [Kivitie-Kallio et al 1997; Author, unpublished data]. However, recurrent infections and aphthous ulcers have been described in affected individuals [Falk et al 2004] (see Immunologic and rheumatologic, following). ANC usually falls into the range of 500 to 1,200/mm³ in all age groups [Author, unpublished data]. Furthermore, low-normal neutrophil counts are common in individuals who do not have frank neutropenia. However, the neutropenia may not necessarily result in an overall low white blood cell count and therefore may be overlooked for many years in some individuals.

More than 65% of affected individuals experience repeated oral mucosal ulcers and gingival infections, prophylactic granulocyte colony-stimulating factor (G-CSF) therapy has been commonly used in these individuals. The etiology of the neutropenia remains unclear. Bone marrow examination performed by the Finnish groups showed a normocellular or hypercellular marrow, with a left-shifted granulopoiesis in about half of those affected. No hematologic malignancies have been reported.

Immunologic and rheumatologic. While neutropenia may contribute to the compromise of immune function in some individuals with Cohen syndrome, it is not clear if it is the sole cause of the dysfunction. More than 80% of children in the NCSD have had more than five episodes of otitis media per year and most of them had tympanostomy tubes placed during early childhood. The majority of children also had an average of 2.5 lifetime episodes of pneumonia.

The frequency and severity of infections in individuals with Cohen syndrome appears to correlate poorly with ANC; individuals with frequent infections have an ANC in the same range as those without increased infections (500-1,200/mm³). Increased neutrophil adhesive capability has been reported in an individual with Cohen syndrome [Olivieri et al 1998].

Other immune disturbances have been observed: De Ravel et al [2002] found rheumatoid arthritis in an individual with Cohen syndrome, and frequent uveitis and recurrent pericarditis have been seen in affected individuals [H Wang, personal observation].

Musculoskeletal. Individuals with Cohen syndrome have characteristic narrow hands and feet, and slender fingers that have frequently been falsely reported to be long. The fingers are in fact short, as shown by hand x-ray analysis of the metacarpophalangeal pattern [Kivitie-Kallio et al 1999a].

Neurologic. Seizures have been reported in a minority of individuals with Cohen syndrome [Coppola et al 2003, Atabek et al 2004]. Anecdotally, two individuals in the NCSD cohort with epilepsy requiring anticonvulsants have phenotypes at the more severe end of the Cohen syndrome spectrum, characterized by an inability to communicate verbally. Most individuals, however, particularly those older than age five years in the Finnish cohort, were reported to have low-voltage EEGs without irritative spikes or epileptiform foci [Kivitie-Kallio et al 1999b].

Magnetic resonance imaging (MRI) of 18 individuals with Cohen syndrome found normal gray and white matter signal intensity but a relatively enlarged corpus callosum compared to 26 controls [Kivitie-Kallio et al 1998], although this abnormal finding appeared to be subtle and nonspecific.

Electromyography is reported to be normal [Kivitie-Kallio et al 1999b].

Cardiovascular. The cardiovascular system is not commonly affected in individuals with Cohen syndrome. An earlier report of mitral valve prolapse in individuals with Cohen-like syndrome of Ashkenazi Jewish ancestry [Sack & Friedman 1980] (see Differential Diagnosis) may be referring to another syndrome. Cardiac evaluation in 22 individuals of Finnish descent identified decreased left ventricular function with advancing age but no evidence for clinically significant mitral valve prolapse [Kivitie-Kallio et al 1999a]. Of the approximately 20 individuals in the NCSD who have had echocardiograms, none showed evidence of mitral valve prolapse.

Other. A majority of infants with Cohen syndrome (95% of those of Amish ancestry and 65% of non-Amish) have an unusually high-pitched and weak cry. Overall, 80% of parents with children in the NCSD recall this cry as resembling a kitten mewing. However, this unique cry is frequently overlooked by clinicians and has not been reported in the medical literature. The cause of the unusual cry in Cohen syndrome remains unknown, although laryngeal abnormalities postulated to cause the "mewing cry" seen in cri-du-chat syndrome have also been found in some individuals with Cohen syndrome [Chandler et al 2003a].

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

Nomenclature

Cohen et al [1973] described a pattern of abnormalities – intellectual deficiency, hypotonia, obesity, high nasal bridge, and prominent central incisors – observed in a pair of sibs and one unrelated individual.

Norio et al [1984] observed six individuals of Finnish descent with the same disorder, known by them as "Pepper syndrome," from the family name. They identified consanguinity among two pairs of parents (confirming autosomal recessive inheritance for this disorder), intermittent granulocytopenia, and marked ophthalmologic changes including decreased visual acuity, hemeralopia (day blindness), constricted visual fields, chorioretinal dystrophy with bull's-eye-like maculae and pigmentary deposits, optic atrophy, and isoelectric electroretinogram.

Prevalence

About 200 individuals have been reported in the literature since the first description by Cohen et al [1973]. The disorder has been confirmed on almost all continents and in a wide variety of ethnic groups [Falk et al 2004, Hennies et al 2004, Kolehmainen et al 2004, Mochida et al 2004, Kondo et al 2005, Katzaki et al 2007, Taban et al 2007, Bugiani et al 2008, Peeters et al 2008, Balikova et al 2009].

There is little doubt that Cohen syndrome is one of the more commonly underdiagnosed conditions. An early study by Rauch et al [2006] indicated that Cohen syndrome accounted for approximately 0.7% of 1070 individuals with unexplained developmental delay or intellectual disability, ranking it as the fifth most common diagnosis, immediately after fragile X syndrome (1.2%). A recent study of 2000 consecutive undiagnosed individuals who had undergone clinical exome sequencing identified two individuals with Cohen syndrome among 504 individuals who received a molecular diagnosis during the study [Yang et al 2014].

Cohen syndrome is overrepresented in the Finnish population [Kolehmainen et al 2003], with more than 35 individuals diagnosed in Finland to date. The Finnish phenotype is comparable to that seen in individuals of non-Finnish descent [Chandler et al 2003a].

Cohen syndrome is overrepresented in the Amish population. Since the first report of Cohen syndrome in the Ohio Geauga Old Order Amish settlement in 2004 [Falk et al 2004], more than 30 affected individuals have been identified in this highly consanguineous, isolated population of approximately 15,000, indicating a prevalence as high as one in 500 and providing evidence for a founder effect.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Cohen syndrome, the following evaluations are recommended:

• Ophthalmologic evaluation to assess visual acuity, position and size of the lens, refractive error, and severity of the retinal dystrophy
• Developmental assessment
• Hematologic evaluation including a white blood cell count with differential to identify neutropenia
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Ophthalmologic issues are among the most concerning for families of individuals with Cohen syndrome registered in the National Cohen Syndrome Database. Management includes the following:

• Spectacle correction of refractive errors
• Low vision assessment with training as needed for the visually impaired
• Psychosocial support for affected individuals and their families

Early intervention and physical, occupational, and speech therapy are appropriate to address gross developmental delay, hypotonia, joint hypermobility, and motor clumsiness.

If neutropenia is documented, consideration may be given to the use of granulocyte-colony stimulating factor (G-CSF). In a study reported by Kivitie-Kallio et al [1997] response to adrenaline stimulation and to hydrocortisone was subnormal in 12 of 14 individuals and in eight of 16 individuals, respectively. However, recombinant G-CSF, administered to three individuals in the study, caused granulocytosis in all three.

Recurrent infections should be treated per standard therapy.

Surveillance

Annual ophthalmologic evaluation should assess visual acuity, refractive error, cataracts in older individuals, and/or retinal dystrophy.

Annual hematologic evaluation should include complete blood count and differential to assess neutropenia. More frequent monitoring may be needed for individuals with lower ANC or more frequent infections.

Growth and weight gain should be monitored.

Agents/Circumstances to Avoid

Caution should be used regarding medications with the potential to decrease the neutrophil count.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Anecdotal reports notwithstanding, pycnogenol, a standard French maritime pine bark extract effective in improving visual acuity in retinal vascular leakage conditions [Schönlau & Rohdewald 2001, Spadea & Balestrazzi 2001], has not proven an effective treatment for the retinal dystrophy in Cohen syndrome.