Waardenburg's anophthalmia syndrome

The disease presents at birth with unilateral, or more often, bilateral anophthalmia or microphthalmia and numerous limb anomalies (including synostosis, syndactyly, oligodactyly, polydactyly and long bone hypoplasia). 

Waardenburg's anophthalmia syndrome

Typically patients have clinical anophthalmia/severe microphthalmia with little/no vision. The most common limb anomalies are synostosis of the fourth and fifth metacarpals, a short 5th finger and only 4 toes bilaterally. Developmental milestones (such as responsive smile) are often delayed and most patients have moderate to severe intellectual deficiencies. Facial features can include flattened midface, sparse eyelashes, short palpebral fissures, high palate and cleft lip. Renal (horseshoe kidney), venous and vertebral anomalies have also been reported in rare cases.

More details:  📖 ABC of Clinical Genetics 3th Edition 

Petrus Johannes Waardenburg (1886 - 1979), Dutch ophthalmologist and geneticist.

Petrus Johannes Waardenburg

Following medical studies at the University of Utrecht, Petrus Johannes Waardenburg trained in ophthalmology and obtained his doctorate for a dissertation on the hereditary basis of the physiological and pathological characteristics of the eye. Genetical eye diseases were his particular field of interest, and this was boosted when his wife gave birth to monozygous twin daughters, occasioning him to extended his research to include twin studies. In 1932 he suggested that Down's syndrome might be the consequence of a chromosomal aberration, a fact that was not confirmed until 27 years later, by Jérôme Jean Louis Marie Lejeune (1926-) and his colleagues.

Waardenburg was almost 50 years of age before he was habilitated as a lecturer in human genetics, and it was not until 1952 that he was finally appointed professor of genetics at the Institute of Preventative Medicine, Leiden. He was then 66 years old. At this time he collaborated with professors Adolphe Franceschetti (1896-1968) and David Klein (1908-) in the publication of a monumental two- volume work, Genetics in Ophthalmology.

During the German occupation of Holland Waardenburg fearlessly opposed Nazi Germany's racist politics. He was described as a strong personality and a man of great moral courage.

In December 1947 at the meeting of the Dutch Ophthalmological Society in Utrecht, Waardenburg presented a deaf-mute tailor aged 72 who had dystopia canthorum and partial atrophy. The first description of the Klein-Waardenburg, however, was made by the German author Karl May (1842-1912), famous for his travel and adventure stories for young people, dealing with desert Arabs or with American Indians in the wild West. In the story "The Ghost of Llano Estacado", first published in 1888, May describes his character "Fred the Juggler" thus:

"Have a close look at him, in particular his eyes, which have different colour. He is 'two-eyed'." . . . "He was of striking appearance. The first thing which one would notice on him, was a considerable hump, which spoiled his otherwise well-structured figure. His body was of middle height and of very strong build, not of a short torso, narrow chest and long arms, as it seems to be the case with most humpbacks. His round, full, clean shaven face was deeply suntanned, however terribly marked on the left side, as if some time ago an awful wound would have been badly stitched together. And in a very strange way his eyes were quite strikingly of different colour, the left was of beautiful sky blue, whereas the right was of the deepest black … If this man would not have the hump, his appearance would be of pleasing powerfulness, even perhaps impressive."

Llano Estacado, also called Staked Plains, is a portion of the High Plains of the United States, along the Texas-New Mexico border.

When Karl May was the editor of "Schacht und Hütte" in 1875-76 he mentioned in No. 21 a group of 760.000 German schoolchildren where the colour of the skin, eyes and hair was recorded. From amongst them 224.000 were found to have blue eyes, 287.000 had grey eyes, 255.000 brown, 450 black, 3 red, and one had one eye blue and the other eye was brown.

References

1: Ullah A, Umair M, Ahmad F, Muhammad D, Basit S, Ahmad W. A novel homozygous

variant in the SMOC1 gene underlying Waardenburg anophthalmia syndrome.

Ophthalmic Genet. 2017 Jul-Aug;38(4):335-339. doi:

10.1080/13816810.2016.1227456. Epub 2017 Jan 13. PMID: 28085523.

2: Galasso C, Bombardieri R, Cerminara C, Stranci G, Curatolo P. Anophthalmia-

Waardenburg syndrome with expanding phenotype: does neural crest play a role? J

Child Neurol. 2007 Nov;22(11):1252-5. doi: 10.1177/0883073807307100. PMID:

18006952.

3: Slavotinek AM. Eye development genes and known syndromes. Mol Genet Metab.

2011 Dec;104(4):448-56. doi: 10.1016/j.ymgme.2011.09.029. Epub 2011 Sep 29.

PMID: 22005280; PMCID: PMC3224152.

4: Ürel-Demir G, Taşkıran EZ, Akgün-Doğan Ö, Şimşek-Kiper PÖ, Utine GE.

Ophthalmo-acromelic syndrome in an infant. Eur J Med Genet. 2019

Jul;62(7):103664. doi: 10.1016/j.ejmg.2019.05.003. Epub 2019 May 5. PMID:

31067494.

5: Suyugül Z, Seven M, Hacihanefioğlu S, Kartal A, Suyugül N, Cenani A.

Anophthalmia-Waardenburg syndrome: a report of three cases. Am J Med Genet. 1996

Apr 24;62(4):391-7. doi: 10.1002/(SICI)1096-8628(19960424)62:4<391::AID-

AJMG12>3.0.CO;2-J. PMID: 8723070.

6: Quarrell OW. Anophthalmia-Waardenburg syndrome or ophthalmo-acromelic

syndrome: what is in a name? Am J Med Genet. 1997 Apr 14;69(4):432. doi:

10.1002/(sici)1096-8628(19970414)69:4<432::aid-ajmg20>3.0.co;2-n. PMID: 9098498.

7: Rainger J, van Beusekom E, Ramsay JK, McKie L, Al-Gazali L, Pallotta R,

Saponari A, Branney P, Fisher M, Morrison H, Bicknell L, Gautier P, Perry P,

Sokhi K, Sexton D, Bardakjian TM, Schneider AS, Elcioglu N, Ozkinay F, Koenig R,

Mégarbané A, Semerci CN, Khan A, Zafar S, Hennekam R, Sousa SB, Ramos L,

Garavelli L, Furga AS, Wischmeijer A, Jackson IJ, Gillessen-Kaesbach G, Brunner

HG, Wieczorek D, van Bokhoven H, FitzPatrick DR. Correction: Loss of the BMP

Antagonist, SMOC-1, Causes Ophthalmo-Acromelic (Waardenburg Anophthalmia)

Syndrome in Humans and Mice. PLoS Genet. 2018 Dec 26;14(12):e1007866. doi:

10.1371/journal.pgen.1007866. Erratum for: PLoS Genet. 2011 Jul;7(7):e1002114.

PMID: 30586382; PMCID: PMC6306194.

8: Abouzeid H, Boisset G, Favez T, Youssef M, Marzouk I, Shakankiry N, Bayoumi

N, Descombes P, Agosti C, Munier FL, Schorderet DF. Mutations in the SPARC-

related modular calcium-binding protein 1 gene, SMOC1, cause waardenburg

anophthalmia syndrome. Am J Hum Genet. 2011 Jan 7;88(1):92-8. doi:

10.1016/j.ajhg.2010.12.002. Epub 2010 Dec 30. PMID: 21194680; PMCID: PMC3014360.

9: Rainger J, van Beusekom E, Ramsay JK, McKie L, Al-Gazali L, Pallotta R,

Saponari A, Branney P, Fisher M, Morrison H, Bicknell L, Gautier P, Perry P,

Sokhi K, Sexton D, Bardakjian TM, Schneider AS, Elcioglu N, Ozkinay F, Koenig R,

Mégarbané A, Semerci CN, Khan A, Zafar S, Hennekam R, Sousa SB, Ramos L,

Garavelli L, Furga AS, Wischmeijer A, Jackson IJ, Gillessen-Kaesbach G, Brunner

HG, Wieczorek D, van Bokhoven H, Fitzpatrick DR. Loss of the BMP antagonist,

SMOC-1, causes Ophthalmo-acromelic (Waardenburg Anophthalmia) syndrome in humans

and mice. PLoS Genet. 2011 Jul;7(7):e1002114. doi: 10.1371/journal.pgen.1002114.

Epub 2011 Jul 7. Erratum in: PLoS Genet. 2018 Dec 26;14(12):e1007866. PMID:

21750680; PMCID: PMC3131273.

10: Cogulu O, Ozkinay F, Gündüz C, Sapmaz G, Ozkinay C. Waardenburg anophthalmia

syndrome: report and review. Am J Med Genet. 2000 Jan 17;90(2):173-4. PMID:

10607960.