DiagnosisClinical DiagnosisWhile diagnostic criteria have been proposed by several groups based on studies of individuals with confirmed VPS13B (COH1) mutations, no clinically based diagnostic criteria have been widely accepted. Prior to identification of the associated gene VPS13B in 2003, Kivitie-Kallio & Norio [2001] and Chandler et al [2003a] identified a variety of clinical features most suggestive of Cohen syndrome including facial dysmorphism, pigmentary retinopathy, neutropenia, and neurologic abnormalities (psychomotor retardation, motor clumsiness, hypotonia, microcephaly).Subsequently, evaluation of individuals in different ethnic populations with known VPS13B mutations revealed that overall "facial gestalt" was an unreliable indicator of Cohen syndrome [Falk et al 2004]. However, specific facial features — thick hair and eyebrows, long eyelashes, wave-shaped palpebral fissures, bulbous nasal tip, smooth or shortened philtrum, and hypotonic appearance — were seen across ethnicities. In contrast to facial gestalt, features common to almost all individuals with VPS13B mutations appear to be better clinical indicators of Cohen syndrome: Retinal dystrophy appearing by mid-childhood Progressive high myopia Acquired microcephaly Non-progressive intellectual disability and global developmental delay Hypotonia Joint hypermobility Other features suggestive of Cohen syndrome are seen in a minority of individuals from various ethnic backgrounds with proven VPS13B mutations [Falk et al 2004]: Short stature Small or narrow hands and feet Truncal obesity appearing in or after mid-childhood Friendly disposition Non-cyclic granulocytopenia or low total white blood cell count with or without aphthous ulcers Kolehmainen et al [2004] studied 76 individuals from 59 families with a provisional diagnosis of Cohen syndrome to correlate molecular and clinical findings. Individuals were assessed for eight clinical criteria: High myopia and/or retinal dystrophy Microcephaly Developmental delay Joint hypermobility Typical Cohen syndrome facial gestalt Truncal obesity with slender extremities Overly sociable behavior Neutropenia Individuals fulfilling six or more criteria were considered likely to have "true Cohen syndrome." Those fulfilling five or fewer criteria were considered to have a provisional "Cohen-like syndrome." Using the above criteria, Kolehmainen et al [2004] found 22 different VPS13B mutations in probands identified as having "true Cohen syndrome." In addition, they identified another three novel mutations in individuals with incomplete clinical data. By contrast, no VPS13B mutations were found in individuals who only met the provisional diagnosis of "Cohen-like syndrome."The broad clinical spectrum of Cohen syndrome and difficulty establishing definitive clinical diagnostic criteria were confirmed by Seifert et al [2006], who identified 25 different VPS13B mutations in 24 ethnically diverse individuals ages two to 60 years. The "typical facial gestalt" was seen in 23/24 individuals. Early-onset progressive myopia was present in all individuals older than age five years (14/14) while widespread pigmentary retinopathy was found in 12/14. Some individuals did not have the characteristic facial gestalt and pigmentary retinopathy at school age. Development and growth parameters varied significantly. Similar variation has been reported more recently in affected persons across the age spectrum who are of Italian, Greek, and Dutch ancestry [Katzaki et al 2007, Bugiani et al 2008, Peeters et al 2008].Molecular Genetic TestingGene. VPS13B (also known as COH1) is the only gene in which mutations are known to cause Cohen syndrome. Clinical testingTargeted mutation analysis. The 2-bp deletion common in individuals of Finnish ancestry (c.3348_3349delCT) accounts for 75% of mutant alleles in Finland [Kolehmainen et al 2003]. Some individuals of Finnish ancestry heterozygous for this 2-bp deletion were found to have a multiexonic deletion on the other VPS13B allele; thus, deletion/duplication analysis may be appropriate for affected individuals with only a single detectable mutation.Sequence analysis of coding and associated intronic regions. Sequencing of all of the 62 exons is indicated for persons who do not have the common Finnish mutation or have ancestry of non-Finnish origin (see Molecular Genetics). Homozygous or compound heterozygous mutations are identified in approximately 70% of individuals with Cohen syndrome; only a single mutation is identified in another 18%; and no mutation in 12% [Balikova et al 2009, Seifert et al 2009].Deletion/duplication analysis. Both intragenic deletions and duplications of VPS13 were detected using a variety of test methods. Balikova et al [2009] screened for VPS13 deletions in 26 families in which the molecular basis of Cohen syndrome was unknown. In all families, affected members had at least six of the eight cardinal clinical findings. In eight families, affected individuals had one known heterozygous sequence variant; in 14 families, affected individuals had no known sequence variants; and in four families with affected individuals, molecular genetic testing had not been performed: Affected individuals from five families were found to be compound heterozygotes for a previously identified pathologic sequence variant and a multiexonic deletion. Four families of Finnish ancestry were heterozygous for the c.3348_3349delCT mutation and a multiexonic deletion. Affected individuals from two families were found to be homozygous for the same deletion.Parri et al [2010] studied 11 families in which sequence analysis failed to identify mutations in both alleles. In all families affected members had at least six of the eight cardinal clinical findings:Affected individuals from four families were found to be compound heterozygotes for a pathologic sequence variant and an intragenic multiexonic deletion. Affected individuals from three families were found to be compound heterozygotes for a pathologic sequence variant and an intragenic multiexonic duplication. An affected individual from one family was a compound heterozygote for two different intragenic multiexonic deletions.An affected individual from one family was homozygous for the same multiexonic deletion.Affected individuals from two families were heterozygous for a pathologic sequence variant and an unknown allele not detected by deletion/duplication analysis.Note: Four of the deletions involved exons 6-16 and appeared to be a common Mediterranean founder allele [Parri et al 2010].Table 1. Summary of Molecular Genetic Testing Used in Cohen SyndromeView in own windowGene Symbol Test MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityVPS13B (COH1)Targeted mutation analysis c.3348_3349delCT75% of mutant alleles in Finland 2, 3 Clinical Whole-gene sequence analysisSequence variants 4See footnotes 5, 6Deletion / duplication analysis 7Multiexonic intragenic deletions~42% of mutant alleles 6Multiexonic intragenic duplications1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Kolehmainen et al [2003]3. At least some of the remaining alleles are VPS13B deletions [Balikova et al 2009].4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. 5. Homozygous or compound heterozygous mutations are identified in approximately 70% of individuals with Cohen syndrome; only a single mutation is identified in another 18%; and no mutation in 12% [Balikova et al 2009, Seifert et al 2009].6. The study of Parri et al [2010] revealed 58% of alleles with pathologic sequence variants and 42% with copy number variations (either deletion or duplication). 7. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.Interpretation of test results. Because the mutations in VPS13B (COH1) are distributed throughout the gene, only sequencing of the entire gene can confirm a diagnosis of Cohen syndrome. For other issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo confirm/establish the diagnosis in a probandEvaluation for the eight cardinal findings. In those with at least six findings perform molecular genetic testing [Balikova et al 2009, Parri et al 2010].In persons of Finnish heritage, perform targeted mutation analysis for the common founder mutation, c.3348_3349delCT, which comprises at least 75% of mutant alleles in this population [Kolehmainen et al 2003]. If only one mutant allele is detected, deletion/duplication analysis should be performed.In individuals of other ethnic backgrounds, perform full VPS13B sequence analysis.If only one or no pathologic sequence variant is identified, perform deletion/duplication analysis. Because of the high proportion of deletion and/or duplication alleles [Table 1, Parri et al 2010], it may be appropriate to perform sequence analysis and deletion/duplication analysis concurrently. Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersNo other phenotypes are associated with mutations in VPS13B.}

Natural HistoryPhenotypic features of Cohen syndrome among the more than 150 affected individuals reported to date are variable and include moderate to severe psychomotor retardation, motor clumsiness, acquired microcephaly, childhood hypotonia and joint laxity, progressive retinochoroidal dystrophy and myopia, neutropenia, truncal obesity, a cheerful disposition, and generally, characteristic facial features. The following prominent clinical features of Cohen syndrome are presented by system.Note: Among individuals included in the National Cohen Syndrome Database (NCSD), the diagnosis of Cohen syndrome has been confirmed by molecular genetic testing primarily in those of Amish heritage; the diagnosis has been genetically confirmed in a limited number of individuals of other ethnic backgrounds.Perinatal. Half of mothers whose children are included in the NCSD recalled reduced fetal movement during an otherwise normal pregnancy. Although most infants were born at term (average gestational age: 38.5 weeks), average birth weight (2.5 kg) and length (47.8 cm) were in the 10^th to 25^th centile.
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].
A majority of infants with Cohen syndrome have an unusually high-pitched and weak cry which is seen in 95% of children of Amish ancestry and 65% of non-Amish children in the NCSD. Overall, 80% of parents with children in the NCSD database 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]. Craniofacial. Microcephaly develops during the first year of life and continues into adulthood. Although 80% of mothers providing data to the NCSD database 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].
Distinctive features have been variably 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] both concluded that although quite consistent among affected individuals within a particular ethnic group, facial gestalt appears to be inconsistent between ethnic populations.
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]. 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 siblings [Horn et al 2000]. Table 2. Timing of Achievement of Developmental Milestones in Cohen SyndromeView in own windowDevelopmental MilestoneAge at Milestone AchievementFinnish Cohort 1 English Cohort 2 NCSD (US) Cohort 3 Roll over4-12 months—7 monthsSit independently10-18 months12 months11 monthsWalk independently2-5 years2.5 years2.5 yearsSpeak first words1-5 years2.5 years3.2 yearsSpeak in sentences5-6 years5 years4.2 years1. Kivitie-Kallio & Norio [2001] 2. Chandler et al [2003a] 3. Nye et al [2005]Ophthalmologic. The range of ophthalmologic findings first identified in affected individuals of Finnish descent included decreased visual acuity, night blindness, constricted visual fields, chorioretinal dystrophy with bull's-eye-like maculae and retinal pigmentary deposits, optic atrophy, and abnormal (isoelectric) electroretinogram (ERG) [Norio et al 1984].
Many of the same ophthalmologic findings have since been confirmed in individuals of non-Finnish descent. Individuals registered in the NCSD 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 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. Progression to complete blindness has not been reported even among individuals with Cohen syndrome who are in their 60s.
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].
Other reported ophthalmic features include astigmatism, strabismus, microcornea, microphthalmia, sluggish pupillary reaction, iris atrophy and oval pupil, lens opacities, optic atrophy, bull’s-eye maculopathy, coloboma of the retina or lids, congenital ptosis, and exophthalmos [Taban et al 2007]. Endocrine and metabolism. Among individuals in the NCSD, the prevalence of short stature is approximately 65%, delayed puberty 74%, and obesity 60%; 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.
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.Hematologic. Neutropenia, defined as an absolute neutrophil count (ANC) lower than 1,500/mm³, was initially documented in individuals of Finnish ancestry [Norio et al 1984] and later found in many individuals with Cohen syndrome who were not of Finnish descent [De Ravel et al 2002b, Chandler et al 2003a]. The neutropenia 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 some 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.
More than 65% of affected individuals experience repeated oral mucosal ulcers and gingival infections, with at least three individuals known to require prophylactic granulocyte colony-stimulating factor (G-CSF) therapy.
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. 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.
Whether other hematologic findings reported in clinically diagnosed individuals —including combined deficiency of protein C, protein S, and antithrombin III causing venous thrombosis in one individual [Schlichtemeier et al 1994] and asymptomatic thrombocytopenia in another [De Ravel et al 2002b] — are present in individuals with molecularly confirmed Cohen syndrome remains to be determined. 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 seems to correlate poorly with ANC; affected individuals are generally more symptomatic than non-affected individuals with an ANC in the same range (500-1,200/mm³). The authors have also observed that when treated with immunomodulators, some individuals with Cohen syndrome appear to have significantly fewer oral ulcers with no change in ANC. Indeed, 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 [2002a] found rheumatoid arthritis in an individual with Cohen syndrome. In addition to rheumatoid arthritis, frequent uveitis and recurrent pericarditis have been seen in affected individuals [Wang, personal observation]. 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].
Childhood hypotonia, one of the most common features in Cohen syndrome, seems 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].
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, further study is warranted.
Electromyography (EMG) is reported to be normal [Kivitie-Kallio et al 1999b]. Musculoskeletal. Joint hypermobility, 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].
Individuals with Cohen syndrome have characteristic narrow hands and feet, and slender fingers that have frequently been falsely reported to be long. In fact, the fingers are short, as shown by hand x-ray analysis of the metacarpophalangeal pattern [Kivitie-Kallio et al 1999a].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].Cardiovascular. The cardiovascular system is not commonly affected in individuals with Cohen syndrome. Mitral valve prolapse has been reported in individuals with Cohen-like syndrome of Ashkenazi Jewish ancestry [Sack & Friedman 1980] but not in individuals with classic Cohen syndrome who have documented VPS13B mutations. 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.
Similarly, while carotid aneurysms and tortuous descending aortas have been reported in the literature [Schlichtemeier et al 1994], they have not been found in individuals with a confirmed VPS13B mutation.

Genotype-Phenotype CorrelationsNo genotype-phenotype correlations have been identified.

Differential DiagnosisThe lack of widely accepted clinically based diagnostic criteria combined with a high cost of clinical laboratory testing for Cohen syndrome are some of the barriers to accurate diagnosis. However, many of the disorders in the differential diagnosis can be diagnosed by molecular genetic testing.Individuals with Cohen syndrome are often suspected of having the following disorders:Prader-Willi syndrome (PWS) is characterized by severe hypotonia and feeding difficulties in early infancy, followed in later infancy or early childhood by excessive eating and, unless eating is externally controlled, gradual development of morbid obesity. All individuals have some degree of cognitive impairment. A distinctive behavioral phenotype (with temper tantrums, stubbornness, manipulative behavior, and obsessive-compulsive characteristics) is common. Hypogonadism is present in both males and females. PWS is caused by absence of the paternally derived PWS/AS region of chromosome 15 by one of several genetic mechanisms. The mainstay of diagnosis is DNA-based methylation testing to detect abnormal parent-specific imprinting within the Prader-Willi critical region (PWCR); this testing identifies more than 99% of affected individuals. Angelman syndrome (AS) is characterized by severe developmental delay or intellectual disability, severe speech impairment, gait ataxia and/or tremulousness of the limbs, and a unique behavior with an inappropriate happy demeanor that includes frequent laughing, smiling, and excitability. Microcephaly and seizures are common. AS is caused by the loss of the maternally imprinted contribution in the 15q11.2-q13 (AS/PWS) region that can occur by one of at least five different known genetic mechanisms. Molecular genetic testing (methylation analysis and UBE3A sequence analysis) identifies alterations in about 90% of individuals. Bardet-Biedl syndrome (BBS) is characterized by cone-rod retinal dystrophy, truncal obesity, postaxial polydactyly, cognitive impairment, male hypogonadotrophic hypogonadism, complex female genitourinary malformations, and renal dysfunction. The visual prognosis for children with Bardet-Biedl syndrome is poor: night blindness is usually evident by age seven to eight years; the mean age at which affected individuals become legally blind is 15.5 years. Birth weight is usually normal; significant weight gain begins within the first year and becomes a lifelong issue for most individuals. A majority of individuals have significant learning difficulties, but only a minority demonstrate severe cognitive impairment on IQ testing. Renal disease is a major cause of morbidity and mortality. The diagnosis of Bardet-Biedl syndrome is established by clinical findings. Mutations in at least 14 genes are known to be associated with Bardet-Biedl syndrome. Inheritance is autosomal recessive. Cri-du-chat syndrome (OMIM 123450) is a multiple congenital anomaly syndrome involving microcephaly and a cat-like cry. It is caused by deletions of chromosome 5p. Williams syndrome (WS) is characterized by cardiovascular disease (elastin arteriopathy, peripheral pulmonary stenosis, supravalvular aortic stenosis, hypertension), distinctive facies, connective tissue abnormalities, intellectual disability (usually mild), a specific cognitive profile, unique personality characteristics, growth abnormalities, and endocrine abnormalities (hypercalcemia, hypercalciuria, hypothyroidism, and early puberty). Hypotonia and hyperextensible joints can result in delayed attainment of motor milestones. More than 99% of individuals with the clinical diagnosis of WS have a contiguous gene deletion of the Williams-Beuren syndrome critical region (WBSCR) encompassing ELN, the gene encoding elastin; the deletion can be detected using fluorescent in situ hybridization (FISH) or targeted mutation analysis. Inheritance is autosomal dominant; most cases are de novo occurrences. Mirhosseini-Holmes-Walton syndrome (OMIM 268050) was described in 1972 in two brothers with pigmentary retinal degeneration, cataracts, microcephaly, severe intellectual disability, hyperextensible joints, scoliosis, and arachnodactyly [Mirhosseini et al 1972]. It has been hypothesized that the disorder in this family is allelic to Cohen syndrome [Horn et al 2000]. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease 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 Hematologic evaluation including a white blood cell count with differential to identify neutropenia Treatment of ManifestationsOphthalmologic 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 Training as needed for the visually impaired Psychosocial support for affected individuals and their families If neutropenia is documented, consideration should 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 was subnormal in 12 of 14 individuals and subnormal in response to hydrocortisone in eight of 16 individuals. However, administration of recombinant G-CSF caused granulocytosis in all three individuals studied. Recurrent infections should be treated per standard therapy; full immunologic evaluation should be considered.Early intervention and physical, occupational, and speech therapy are appropriate to address gross developmental delay, hypotonia, joint hypermobility, and motor clumsiness. SurveillanceAnnual ophthalmologic evaluation should assess visual acuity, refractive error, and/or retinal dystrophy.Repeat testing of white blood cell count with differential over time to identify intermittent neutropenia is indicated. Evaluation of Relatives at Risk See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov 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.OtherAnecdotal reports notwithstanding, pycnogenol, a standard French maritime pine bark extract effective in improving visual acuity in retinal vascular leakage conditions [Schonlau & Rohdewald 2001, Spadea & Balestrazzi 2001], has not been proven to be an effective treatment for the retinal dystrophy in Cohen syndrome.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Cohen Syndrome: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDVPS13B8q22​.2Vacuolar protein sorting-associated protein 13BFinnish Disease DatabaseVPS13BData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Cohen Syndrome (View All in OMIM) View in own window 216550COHEN SYNDROME; COH1 607817VACUOLAR PROTEIN SORTING 13, YEAST, HOMOLOG OF, B; VPS13BNormal allelic variants. The longest VPS13B transcript (14,093 bp) is widely expressed and is transcribed from 62 exons that span a genomic region of approximately 864 kb [Kolehmainen et al 2003]. VPS13B contains 66 exons, including four alternative exons; the translation start codon is in exon 2 [Velayos-Baeza et al 2004]. VPS13B has a complicated pattern of alternative splicing that potentially leads to the use of four different termination codons and to three additional in-frame, alternatively spliced forms [Kolehmainen et al 2003]. Pathologic allelic variants. Common founder mutations have been identified in the Finnish and Old Order Amish populations. The common mutation described in the Finnish population is homozygosity for c.3348_3349delCT, seen in 75% of mutant alleles [Kolehmainen et al 2003]. Affected individuals of Amish descent have been found to be homozygous for both a nonsense mutation involving a 1-bp insertion (c.9258_9259insT) and a missense mutation involving a c.8459T>C (p.Ile2820Thr) substitution [Falk et al 2004]. No major mutational hotspot in individuals with Cohen syndrome of non-Finnish, non-Amish ancestry appears to exist [Hennies et al 2004]. Extensive allelic heterogeneity has now been described in a wide range of ethnic and geographically distributed populations, with more than 100 novel mutations (primarily null alleles caused by nonsense or frameshift mutations resulting in a premature stop codon, or intragenic deletion or duplication) subsequently identified throughout VPS13B [Hennies et al 2004, Kolehmainen et al 2004, Mochida et al 2004, Seifert et al 2006]. While several missense mutations have been described in clinically affected individuals, the absence of a functional assay leaves the possibility that these represent rare non-pathogenic variants. Indeed, a large number of silent and missense amino acid changes (18 out of 114 reported VPS13B sequence variants) have been detected in the coding region of VPS13B which do not cause a Cohen syndrome phenotype [Kolehmainen et al 2004, Seifert et al 2009]. Pathologic alleles may also have altered splicing or involve the deletion or duplication of VPS13 exon(s) [Kolehmainen et al 2004, Balikova et al 2009, Parri et al 2010; see Molecular Genetic Testing]. The studies of Parri et al [2010] showed 58% of alleles with pathologic sequence variants and 42% with copy number varations (either deletion or duplication). This led the authors to suggest that deletion/duplication analysis be used as an initial molecular screening method for the molecular diagnosis of Cohen syndrome [Parri et al 2010].Deletions in VPS13B are postulated to result from non-homologous end-joining (NHEJ) due to sequence microhomology, small deletions and insertions at the junction, and the variation in size and affected region of deletions in affected individuals [Balikova et al 2009]. A higher frequency of LINEs, SINEs, and DNA repeat elements occurs in VPS13B in comparison to the average for autosomal sequences, and deletion breakpoints have mainly been found in interspersed repetitive sequences – predominantly in the sequence between introns 16 and 21 [Balikova et al 2009].The full-length splice form (exons 1-62) with the complete C-terminal VPS13 domain is essential for normal development and, when absent, results in classic Cohen syndrome [Kolehmainen et al 2004]. Table 3. Selected VPS13B (COH1) Pathologic Allelic Variants View in own windowDNA Nucleotide Change
(Alias ¹)Protein Amino Acid ChangeReference Sequencesc.3348_3349delCTp.Cys1117Phefs*8NM_017890​.3
NP_060360​.3c.8459T>Cp.Ile2820Thrc.9259dupT
(c.9258_9259insT)p.Leu3087Phefs*20See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). 1. Variant designation that does not conform to current naming conventionsNormal gene product. VPS13B encodes vacuolar protein sorting 13B (VPS13B), a putative transmembrane protein of 4,022 amino acids with a complex domain structure [Kolehmainen et al 2003]. The exact function of VPS13B is unknown. Homology to the Saccharomyces cerevisiae VPS13 protein suggests a role for VPS13B in intracellular vesicle-mediated sorting and protein transport [Kolehmainen et al 2003]. The complex domain structure of VPS13B includes ten predicted transmembrane domains, a potential vacuolar targeting motif, an endoplasmic reticulum retention signal in the C terminus, and two peroxisomal matrix protein targeting signal-2 (PTS2) consensus sequences, one near the N terminus and the other near the C terminus [Kolehmainen et al 2003]. Various VPS13B isoforms may have different functions within the cell. Velayos-Baeza et al [2004] described several alternative splicing variants, at least two transcripts of which are major forms. The full-length VPS13B transcript containing exon 28b now appears to be the major, ubiquitously expressed transcript in both humans and mice, although human brain and retina show differential splicing of exon 28 (NM_017890) [Seifert et al 2009]. Diagnostic testing should include exon 28b.Wide expression of VPS13B is seen on Northern blot analysis in human tissues, with differential expression of different transcripts. Transcripts of approximately 2.0 and 5.0 kb are expressed in fetal brain, lung, liver, and kidney, and in all adult tissues analyzed. A transcript of approximately 12-14 kb is expressed in prostate, testis, ovary, and colon in the adult. Expression is very low in adult brain tissue [Kolehmainen et al 2003]. In contrast, expression analysis of the mouse ortholog (Coh1) in brain showed wide expression in neurons of the postnatal brain but only at low levels in the embryonic brain, suggesting that VPS13B may be more important in neuronal differentiation than in proliferation [Mochida et al 2004]. The expression pattern was found by Velayos-Baeza et al [2004] to be ubiquitous, with some tissue-specific differences between several transcript variants. Abnormal gene product. The majority of VPS13B mutations (84/96) detected to date result in a premature termination signal because of nonsense or deletion mutations, although no mutational hotspot has been identified [Seifert et al 2009]. As the majority of mutant alleles in individuals with Cohen syndrome are null (nonsense or frameshift), the effects are predicted to be premature protein truncation or mRNA instability. It is not known whether proteins encoded by mutant VPS13B transcripts are expressed or degraded. The mechanism by which premature protein truncation or mRNA instability results in the clinical manifestations of Cohen syndrome is not currently understood.