Takenouchi-Kosaki Syndrome Clinical CharacteristicsOcular Features: The ocular phenotype consists of mild ptosis, synophrys, exotropia, and eversion of the lower eyelids. One of two reported patients was described as having bilateral retinal dysplasia and a falciform retinal detachment in one eye. Visual acuity is significantly impaired. Systemic Features: Affected individuals may be of normal birth weight but skeletal growth is subnormal and there is general developmental delay. Congenial cardiac anomalies such as persistent ductus arteriosus may be present. Lymphedema has been noted at one year of age and probably persists throughout life. Protein-losing enteropathy secondary to intestinal lymphangiectasia was present in one individual. The same patient had pericardial effusion, hydrothorax, and ascites. Intellectual disability may be severe although there is no evidence of progression. Neurosensory hearing loss has been described in one patient. Thrombocytopenia is a consistent finding and has been described as early as one year of age. Platelet numbers as low as 52,000/microL have been recorded and appear larger than normal. GeneticsBoth unrelated female patients reported have heterozygous missense mutations in the CDC42 gene (1p36). Pedigree: Autosomal dominantTreatmentTreatment Options: No treatment has been reported. ReferencesArticle Title: Macrothrombocytopenia and developmental delay with a de novo CDC42 mutation: Yet another locus for thrombocytopenia and developmental delay Takenouchi T, Kosaki R, Niizuma T, Hata K, Kosaki K. Macrothrombocytopenia and developmental delay with a de novo CDC42 mutation: Yet another locus for thrombocytopenia and developmental delay. Am J Med Genet A. 2015 Nov;167A(11):2822-5. PubMed ID: 26386261 Read more about Takenouchi-Kosaki Syndrome
Macrothrombocytopenia and developmental delay with a de novo CDC42 mutation: Yet another locus for thrombocytopenia and developmental delay Takenouchi T, Kosaki R, Niizuma T, Hata K, Kosaki K. Macrothrombocytopenia and developmental delay with a de novo CDC42 mutation: Yet another locus for thrombocytopenia and developmental delay. Am J Med Genet A. 2015 Nov;167A(11):2822-5. PubMed ID: 26386261
Hypotrichosis-Lymphedema-Telangiectasia-Renal Defect Syndrome Clinical CharacteristicsOcular Features: Sparse hair can be noted at birth and by several years of age the alopecia of the eyelids and eyebrows is complete. The upper eyelids may be swollen at birth as well. Systemic Features: The facial features are unusual. The nose appears long and may have a broad nasal root. The lips are full and the lower jaw is prominent. Evidence of developmental delay has been reported in one patient. The scrotum can be edematous at birth and sometimes contains large hydroceles. Hair is sparse in infancy but within a few years alopecia is complete. Telangiectases on the scalp, scrotum, and limbs are evident at several years of age. Pulmonary vascular congestion and lymphangiectasia may be present in some individuals antenatally. Renal failure, sometimes with hypertension can occur at any time from early childhood to young adulthood. Renal biopsy has shown histologic features consistent with membranoproliferative glomerulonephritis and thrombotic microangiopathy. This may be preceded by proteinuria in infants as young as 2 years. GeneticsThis condition is the result of heterozygous mutations in the SOX18 gene (20q13.33). Homozygous mutations in the same gene may be responsible for a somewhat similar disorder (HLTS) (607823) which has many of the same facial and systemic features but lacks the renal disease. Pedigree: Autosomal dominantTreatmentTreatment Options: Some patients have benefitted from renal transplantation. ReferencesArticle Title: Hypotrichosis-lymphedema-telangiectasia-renal defect associated with a truncating mutation in the SOX18 gene Moalem S, Brouillard P, Kuypers D, Legius E, Harvey E, Taylor G, Francois M, Vikkula M, Chitayat D. Hypotrichosis-lymphedema-telangiectasia-renal defect associated with a truncating mutation in the SOX18 gene. Clin Genet. 2015 Apr;87(4):378-82. PubMed ID: 24697860 Dominantly inherited glomerulonephritis and an unusual skin disease Sherwood MC, Pincott JR, Goodwin FJ, Dillon MJ. Dominantly inherited glomerulonephritis and an unusual skin disease. Arch Dis Child. 1987 Dec;62(12):1278-80. PubMed ID: 3435166 Read more about Hypotrichosis-Lymphedema-Telangiectasia-Renal Defect Syndrome
Hypotrichosis-lymphedema-telangiectasia-renal defect associated with a truncating mutation in the SOX18 gene Moalem S, Brouillard P, Kuypers D, Legius E, Harvey E, Taylor G, Francois M, Vikkula M, Chitayat D. Hypotrichosis-lymphedema-telangiectasia-renal defect associated with a truncating mutation in the SOX18 gene. Clin Genet. 2015 Apr;87(4):378-82. PubMed ID: 24697860
Dominantly inherited glomerulonephritis and an unusual skin disease Sherwood MC, Pincott JR, Goodwin FJ, Dillon MJ. Dominantly inherited glomerulonephritis and an unusual skin disease. Arch Dis Child. 1987 Dec;62(12):1278-80. PubMed ID: 3435166
Lymphedema-Distichiasis Syndrome Clinical CharacteristicsOcular Features: This form of lymphedema is associated with distichiasis, often with trichiasis and significant corneal damage in about 75% of patients. Onset of symptoms may occur at any age but usually during childhood or adolescence. Photophobia, epiphora, corneal erosions, ptosis, and partial ectropion of the lids may also be seen. The secondary symptoms of trichiasis are not always present and slit lamp examination of the lashes may be necessary to see the duplicated row of lashes. The lashes often grow out of the Meibomian orifices. Systemic Features: Cardiac defects, cleft palate, and spinal extradural cysts occur in some families. Type II diabetes and interstitial nephritis have been reported. The lymph channels in the lower extremities may be normal or increased in number, especially below the knee where pitting edema is most often first seen, even as early as the first decade of life. Lymphedema occurs earlier in males and secondary cellulitis is a greater risk. It is usually confined to the lower extremities and is often asymmetrical. Not all patients have the complete syndrome, while lymphedema and distichiasis can be inherited as individual disorders without being associated. Males are more likely to have the complete syndrome. Several families with this syndrome secondary to mutations in the FOXC2 have been reported to have renal anomalies ranging from kidney agenesis to malrotation. GeneticsThis disorder is inherited in an autosomal dominant pattern and several families have been found to have mutations in the FOXC2 gene on chromosome 16 (16q24.3). A Chinese family with an affected father and two affected offspring (one male and one female) has been reported with distichiasis but no lymphedema. A premature stop codon was found in the FOXC2 transcription gene (16q24.1) in these family members suggesting that they may have had the lymphedema-distichiasis syndrome instead. Blatt distichiasis is a unique disorder without the lymphedema (126300). Double rows of eyelashes are also part of the blepharocheilodontic syndrome (119580). Pedigree: Autosomal dominantTreatmentTreatment Options: Electrolysis of individual misdirected lashes can be applied. Prompt treatment of lid cellulitis is important. Surgical repair of scarred lid tissue can restore cosmesis lid function and improve cosmesis. ReferencesArticle Title: A new perspective in oculoplastic surgical management of symptomatic distichiasis in lymphedema-distichiasis syndrome Sheth T, Attzs M, Tambe K. A new perspective in oculoplastic surgical management of symptomatic distichiasis in lymphedema-distichiasis syndrome. Orbit. 2018 Dec 5:1-4. doi: 10.1080/01676830.2018.1546749. [Epub ahead of print]. PubMed ID: 30516410 Renal anomalies and lymphedema distichiasis syndrome Jones GE, Richmond AK, Navti O, Mousa HA, Abbs S, Thompson E, Mansour S, Vasudevan PC. Renal anomalies and lymphedema distichiasis syndrome. A rare association? Am J Med Genet A. 2017 May;173(8):2251-2256. PubMed ID: 28544699 Novel FOXC2 Mutation in Hereditary Distichiasis Impairs DNA-Binding Activity and Transcriptional Activation Zhang L, He J, Han B, Lu L, Fan J, Zhang H, Ge S, Zhou Y, Jia R, Fan X. Novel FOXC2 Mutation in Hereditary Distichiasis Impairs DNA-Binding Activity and Transcriptional Activation. Int J Biol Sci. 2016 Aug 6;12(9):1114-20. PubMed ID: 27570485 FOXC2 Mutations in Familial and Sporadic Spinal Extradural Arachnoid Cyst Ogura Y, Yabuki S, Iida A, Kou I, Nakajima M, Kano H, Shiina M, Kikuchi S, Toyama Y, Ogata K, Nakamura M, Matsumoto M, Ikegawa S. FOXC2 Mutations in Familial and Sporadic Spinal Extradural Arachnoid Cyst. PLoS One. 2013 Nov 22;8(11):e80548. PubMed ID: 24278289 A novel complex insertion-deletion mutation in the FOXC2 gene in a Japanese patient with Lymphedema-Distichiasis Syndrome Itoh M, Nakagawa H. A novel complex insertion-deletion mutation in the FOXC2 gene in a Japanese patient with Lymphedema-Distichiasis Syndrome. Eur J Dermatol. 2013 Jun 7. [Epub ahead of print]. PubMed ID: 23747797 Novel mutation in the FOXC2 gene in three generations of a family with lymphoedema-distichiasis syndrome Sutkowska E, Gil J, Stembalska A, Hill-Bator A, Szuba A. Novel mutation in the FOXC2 gene in three generations of a family with lymphoedema-distichiasis syndrome. Gene. 2012 Feb 14. [Epub ahead of print] PubMed PMID: 22349027. PubMed ID: 22349027 Analysis of the phenotypic abnormalities in lymphoedema-distichiasis syndrome in 74 patients with FOXC2 mutations or linkage to 16q24 Brice G, Mansour S, Bell R, Collin JR, Child AH, Brady AF, Sarfarazi M, Burnand KG, Jeffery S, Mortimer P, Murday VA. Analysis of the phenotypic abnormalities in lymphoedema-distichiasis syndrome in 74 patients with FOXC2 mutations or linkage to 16q24. J Med Genet. 2002 Jul;39(7):478-83. PubMed ID: 12114478 Hereditary lymphedema and distichiasis Kolin T, Johns KJ, Wadlington WB, Butler MG, Sunalp MA, Wright KW. Hereditary lymphedema and distichiasis. Arch Ophthalmol. 1991 Jul;109(7):980-1. PubMed ID: 2064580 Read more about Lymphedema-Distichiasis Syndrome
A new perspective in oculoplastic surgical management of symptomatic distichiasis in lymphedema-distichiasis syndrome Sheth T, Attzs M, Tambe K. A new perspective in oculoplastic surgical management of symptomatic distichiasis in lymphedema-distichiasis syndrome. Orbit. 2018 Dec 5:1-4. doi: 10.1080/01676830.2018.1546749. [Epub ahead of print]. PubMed ID: 30516410
Renal anomalies and lymphedema distichiasis syndrome Jones GE, Richmond AK, Navti O, Mousa HA, Abbs S, Thompson E, Mansour S, Vasudevan PC. Renal anomalies and lymphedema distichiasis syndrome. A rare association? Am J Med Genet A. 2017 May;173(8):2251-2256. PubMed ID: 28544699
Novel FOXC2 Mutation in Hereditary Distichiasis Impairs DNA-Binding Activity and Transcriptional Activation Zhang L, He J, Han B, Lu L, Fan J, Zhang H, Ge S, Zhou Y, Jia R, Fan X. Novel FOXC2 Mutation in Hereditary Distichiasis Impairs DNA-Binding Activity and Transcriptional Activation. Int J Biol Sci. 2016 Aug 6;12(9):1114-20. PubMed ID: 27570485
FOXC2 Mutations in Familial and Sporadic Spinal Extradural Arachnoid Cyst Ogura Y, Yabuki S, Iida A, Kou I, Nakajima M, Kano H, Shiina M, Kikuchi S, Toyama Y, Ogata K, Nakamura M, Matsumoto M, Ikegawa S. FOXC2 Mutations in Familial and Sporadic Spinal Extradural Arachnoid Cyst. PLoS One. 2013 Nov 22;8(11):e80548. PubMed ID: 24278289
A novel complex insertion-deletion mutation in the FOXC2 gene in a Japanese patient with Lymphedema-Distichiasis Syndrome Itoh M, Nakagawa H. A novel complex insertion-deletion mutation in the FOXC2 gene in a Japanese patient with Lymphedema-Distichiasis Syndrome. Eur J Dermatol. 2013 Jun 7. [Epub ahead of print]. PubMed ID: 23747797
Novel mutation in the FOXC2 gene in three generations of a family with lymphoedema-distichiasis syndrome Sutkowska E, Gil J, Stembalska A, Hill-Bator A, Szuba A. Novel mutation in the FOXC2 gene in three generations of a family with lymphoedema-distichiasis syndrome. Gene. 2012 Feb 14. [Epub ahead of print] PubMed PMID: 22349027. PubMed ID: 22349027
Analysis of the phenotypic abnormalities in lymphoedema-distichiasis syndrome in 74 patients with FOXC2 mutations or linkage to 16q24 Brice G, Mansour S, Bell R, Collin JR, Child AH, Brady AF, Sarfarazi M, Burnand KG, Jeffery S, Mortimer P, Murday VA. Analysis of the phenotypic abnormalities in lymphoedema-distichiasis syndrome in 74 patients with FOXC2 mutations or linkage to 16q24. J Med Genet. 2002 Jul;39(7):478-83. PubMed ID: 12114478
Hereditary lymphedema and distichiasis Kolin T, Johns KJ, Wadlington WB, Butler MG, Sunalp MA, Wright KW. Hereditary lymphedema and distichiasis. Arch Ophthalmol. 1991 Jul;109(7):980-1. PubMed ID: 2064580