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Congenital cataracts-facial dysmorphism-neuropathy syndrome(CCFDN)

MedGen UID:
346973
Concept ID:
C1858726
Congenital Abnormality; Disease or Syndrome
Synonyms: CATARACT, CONGENITAL, WITH FACIAL DYSMORPHISM AND NEUROPATHY; CCFDN; Congenital Cataracts, Facial Dysmorphism, and Neuropathy
SNOMED CT: CCFDN - congenital cataracts, facial dysmorphism and neuropathy (702433001); Congenital cataracts, facial dysmorphism and neuropathy (702433001)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): CTDP1 (18q23)
 
Monarch Initiative: MONDO:0011402
OMIM®: 604168
Orphanet: ORPHA48431

Disease characteristics

CTDP1-related congenital cataracts, facial dysmorphism, and neuropathy (CTDP1-CCFDN) is characterized by abnormalities of the eye (bilateral congenital cataracts, microcornea, microphthalmia, micropupils), mildly dysmorphic facial features apparent in late childhood, and a hypo-/demyelinating, symmetric, distal peripheral neuropathy. The neuropathy is predominantly motor at the onset and results in delays in early motor development, progressing to severe disability by the third decade of life. Secondary foot deformities and scoliosis are common. Sensory neuropathy develops after age ten years. Most affected individuals have a mild nonprogressive intellectual deficit and cerebellar involvement including ataxia, nystagmus, intention tremor, and dysmetria. All have short stature and most have subnormal weight. Adults have hypogonadotropic hypogonadism. Parainfectious rhabdomyolysis (profound muscle weakness, myoglobinuria, and excessively elevated serum concentration of creatine kinase usually following a viral infection) is a potentially life-threatening complication. To date all affected individuals and carriers identified have been from the Romani population. [from GeneReviews]
Authors:
Luba Kalaydjieva  |  Teodora Chamova   view full author information

Additional descriptions

From OMIM
Congenital cataracts, facial dysmorphism, and neuropathy is an autosomal recessive disorder that is prevalent among Bulgarian Gypsies. Additional features include delayed psychomotor development, skeletal anomalies, and hypogonadism. The predominantly motor neuropathy becomes evident during childhood and progresses to severe disability by the third decade (Tournev et al., 1999). CCFDN is genetically distinct from Marinesco-Sjogren syndrome (MSS; 248800), although the 2 disorders share some overlapping features, including congenital cataracts, delayed psychomotor development, and ataxia (Merlini et al., 2002).  http://www.omim.org/entry/604168
From MedlinePlus Genetics
Congenital cataracts, facial dysmorphism, and neuropathy (CCFDN) is a rare disorder that affects several parts of the body. It is characterized by a clouding of the lens of the eyes at birth (congenital cataracts) and other eye abnormalities, such as small or poorly developed eyes (microphthalmia) and abnormal eye movements (nystagmus). Affected individuals, particularly males, often have distinctive facial features that become more apparent as they reach adulthood. These features include a prominent midface, a large nose, protruding teeth, and a small lower jaw.

CCFDN causes progressive damage to the peripheral nerves, which connect the brain and spinal cord to muscles and sensory cells. This nerve damage is known as peripheral neuropathy. Weakness in the legs, followed by the arms, begins in the first few years of life, and as a result children with CCFDN have delayed development of motor skills such as standing and walking. In adolescence, affected individuals develop sensory abnormalities such as numbness and tingling, mainly in the legs. By adulthood they typically have significant difficulties with mobility. Muscle weakness can also lead to skeletal abnormalities such as hand and foot deformities and abnormal curvature of the spine.

People with CCFDN may have problems with balance and coordination (ataxia), tremors, and difficulty with movements that involve judging distance or scale (dysmetria). Some have mild intellectual disability. Individuals with CCFDN have short stature, are typically underweight, and have reduced bone density.

A complication called rhabdomyolysis occurs in some people with CCFDN, typically following a viral infection or, in rare cases, during or after surgery. Rhabdomyolysis is a breakdown of muscle tissue that results in severe muscle weakness. The destruction of muscle tissue releases a protein called myoglobin, which is processed by the kidneys and released in the urine (myoglobinuria). The presence of myoglobin causes the urine to be red or brown. The muscles may take up to a year to recover, and the episodes may worsen the muscle weakness caused by the neuropathy.  https://medlineplus.gov/genetics/condition/congenital-cataracts-facial-dysmorphism-and-neuropathy

Clinical features

From HPO
Primary amenorrhea
MedGen UID:
115918
Concept ID:
C0232939
Disease or Syndrome
Abnormally late or absent menarche in a female with normal secondary sexual characteristics.
Decreased testicular size
MedGen UID:
66027
Concept ID:
C0241355
Finding
Reduced volume of the testicle (the male gonad).
Talipes equinovarus
MedGen UID:
3130
Concept ID:
C0009081
Congenital Abnormality
Clubfoot is a congenital limb deformity defined as fixation of the foot in cavus, adductus, varus, and equinus (i.e., inclined inwards, axially rotated outwards, and pointing downwards) with concomitant soft tissue abnormalities (Cardy et al., 2007). Clubfoot may occur in isolation or as part of a syndrome (e.g., diastrophic dysplasia, 222600). Clubfoot has been reported with deficiency of long bones and mirror-image polydactyly (Gurnett et al., 2008; Klopocki et al., 2012).
Genu recurvatum
MedGen UID:
107486
Concept ID:
C0546964
Anatomical Abnormality
An abnormally increased extension of the knee joint, so that the knee can bend backwards.
Pes cavus
MedGen UID:
675590
Concept ID:
C0728829
Congenital Abnormality
An increase in height of the medial longitudinal arch of the foot that does not flatten on weight bearing (i.e., a distinctly hollow form of the sole of the foot when it is bearing weight).
Split hand
MedGen UID:
397570
Concept ID:
C2699510
Congenital Abnormality
A condition in which middle parts of the hand (fingers and metacarpals) are missing giving a cleft appearance. The severity is very variable ranging from slightly hypoplastic middle fingers over absent middel fingers as far as oligo- or monodactyl hands.
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Chorea
MedGen UID:
3420
Concept ID:
C0008489
Disease or Syndrome
Chorea (Greek for 'dance') refers to widespread arrhythmic involuntary movements of a forcible, jerky and restless fashion. It is a random-appearing sequence of one or more discrete involuntary movements or movement fragments. Movements appear random because of variability in timing, duration or location. Each movement may have a distinct start and end. However, movements may be strung together and thus may appear to flow randomly from one muscle group to another. Chorea can involve the trunk, neck, face, tongue, and extremities.
Babinski sign
MedGen UID:
19708
Concept ID:
C0034935
Finding
Upturning of the big toe (and sometimes fanning of the other toes) in response to stimulation of the sole of the foot. If the Babinski sign is present it can indicate damage to the corticospinal tract.
Cerebral atrophy
MedGen UID:
116012
Concept ID:
C0235946
Disease or Syndrome
Atrophy (wasting, decrease in size of cells or tissue) affecting the cerebrum.
Motor polyneuropathy
MedGen UID:
82885
Concept ID:
C0271683
Disease or Syndrome
Inflammation or degeneration of the peripheral motor nerves.
Cognitive impairment
MedGen UID:
90932
Concept ID:
C0338656
Mental or Behavioral Dysfunction
Abnormal cognition is characterized by deficits in thinking, reasoning, or remembering.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Peripheral demyelination
MedGen UID:
451074
Concept ID:
C0878575
Pathologic Function
A loss of myelin from the internode regions along myelinated nerve fibers of the peripheral nervous system.
Axonal degeneration
MedGen UID:
332464
Concept ID:
C1837496
Finding
Motor delay
MedGen UID:
381392
Concept ID:
C1854301
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
Decreased motor nerve conduction velocity
MedGen UID:
388130
Concept ID:
C1858729
Finding
A type of decreased nerve conduction velocity that affects the motor neuron.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Peripheral hypomyelination
MedGen UID:
870480
Concept ID:
C4024927
Finding
Reduced amount of myelin in the nervous system resulting from defective myelinogenesis in the peripheral nervous system.
Peripheral axonal degeneration
MedGen UID:
871339
Concept ID:
C4025830
Finding
Progressive deterioration of peripheral axons.
Kyphoscoliosis
MedGen UID:
154361
Concept ID:
C0575158
Anatomical Abnormality
An abnormal curvature of the spine in both a coronal (lateral) and sagittal (back-to-front) plane.
Malar prominence
MedGen UID:
346975
Concept ID:
C1858732
Finding
Prominence of the malar process of the maxilla and infraorbital area appreciated in profile and from in front of the face.
Acute rhabdomyolysis
MedGen UID:
813636
Concept ID:
C3807306
Finding
An acute form of rhabdomyolysis.
Abnormality of the dentition
MedGen UID:
78084
Concept ID:
C0262444
Finding
Any abnormality of the teeth.
Abnormal facial shape
MedGen UID:
98409
Concept ID:
C0424503
Finding
An abnormal morphology (form) of the face or its components.
Decreased serum estradiol
MedGen UID:
69129
Concept ID:
C0241011
Finding
A reduction below normal concentration of estradiol in the circulation.
Hypogonadotropic hypogonadism
MedGen UID:
82883
Concept ID:
C0271623
Disease or Syndrome
Hypogonadotropic hypogonadism is characterized by reduced function of the gonads (testes in males or ovaries in females) and results from the absence of the gonadal stimulating pituitary hormones
Hypergonadotropic hypogonadism
MedGen UID:
184926
Concept ID:
C0948896
Disease or Syndrome
Reduced function of the gonads (testes in males or ovaries in females) associated with excess pituitary gonadotropin secretion and resulting in delayed sexual development and growth delay.
Developmental cataract
MedGen UID:
3202
Concept ID:
C0009691
Congenital Abnormality
A cataract that occurs congenitally as the result of a developmental defect, in contrast to the majority of cataracts that occur in adulthood as the result of degenerative changes of the lens.
Nystagmus
MedGen UID:
45166
Concept ID:
C0028738
Disease or Syndrome
Rhythmic, involuntary oscillations of one or both eyes related to abnormality in fixation, conjugate gaze, or vestibular mechanisms.
Microcornea
MedGen UID:
78610
Concept ID:
C0266544
Congenital Abnormality
A congenital abnormality of the cornea in which the cornea and the anterior segment of the eye are smaller than normal. The horizontal diameter of the cornea does not reach 10 mm even in adulthood.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVCongenital cataracts-facial dysmorphism-neuropathy syndrome

Recent clinical studies

Etiology

Chamova T, Zlatareva D, Raycheva M, Bichev S, Kalaydjieva L, Tournev I
Behav Neurol 2015;2015:639539. Epub 2015 Apr 28 doi: 10.1155/2015/639539. PMID: 26060356Free PMC Article
Müllner-Eidenböck A, Moser E, Klebermass N, Amon M, Walter MC, Lochmüller H, Gooding R, Kalaydjieva L
Ophthalmology 2004 Jul;111(7):1415-23. doi: 10.1016/j.ophtha.2003.11.007. PMID: 15234148
Varon R, Gooding R, Steglich C, Marns L, Tang H, Angelicheva D, Yong KK, Ambrugger P, Reinhold A, Morar B, Baas F, Kwa M, Tournev I, Guerguelcheva V, Kremensky I, Lochmüller H, Müllner-Eidenböck A, Merlini L, Neumann L, Bürger J, Walter M, Swoboda K, Thomas PK, von Moers A, Risch N, Kalaydjieva L
Nat Genet 2003 Oct;35(2):185-9. Epub 2003 Sep 21 doi: 10.1038/ng1243. PMID: 14517542
Navarro C, Teijeira S
Acta Myol 2003 May;22(1):11-4. PMID: 12966699

Diagnosis

Chamova T, Zlatareva D, Raycheva M, Bichev S, Kalaydjieva L, Tournev I
Behav Neurol 2015;2015:639539. Epub 2015 Apr 28 doi: 10.1155/2015/639539. PMID: 26060356Free PMC Article
Claramunt R, Sevilla T, Lupo V, Cuesta A, Millán JM, Vílchez JJ, Palau F, Espinós C
Clin Genet 2007 Apr;71(4):343-9. doi: 10.1111/j.1399-0004.2007.00774.x. PMID: 17470135
Mastroyianni SD, Garoufi A, Voudris K, Skardoutsou A, Stefanidis CJ, Katsarou E, Gooding R, Kalaydjieva L
Eur J Pediatr 2007 Jul;166(7):747-9. Epub 2006 Dec 30 doi: 10.1007/s00431-006-0307-9. PMID: 17195938
Shabo G, Scheffer H, Cruysberg JR, Lammens M, Pasman JW, Spruit M, Willemsen MA
Pediatr Neurol 2005 Oct;33(4):277-9. doi: 10.1016/j.pediatrneurol.2005.04.011. PMID: 16194727
Müllner-Eidenböck A, Moser E, Klebermass N, Amon M, Walter MC, Lochmüller H, Gooding R, Kalaydjieva L
Ophthalmology 2004 Jul;111(7):1415-23. doi: 10.1016/j.ophtha.2003.11.007. PMID: 15234148

Prognosis

Müllner-Eidenböck A, Moser E, Klebermass N, Amon M, Walter MC, Lochmüller H, Gooding R, Kalaydjieva L
Ophthalmology 2004 Jul;111(7):1415-23. doi: 10.1016/j.ophtha.2003.11.007. PMID: 15234148

Clinical prediction guides

Chamova T, Zlatareva D, Raycheva M, Bichev S, Kalaydjieva L, Tournev I
Behav Neurol 2015;2015:639539. Epub 2015 Apr 28 doi: 10.1155/2015/639539. PMID: 26060356Free PMC Article
Müllner-Eidenböck A, Moser E, Klebermass N, Amon M, Walter MC, Lochmüller H, Gooding R, Kalaydjieva L
Ophthalmology 2004 Jul;111(7):1415-23. doi: 10.1016/j.ophtha.2003.11.007. PMID: 15234148
Merlini L, Gooding R, Lochmüller H, Müller-Felber W, Walter MC, Angelicheva D, Talim B, Hallmayer J, Kalaydjieva L
Neurology 2002 Jan 22;58(2):231-6. doi: 10.1212/wnl.58.2.231. PMID: 11805249
Tournev I, King RH, Workman J, Nourallah M, Muddle JR, Kalaydjieva L, Romanski K, Thomas PK
Acta Neuropathol 1999 Aug;98(2):165-70. doi: 10.1007/s004010051065. PMID: 10442556
Tournev I, Kalaydjieva L, Youl B, Ishpekova B, Guergueltcheva V, Kamenov O, Katzarova M, Kamenov Z, Raicheva-Terzieva M, King RH, Romanski K, Petkov R, Schmarov A, Dimitrova G, Popova N, Uzunova M, Milanov S, Petrova J, Petkov Y, Kolarov G, Aneva L, Radeva O, Thomas PK
Ann Neurol 1999 Jun;45(6):742-50. PMID: 10360766

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